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Contents
v
Contents
19. Chemotherapy and hormones .............. 301 29. Lymphoma and disease of bone
Anne L. Thomas marrow ................................................... 511
20. Skin and lip cancer ................................ 317 Gillian D. Thomas, Matthew Ahearne and
Charles Kelly, Trevor Roberts and Cliff Martin J.S. Dyer
Lawrence 30. Tumours of the central nervous
21. Head and neck cancer general system ..................................................... 529
principles ................................................ 341 Neil G. Burnet, Kate E. Burton and
Christopher D. Scrase Sarah J. Jefferies
22. Sino-Nasal, Oral, Larynx and Pharynx 31. Eye and orbit.......................................... 557
Cancers ................................................... 357 Adrian Harnett
Christopher D. Scrase and Paul Symonds
32. Sarcomas................................................. 569
23. Thyroid cancer........................................ 385
Martin Robinson, Paul Symonds and
Ujjal Mallick, Joyce Wilkinson and
Michael Sokal
Charles Kelly
24. Gastrointestinal cancer .......................... 395 33. Paediatric oncology................................ 585
Ramesh Bulusu Roger E. Taylor
25. Tumours of the thorax........................... 417 34. Care of patients during
Alison Armour radiotherapy ........................................... 601
26. Breast cancer........................................... 431 Cathy Meredith and Lorraine Webster
Ian Kunkler 35. Medical complications of malignant
27. Gynaecological cancer ........................... 467 disease..................................................... 611
Paul Symonds Robert Coleman
28. Kidney, Bladder, Prostate, Testis, Urethra,
Penis ....................................................... 485 Index ................................................................. 617
Duncan B. McLaren
vi
Contributors
Alison Armour, MB ChB BSc MSc MD MRCP FRCR Julie Clark, DCR[T] BA
Vice-President Oncology Global Business, Quality Assurance Superintendent,
GlaxoSmithKline, Philadelphia, Department of Radiotherapy,
USA Leicester Royal Infirmary,
University Hospitals of Leicester NHS Trust,
Matthew Ahearne, MBChB MRCP Leicester, UK
Clinical Research Fellow,
University Hospitals of Leicester, Robert Coleman, MD FRCP FRCPE
Leicester, UK Yorkshire Cancer Research Professor of Medical Oncology and
Associate Director of the National Cancer Research Network
Colin Baker, PhD MIPEM MInstP (NCRN), Academic Unit of Clinical Oncology,
Physics Department, Weston Park Hospital, Sheffield, UK
Clatterbridge Centre for Oncology,
UK John Conway, PhD MIPEM CSi
Radiotherapy Research Governance Manager
Margaret Bidmead, MSc FIPEM Cancer Clinical Trials Centre,
Head of Physics, Weston Park Hospital,
Royal Marsden NHS Trust, Sheffield, UK
Fulham Road,
London, UK Charles Deehan, BSc(Hons) MSc(Med Sci) PhD MInstP
MIPEM CSci
Ramesh Bulusu, MD MRCP MSc FRCR (Onc) Head of Radiotherapy Physics,
Consultant Clinical Oncologist, Department of Medical Physics,
Primrose Oncology Unit, Guys and St Thomas NHS Foundation Trust,
Bedford Hospital & Oncology Centre, London; Honorary Senior Lecturer, Imaging Sciences Division,
Addenbrookes Hospital, School of Medicine, Kings College, London, UK
Cambridge, UK
Mike Dunn, MSc MIPEM
Neil G. Burnet, FRCS FRCR MD Head of Radiation Protection,
University Reader and Honorary Consultant Oncologist, Leicester Royal Infirmary,
Department of Oncology, Leicester, UK
Oncology Centre,
Addenbrookes Hospital, Martin J.S. Dyer, MA DPhil FRCP FRCPath
University of Cambridge, Professor of Haemato-Oncology,
Cambridge, UK University of Leicester,
Leicester, UK
Kate E. Burton, MSc DCRT
Consultant Radiographer in Neuro-Oncology, Jill Emmerson, DCR[T]
Oncology Centre, Quality Radiographer,
Addenbrookes Hospital, University Hospital Coventry and Warwickshire,
Cambridge, UK Coventry, UK
vii
Contributors
viii
Contributors
ix
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Section | 1 |
1
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Chapter |1|
Atoms, nuclei and radioactivity
Colin Baker
to the walls of the room. Most of the volume the atom occu-
CHAPTER CONTENTS
pies therefore consists of empty space, which makes it rela-
Introduction 3 tively easy for uncharged particles, such as photons, to pass
Atomic structure 4 through an atom without undergoing any interaction. An
atom of carbon has six protons and six neutrons in the
Electromagnetic force 4
nucleus, surrounded by six electrons. Protons and neutrons
Electromagnetic waves and wave-particle
have almost the same mass, while electrons have a mass
duality 5
roughly 2000 times smaller (shown in Table 1.1). The
Electron shells and binding energy 6 atomic nucleus therefore occupies a minute fraction
Characteristic radiation 6 (1010 %) of the atomic volume, yet contains more than
Nuclear structure 6 99.9% of the atoms mass. Electrons and protons each carry
Radioactivity 9 the same magnitude of electric charge (1.602 1019 Cou-
Exponential decay 9 lombs), but of opposite sign. The difference in the observed
Alpha decay 9 interactions of electrons and protons is therefore mostly
due to their different masses: Electrons are relatively light,
Beta decay 10
so scatter easily in a material while protons are less easily
Internal conversion and electron capture 11 scattered.
Decay series and radioactive equilibrium 11 Table 1.1 lists properties of subatomic particles of rele-
Radionuclides of interest 11 vance to radiotherapy. Strictly, only the electron, positron
References 13 and neutrinos (n and n) are fundamental particles, while
protons, neutrons and pions are composed of quarks.
Further reading 13
Atoms are composed of just electrons, protons and neu-
trons. The positron is the anti-particle of the electron (hav-
ing the same mass but opposite charge) and is emitted
INTRODUCTION during beta decay (b) and in interactions of high energy
photons with matter (see pair-production, Chapter 2). The
The smallest identifiable amount of an element is an atom, annihilation of a positron with an electron provides the
consisting of a central nucleus composed of protons and mechanism for positron emission tomography (PET). Neu-
neutrons which is orbited by electrons. The diameter of trinos are uncharged particles of very small mass emitted
an atom and nucleus are typically 1010 m and 1014 m, during beta decay, sharing the energy released from the
respectively. To put these dimensions into a more accessi- decay with the emitted beta particle (b or b). Negative
ble perspective, if the atomic nucleus is represented by the pions (p), one of the triplet of pions (p0, p, p) are found
point of a pencil (diameter approximately 0.5 mm) held in in cosmic rays and are thought to be carriers of the strong
the centre of a medium-sized room (say, 5 m 5 m), then force between nucleons. Despite their short life time (2.6
the electron cloud surrounding the nucleus would extend 108 s), beams of these particles generated in physics
Photon g 0 0 0
4
Chapter |1| Atoms, nuclei and radioactivity
5
Walter and Millers Textbook of Radiotherapy
1.2 shells is given by 2n2, this rule, combined with a further one
Realtive photon fluence
6
Chapter |1| Atoms, nuclei and radioactivity
Lithium Li 3 7 0.53 2 1
Beryllium Be 4 9 1.85 2 2
Boron B 5 11 2.34 2 3
Carbon C 6 12 2.26 2 4
3
Nitrogen N 7 14 1.310 2 5
3
Oxygen O 8 16 1.410 2 6
Fluorine F 9 19 1.7103 2 7
Sodium Na 11 23 0.97 2 8 1
Magnesium Mg 12 24 1.74 2 8 2
Aluminium Al 13 27 2.7 2 8 3
Silicon Si 14 28 2.33 2 8 4
Phosphorus P 15 31 1.82 2 8 5
Calcium Ca 20 40 1.55 2 8 8 2
Iron Fe 26 56 7.87 2 8 14 2
Cobalt Co 27 59 8.9 2 8 15 2
Copper Cu 29 64 8.96 2 8 18 1
Germanium Ge 32 73 5.32 2 8 18 4
Strontium Sr 38 88 2.54 2 8 18 8 2
Yttrium Y 39 89 4.47 2 8 18 9 2
Molybdenum Mo 42 96 10.2 2 8 18 13 1
Technetium Tc 43 98 11.5 2 8 18 14 1
Continued
7
Walter and Millers Textbook of Radiotherapy
3
Historically the principal quantum number, n 1, 2, 3. . ., may also be expressed as K, L, M . . .
2.8 n = 3 (M)
Proton
-r +r
12.1 n = 2 (L) Energy
L, L, L
Figure 1.5 Illustration of the electrostatic (Coulomb) and strong
69.5 n = 1 (K) force experienced by a charged particle approaching a nucleus.
Once within range of the attractive strong force, the repulsive
Coulomb force is overcome to hold nucleons together in the
K, K, K nucleus (the binding property of the strong force is represented
Nucleus as negative energy).
Figure 1.4 Electron energy levels and transitions leading to
characteristic photons for tungsten. Strictly, each principal shell, 160
n, has one or more associated energy levels, only the lowest 140
energy levels for each value of n are shown.
120
Neutron number, A-Z
for particles that experience the strong force is hadron (hence 100
hadron therapy). Figure 1.5 illustrates the forces experienced
80
by a proton being brought toward a nucleus; initially, an
electrostatic (Coulomb) force of repulsion between the 60
incoming proton and protons in the nucleus is present,
40
which increases in magnitude (becoming more positive)
as the incoming proton is brought closer, according to equa- 20
tion 1.5. Once within range of the strong force, however, the
0
electrostatic force is overcome (the overall force is negative) 0 20 40 60 80 100
and the proton is bound within the nucleus.
Proton number, Z
Plotting the number of protons against the number of
neutrons for each stable nucleus results in the stability line, Figure 1.6 Stability line of naturally occurring isotopes
shown in Figure 1.6. We see that for low atomic number (for elements listed in Table 1.2). Filled circles represent stable
nuclei, an equal number of protons and neutrons is favoured, isotopes while the solid line represents ZAZ.
8
Chapter |1| Atoms, nuclei and radioactivity
Relative activity
Evidence suggests that protons and neutrons within a
nucleus adopt a shell-like structure analogous to electron 0.6
orbits and show particular stability when the number of
protons or neutrons, or both, corresponds to a magic num- 0.4
ber (2, 8, 20, 28, 50, 82, 126). The strength of the nuclear
force is associated with a nuclear binding energy which must
be overcome to break the nucleus apart. Representing this 0.2
in terms of mass leads to a mass-defect, whereby the mass of
a given nucleus is less than the sum of its constituent pro- 0
tons and neutrons. Nuclei with even numbers of protons or 0 2 4 6 8 10
A
neutrons are found to be more stable than those with an Time
odd number of one or both. 0.0
RADIOACTIVITY
1.0
In (Relative activity)
A nucleus lying off the stability line, shown in Figure 1.6, is
unstable and decays by rearranging its nucleon numbers. 2.0
This is achieved by releasing particles, changing a proton
to a neutron or vice versa, or by absorbing nearby particles.
The activity of an unstable, or radioactive isotope is the rate 3.0
at which its nuclei decay, expressed in Becquerels (Bq)
which correspond to one decay or disintegration per second.
The activity of practical sources is generally represented in 4.0
MBq (1 106 disintegrations per second). The old unit 0 2 4 6 8 10
of activity, the Curie (Ci) is commonly retained (1 Ci B
Time
37 000 MBq). In the construction of practical radioactive
sources, we are also interested in the amount of material Figure 1.7 Exponential decay of radioactivity. (A) Linear plot
that is needed to manufacture a source with a required showing exponential decrease of relative activity with time, and
activity, determined by the specific activity (MBq kg1). (B) logarithmic activity axis, giving a straight line of slope l.
9
Walter and Millers Textbook of Radiotherapy
is particularly stable and may often be emitted by a heavy The Q value of 1.7 MeV is shared between the kinetic ener-
unstable nucleus such as radium, uranium or plutonium. gies of the emitted b particle (electron) and anti-neutrino,
In emitting an a particle, the parent nucleus decreases its n The corresponding energy level diagram is shown in
mass number by four and its atomic number by two: Figure 1.9A, while the general scheme is shown in
Figure 1.9B. The spectrum of b particle energies released
A
Z X!A4 Z2 Y 1:14 is indicated in Figure 1.10. The average energy of the emit-
ted b particle is approximately 30% to 40% of the maxi-
For example, radium (22688Ra) decays to radon (22286Rn) as
mum energy, depending on the isotope.
shown schematically in Figure 1.8A. Energy must be con-
Fluorine 18 (189F) provides an example of b decay in its
served in the transformation, so any difference, Q, between
transformation to oxygen 18 (188O):
the nuclear binding energies of the parent and daughter
nuclei is shared between the emitted a particle (in the form
18
9F ! 18 8 O b n Q0:64MeV
of kinetic energy) and any photons that are produced: p ! n e ; Z ! Z 1 1:17
226
! 226
4
Q4:79MeV 1:15 The emitted positron (b) travels through matter, rapidly
88 Ra 86 Rn 2 He
losing kinetic energy through interactions with atomic elec-
Being relatively heavy (approximately four times the mass trons. It eventually annihilates with an electron (its anti-
of a proton) and highly charged (containing two protons), particle), releasing two photons of 0.511 MeV, traveling
a particles are readily stopped in matter. The 4.79 MeV a in opposite directions to provide momentum conserva-
particle emitted from radium has a range of less than tion. The average energy of the positron, at 0.25 MeV leads
4 cm in air, or less than 0.004 cm in tissue. to it being stopped within approximately 0.5 mm of the site
of emission in tissue. The annihilation photons, on the
Beta decay other hand, at 0.511 MeV each can relatively easily pass
This involves the ejection of an electron (b) or positron
(b) from a nucleus as either a neutron is converted to a 32
15P
A
ZX
proton (in b emission) or a proton into a neutron (in
b emission). A nucleus lying above the stability line in
Figure 1.6 is neutron-rich and, by converting a neutron
to a proton, can approach the stability line. Similarly,
proton-rich nuclei can undergo the opposite transforma- 1.71 MeV Q (energy)
_
tion. Observation that the b particles produced display a
spectrum of kinetic energies, rather than the discrete energy
difference between parent and daughter nuclei, indicates
that a further particle must be involved. This particle is 32 A
16S Z+1Y
the neutrino (n) or its anti-particle (n). The process for
phosphorus 32 (3215P) is shown below: A B
32
15 P ! 32
16 S b n Q1:7MeV Figure 1.9 Energy level diagram showing (A) the b decay of
16S and (B) the general process of b decay.
32 32
n ! p e ;Z ! Z 1
1:16 15P to
Realtive anumber of beta particles
226 A
88Ra ZX
(4.61 MeV)
(4.79 MeV)
10
Chapter |1| Atoms, nuclei and radioactivity
through tissue. Detection of these coincident photons via step can be deduced from the change in A and Z in the fig-
positron emission tomography (PET), following administra- ure. The series terminates in a stable isotope of lead.
tion of a positron-emitting radionuclide to a patient, there- Where the activity of a parent nucleus decays to a radio-
fore reveals where the annihilation event occurred and active daughter, the growth of activity of the daughter with
hence where the radionuclide was taken up within the body. time depends on the relative decay constants between par-
Beta decay frequently occurs by more than one route (or ent and daughter. A common example is molybdenum 99
channel) and may be accompanied by photon (g) emis- (9942Mo) which has an 86% likelihood of decaying to tech-
sion, as in the case of the b decay of 13757Cs to 13758Ba, netium 99m (99m43Tc), which subsequently decays by pho-
where 95% of the disintegrations are via a meta-stable state ton emission (140 keV) to stable technetium. In the
(denoted by the letter, m) of barium (137m58Ba). 137m58Ba remaining 14% of cases, molybdenum 99 decays directly
subsequently decays to stable 13758Ba, mostly by the emis- by b decay to stable technetium. If we assume that there
sion of a 0.662 MeV photon. This emitted photon is used in is no daughter product present at time, t 0, and that all
brachytherapy with the beta particles being absorbed parent disintegrations (100%) lead to the daughter product
within the source encapsulation. The energy level diagram of interest, the activity of the parent, Ap and daughter, Ad, at
for this disintegration is shown in Figure 1.11. time, t, are related by [4]:
Ad t ld
1 eld lp t 1:18
Internal conversion and electron Ap t ld lp
capture Where lp and ld are the decay constants of the parent and
daughter nucleus respectively and the initial activity of the
As an alternative to positron emission (b decay), the nucleus
parent Ap(0) is given by:
of a proton-rich atom may capture one of its own inner shell
electrons, via electron capture (EC). The captured electron Ap 0 Ap t elp t 1:19
combines with a proton in the nucleus to produce a neutron The build up of daughter activity as expressed in equation
and neutrino, the latter being emitted from the nucleus carry- 1.18 is of relevance to radionuclide generators. If the decay
ing kinetic energy equal to the difference in nuclear binding of the parent occurs at a much slower rate than that of the
energy between the parent and daughter nuclei. daughter, then ld>>lp and equation 1.18 reduces to:
An excited nucleus may de-excite by emitting a single
Ad t
photon, or by internal conversion (IC), in which the excita- 1 eld t 1:20
tion energy is transferred to an inner shell electron. The Ap t
electron is ejected from the atom with kinetic energy equal The right-hand side of equation 1.20 tends to unity for
to the excitation energy minus the electron binding energy; t>>1/ld, in which case the activity of the daughter and par-
characteristic photons will subsequently be emitted by the ent radionuclide are the same. This is the situation for ioni-
atom as the electron shell vacancy is filled. zation chamber consistency check devices containing a
strontium-90 source. Strontium-90 undergoes beta decay
Decay series and radioactive with a half-life of 28.7 years to yttrium 90, which itself
decays via beta decay with a half-life of 64 hours. The activ-
equilibrium ity of the long-lived strontium parent determines and
Large nuclei, such as 23892U, decay to radioactive daughter maintains the activity of the short-lived yttrium daughter.
nuclei which themselves decay, leading to a decay series, as
shown in Figure 1.12. The type of decay occurring at each
Radionuclides of interest
5% 95%
137
57Cs
Table 1.3 lists some common isotopes applied to radiother-
apy and nuclear medicine. The choice of isotope for a par-
ticular application is based on decay product type (g, b or
[0.514 MeV]
a), product energy(ies), half-life, specific activity (activity
137 per unit mass or per unit volume) and availability. b
[1.176 MeV] 58Ba
particles (electrons) have a relatively short range in tissue,
so will deposit energy close to the site at which a radio-
[0.662 MeV] nuclide is taken up in the body. If the site of disease can
be preferentially targeted, this leads to significant sparing
e of surrounding normal tissues in therapeutic applications.
137
58Ba
If greater penetration is required, of the order of centimetre
Figure 1.11 Energy level diagram for the b decay of caesium- for brachytherapy, or imaging of radioactivity uptake
137. Decay from 137m58Ba is mostly via the emission of a through external detection of radiation is required, then
0.662 MeV photon, but may also occur via internal conversion. photons (g) will be the product of choice.
11
Walter and Millers Textbook of Radiotherapy
238 U
92
109y
234 T 234 Pa 234 U
90 91 92
24d 7h 105y
230 T
90
226 R 104y
88
222 R 103y
86
218 P
84
4d
3m
214 Pb
82
214 Bi
83
214 P
84
206 Pb
82
Figure 1.12 Decay series for 23892U (redrawn from [5]). Half-lives are indicated in seconds (s), minutes (m), hours (h) and years (y).
Unsealed sources:
11
C b (2.0 MeV) PET imaging 20 m
13
N b (2.2 MeV) PET imaging 10 m
15
O b (2.8 MeV) PET imaging 122 s
18
F b (1.7 MeV) PET imaging 109 m
32
P b (695 keV) Polycythaemia vera 14.3 d
89
Sr b (500 keV) Bone metastases (palliation) 50.5 d
99m
Tc g (143 keV) Diagnostic imaging: 6.0 h
12
Chapter |1| Atoms, nuclei and radioactivity
Sealed sources:
60
Co b, g (1.17, 1.33 MeV) External beam units 5.26 y
103
Pd EC, g (21 keV) Brachytherapy (seeds) 17 d
125
I EC, g (27-36 keV) Brachytherapy (seeds) 60 d
137
Cs b, g (662 keV) Brachytherapy (pellets) 30 y
192
Ir b, g (300-400 keV) Brachytherapy (wire) 74 d
REFERENCES
[1] Yao W-M, et al. Review of particle [3] Catalogue of diagnostic x-ray radiation dosimetry. Wiley and
physics. Journal of Physics G: Nuclear spectra and other data. IPEM Report Sons Inc; 1986.
and Particle Physics 2006;33:1. 78. IPEM Publications; 1997. [5] Khan FM. The physics of radiation
[2] Wilks R. Principles of radiological [4] Attix FH. Introduction to therapy. 3rd ed. Lippincott Williams
physics. 2nd ed. Churchill radiological physics and & Wilkins; 2003.
Livingstone; 1987.
FURTHER READING
13
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Chapter |2|
Radiation interactions with matter
Colin Baker
CHAPTER CONTENTS
INTRODUCTION
Introduction 15
Charged and uncharged particles 15
Excitation and ionization 16 Charged and uncharged particles
Electron interactions 16 In this chapter we are mostly concerned with the interac-
Range and path-length 16 tions of electrons and photons with matter, as these are
the most commonly used particles in radiotherapy. The
Collisional and radiative (bremsstrahlung)
dominating feature of any particle is its charge. Electrons
energy loss 17
carrying a charge of 1.61019 C readily interact via
Stopping power and linear energy the Coulomb force with other charged particles in the mat-
transfer (LET) 18 ter they traverse, predominantly with atomic electrons and,
X-ray production 19 to a lesser extent, with protons in atomic nuclei. Photons,
Beam hardening 20 on the other hand, carrying no charge, interact relatively
Photon interactions 21 rarely with matter. The use of clinical proton beams for radio-
therapy is increasing as new facilities are constructed world-
Exponential attenuation 21
wide. As charged particles, proton beams passing through
Attenuation of photon spectra 22 matter behave in a similar way to electrons, that is, they read-
Energy absorption 23 ily undergo interactions with atomic electrons. The differ-
From attenuation to individual interactions 24 ence between proton and electron interactions lies in the
The photoelectric effect 25 proton having a mass roughly two thousand times greater
than the electron (1.671027 kg and 9.111031 kg for
The Compton effect 25 the proton and electron mass, respectively). The characteris-
Pair-production 26 tics of proton energy loss in matter makes them highly suit-
Nuclear interactions 27 able for radiotherapy, offering distinct advantages over
Photon depth-dose and the build-up effect 27 photons and electrons, as will be discussed below. Neutron
beams are less often selected as the beam of choice for radio-
Protons and ion beams 28 therapy at the present time, however, they also offer advan-
Protons 28 tages over photon beams for some tumours due to their
Clinical use of proton beams 29 biological effect on tissue. Being uncharged, neutrons inter-
Carbon ions and pions 29 act in a similar manner to photons and, in fact, produce very
similar depth-dose characteristics.
Neutron interactions 30
It should be remembered that radiotherapy is not
References 32 restricted to these particles alone. Ion beams consisting
Further reading 32 of atomic nuclei stripped of their electrons may also be
used (a proton is, after all, a hydrogen atom without its It will eventually lose this excess energy to return to its low-
electron). Carbon ions, in particular, have been used to est energy state, or ground state. An electron occupying an
treat a number of cancers in what is, at present, a small outer shell relative to the vacancy may achieve a lower
number of facilities world-wide and their characteristics energy state by filling the vacancy (Figure 2.1C). The excess
are being actively researched. Negative pions (p), were energy is released as a characteristic photon (of energy equal
also at one time thought to have great potential for radio- to the difference in shell binding energies). If this electron is
therapy due to the nature of their interactions and their also in an inner shell, it too will leave behind a vacancy
energy loss at the end of their range, in particular, which which an outer electron can again occupy (Figure 2.1C)
is discussed below. Clinical studies of the use of pions have losing energy in the form of a characteristic photon. This
not demonstrated this advantage to date. process results in a cascade of electrons moving between
shells and a corresponding set of characteristic photons
which eventually returns the atom to its ground state.
Excitation and ionization Even if its own kinetic energy exceeds the atomic elec-
Ionizing radiation, by definition, has sufficient energy to ion- trons binding energy, an incoming particle (electron, pho-
ize matter. That is, it has sufficient energy to overcome the ton etc.) may transfer just part of its kinetic energy to an
binding energy of atomic electrons. Radiation of energy below atomic electron to produce excitation. Where the incoming
the binding energy of a particular electron shell may still particle transfers more than the binding energy of an
interact with an electron by raising it to a higher, vacant shell atomic electron to the atom, the electron in question is
(see Chapter 1). As a result of this interaction, the atom has ejected from the atom, with kinetic energy equal to the total
gained energy and is left in an excited state (Figure 2.1A). energy transferred, minus the binding energy. As a result of
losing an electron, the atom has been ionized (Figure 2.1B).
As well as being chemically reactive as a result of this inter-
action (the positive ion will seek an electron from its sur-
roundings to return to its uncharged state), any electron
ejected from an inner shell will leave a vacancy behind,
which represents an excited state. A cascade process will
then follow as described above as de-excitation takes place
K (Figure 2.1D).
L K
M L
ELECTRON INTERACTIONS
A B
16
Chapter |2| Radiation interactions with matter
17
Walter and Millers Textbook of Radiotherapy
8
e- Collision
0
e-
0 10 20 30 40 50
A Electron energy [MeV]
Figure 2.4 Schematic representation of photon production
by electrons (bremsstrahlung). An incident electron deflected by 8
Collision
the nuclear Coulomb field loses energy, which appears in the form
18
Chapter |2| Radiation interactions with matter
0.05 0.5
0.25 2
1 6
Low LET High LET
10 30
Figure 2.6 Comparison of dose deposition and biological effect
for low and high LET beams. Circles refer to ionizing events. The 50 63
increased track density of ionization events occurring for the
Data calculated using ESTAR [1]
higher LET beam leads to greater biological (DNA) damage.
This increase in biological damage in comparison to low LET
radiation (e.g. photons) can be expressed as a relative biological
effectiveness (RBE), defined as the ratio of radiation doses
required to produce the same degree of biological damage.
For example, if an RBE of 1.1 is assumed for protons, then a
de-excitation of atoms, a continuous spectrum of photon
prescribed proton dose of 70 Gy would achieve the same energies is produced. An example of the photon spectra
biological effect as a dose of 77 Gy delivered by photons. produced when electrons are used to generate a 100 kV
and 6 MV photon beam is shown in Figure 2.7. Photon
spectra are commonly designated by kV or MV to indicate
the nominal potential used to accelerate the electrons that
between energy deposition for high and low LET beams is created the spectrum. For example, a potential difference
illustrated in Figure 2.6. of 100 kV between cathode and anode in an x-ray tube
will result in 100 keV electrons striking the target, produc-
ing a 100 kV photon spectrum. While there is no lower
X-ray production limit on the energy of photons produced, the low energy
components of the spectrum are preferentially removed
The conversion of electron kinetic energy into photons as a
by photon attenuation within the target and other machine
beam of electrons striking a target is decelerated in the
components, so that the peak in the spectrum occurs at
nuclear Coulomb field (bremsstrahlung) is the primary
approximately one-third of the maximum photon energy.
method for obtaining clinical photon beams. As suggested
Discrete spectral lines can be seen superimposed on the
earlier, however, for the normal range of energies con-
continuous 100 kV spectrum, these are due to characteristic
sidered for diagnostic imaging and radiotherapy (20 keV
photons being produced during de-excitation of tungsten
to 25 MeV), electrons are far more likely to interact through
atoms after inner shell electrons have been excited or
collisions with atomic electrons. The efficiency of this pro-
ejected through collisions with the incident electron beam.
cess is therefore generally low. The likelihood of brems-
The energies of these characteristic photons correspond to
strahlung depends on the atomic number of the material
the difference between the binding energies of the inner
traversed, Z (the total charge of the nucleus) and the energy
shell vacancy and the outer shell electron that fills the
of the incident electron, E, according to:
vacancy. The difference between electron binding energies
Probability ZE 2:5 depends on the atomic number of the target. For tungsten,
The energy of the electron beam is dictated by the maximum with a K-shell binding energy of 69 keV and L-shell binding
photon energy required. The use of high atomic number energy of 12 keV, it follows that the minimum energy of a
materials, gives the best yield of photons. Table 2.2 indicates characteristic photon produced by filling an electron
the proportion of electron beam kinetic energy converted vacancy in the K-shell is 57 keV. The same characteristic
to photons for a tungsten target. The remainder of the inci- photons are not observed in the 6 MV spectrum, as they
dent electrons kinetic energy is lost through collisions with now represent very low energies within this spectrum
atomic electrons in the target, causing excitation and ioniza- and are preferentially removed by photon attenuation.
tion. A large amount of this energy is eventually released in For electrons striking a thin target, photons are produced in
the form of heat, requiring the target to be cooled. all directions. The intensity (or number) in a particular direc-
In the bremsstrahlung process, an electron may lose any tion depends on the energy of the incident electrons, and the
amount of energy, up to its total kinetic energy. Rather atomic number of the target. For low electron energies (up to
than discrete photon energies, as are observed during 100 keV), the intensity is almost equal in all directions and as
19
Walter and Millers Textbook of Radiotherapy
1.0
Relative energy fluence
0.8
0.6
0.4
0.2
1.0
Relative energy fluence
0.8
0.6
1 MeV
0.4
0.2
0.0
10 MeV
0 1 2 3 4 5 6 7
B
Photon energy [keV]
20
Chapter |2| Radiation interactions with matter
1.01
PHOTON INTERACTIONS
0.10
Exponential attenuation
0.01
Figure 2.10 shows an experimental arrangement for mea-
suring the number of photons that reach a detector as a
filter, or attenuator, is placed in the beam path. We are 0.00
interested in measuring how many photons arrive at the 0.01 0.10 1.00 10.00 100.00
detector without undergoing any interaction in the filter, Photon energy [MeV]
i.e. how many photons are unattenuated. The purpose of
Figure 2.11 Mass attenuation coefficient variation with photon
the collimators is to prevent any scattered photons, result- energy in water and lead (data from [2, 3]). The light and dark
ing from an interaction in the filter, from reaching the shaded regions indicate the approximate range of photon
detector and so causing us to overestimate the number of energies commonly used for diagnostic imaging and
photons that have not interacted. If scattered photons are radiotherapy, respectively.
21
Walter and Millers Textbook of Radiotherapy
Relative intensity
below) and the minimum attenuation occurs at a much
lower energy of approximately 4 MeV, after which it begins 0.6
to rise. It follows that the thickness of lead required to
provide a chosen degree of attenuation would be greater
0.4
for 4 MeV photons than it would be for 20 MeV photons.
Note that here we are considering monoenergetic photons
(MeV), whereas in practice, clinical photon beams contain 0.2
a spectrum of energies (denoted by MV to indicate this).
The effective attenuation coefficients (averaged over all
0.0
energies in the spectra) in lead for 6 MV and 15 MV beams
0 0.5 1 1.5 2 2.5 3
are roughly equal. The mass attenuation coefficients of A
water and lead are approximately equal for 1 MeV photons, Filter thickness [cm]
at 10 MeV the coefficient for lead is a little over twice that of
water, whereas at 100 keV, the coefficient for lead is over 30 0.2
times that of water. The reason for the particular shape of the
attenuation curves for water and lead is explained by the 0.2
varying probability with energy of the underlying photon In [Relative intensity] 0.6
interactions that combine to give the total interaction proba-
bility and hence attenuation coefficient. These interactions 1.0
are described in subsequent sections.
The mathematical form of equation 2.7 is identical to 1.4
that describing radioactive decay. For a chosen material 1.8
and filter thickness placed in the path of a monoenergetic
photon beam, adding additional filters of the same mate- 2.2
rial and thickness will result in the same fraction of beam
2.6
being transmitted, for example, if 1 cm of a filter results in
the beam intensity falling to 70% of its original value, then 3.0
2 cm will result in 49% of the original intensity being trans- 0 0.5 1 1.5 2 2.5 3
mitted. Figure 2.12A shows a plot of relative transmitted B
Filter thickness [cm]
photon intensity (N/N0 e mx) for a monoenergetic beam
of photons incident on aluminium filters. Taking natural Figure 2.12 Exponential attenuation of monoenergetic
logarithms of this equation yields a linear function, shown photons. (A) Relative transmission versus filter thickness and
in Figure 2.12B. The slope of the straight line is equal to m. (B) ln (relative transmission) versus thickness. The HVL of
For a filter thickness that reduces the intensity to half the 0.7 cm Al is indicated on each plot.
original value, we have:
N
0:5 emt1=2 2:8
N0 Attenuation of photon spectra
t1/2 is denoted the half-value layer (HVL) or half-value thick-
We have so far considered only monoenergetic beams
ness. Rearranging this expression and taking natural loga-
of photons. In practice, photon beams generated by
rithms gives:
fast-moving electrons striking a high atomic number tar-
ln 2 get will have a spectrum of energies, as described above.
t1=2 HVL 2:9
m We may expect the attenuation coefficient to decrease as
For a chosen filter material, the HVL of a beam of photons photon energy is increased, i.e. that higher energy
provides a measure of the beams power of penetration. In photons are more penetrating. In the kilovoltage region,
the kilovoltage region, HVL is therefore used to represent at least, this is indeed the case and is the reason for beam
the quality of a beam of photons. For a monoenergetic hardening, discussed above. As a photon spectrum (poly-
beam of photons, it follows that after one HVL, the inten- energetic beam) is filtered, lower energy photons will be
sity drops to 50%, after two HVLs 25%, after three HVLs preferentially removed from the beam due to their larger
12.5% and so on. The presence of inherent filtration for attenuation coefficients. This results in the average energy
a monoenergetic source of photons would therefore have of the beam increasing and the average attenuation coef-
no effect on the measured beam quality. ficient decreasing. As a result of this changing attenuation
22
Chapter |2| Radiation interactions with matter
10
0.0
0 0.5 1 1.5 2
Filter thickness [cm] Attenuation
Absorption
Figure 2.13 Attenuation comparison between a 100 kV
Coefficient [cm2g1]
photon spectrum (solid line) and a monoenergetic beam (dashed 1
line) of the same first HVL. The first and second HVLs (0.7 and
0.9 cm Al respectively) for the spectrum are indicated. For the
monoenergetic beam, the first and second HVLs would be
equal, while for a spectrum of energies, the subsequent HVLs
increase due to beam hardening, as indicated. 0.1
1.1
Energy absorption
(en /)w / (en /)air
23
Walter and Millers Textbook of Radiotherapy
Coefficient [cm2g1]
Pair production
dosimetry in a similar way to that in which electron
stopping powers are used for electron beams described
0.1
earlier. Taking again the example of an air-filled ionization
chamber in water, having determined the dose deposited
by photons in the air cavity, Dair, the dose to the same
region when filled with water, Dw, is given by: 0.01
m =r
Dw Dair en w 2:10
men =r air
(see Figure 2.14B). 0.001
The above expression assumes that all electrons set in 0.01 0.1 1 10
A
motion by the incident photons deposit their energy within Photon energy [MeV]
the chamber. This is a reasonable assumption for kV
photon beams. For MV photon beams, however, the ranges
of secondary electrons become significant and must be 100 Total
considered. PE
Compton
Coefficient [cm2g1]
10 Pair production
From attenuation to individual
interactions 1
24
Chapter |2| Radiation interactions with matter
25
Walter and Millers Textbook of Radiotherapy
0.7
Average fraction of incident
0.6
0.5
0.4
0.3
0.2 e+ + e
0.1
0
0.01 0.1 1 10
Photon energy [MeV]
e+ e
Figure 2.19 Average proportion of photon energy transferred
to secondary electrons during the Compton effect. Figure 2.20 Schematic representation of pair production in the
(derived from [7]) nuclear Coulomb field.
26
Chapter |2| Radiation interactions with matter
PDD [%]
to 0.511 MeV, the electron (and positron) rest-mass. To con-
serve momentum, these two photons must travel in opposite
40
directions. This feature of positronelectron annihilation is
the key to positron emission tomography (PET), as coincident
detection of the two photons produced reveals information 20
on the position of the annihilation event.
Photons may undergo a similar interaction to the
0
nuclear pair-production interaction described above in
0 100 200 300
the Coulomb field of an electron. However, the probability
of this is very low compared to the interaction in the Depth in water [mm]
nuclear Coulomb field. Figure 2.21 Example percentage depth-dose profiles (PDDs) for
photon beams in water.
Reprinted with the permission of the Clatterbridge Centre for Oncology
Nuclear interactions
NHS Foundation Trust: Douglas Cyclotron
At sufficiently high energies (above approximately 8 MeV,
or 15 MV spectra), photons may interact directly with the dominates in low atomic number materials, such as tissue,
atomic nucleus, releasing neutrons or protons: right across the MeV range of photon energies commonly
g A Z X ! A1 Z X n used for radiotherapy. This interaction provides a scattered
2:15 photon, which generally leaves the site of interaction and a
g A Z X ! A1 Z1 Y p secondary electron which has a finite range over which
These interactions do not lead to a significant patient dose, it deposits its energy. For an incident 1 MeV photon,
but the production of neutrons can lead to additional Figure 2.19 shows us that approximately 0.4 MeV, on aver-
shielding requirements for the treatment room. Activation age, is passed to the secondary electron, whereas for a
of linear accelerator components, particularly the photon 10 MeV incident photon, roughly 6.8 MeV on average
target, can also occur, which must be allowed to decay to would be passed on. This kinetic energy of the secondary
acceptable levels before any intervention, such as machine electrons is not all deposited at the site of the Compton
servicing. interaction, but is spread out over the electrons range,
which depends on the electrons energy (as shown in
Table 2.1). Lets now consider the total absorbed dose from
Photon depth-dose and the secondary electrons as we move between thin layers from
build-up effect the surface to the depth of dmax, in steps of some fraction of
Figure 2.12 showed how the transmission of photons dmax. As illustrated in Figure 2.22, some energy is deposited
decreases exponentially as the amount of matter traversed in the surface layer by secondary electrons set in motion
is increased. The quantity we are generally more interested within this layer and some is transported along with the
in, however, is the absorbed dose received at a depth in tis- electrons to underlying layers. Taking a step deeper, we
sue and how this varies with depth. This quantity is com- again have a dose from secondary electrons set in motion
monly described as percentage depth-dose, PDD: within this layer, and we have an additional dose contribu-
tion from secondary electrons entering from the surface
Dd
PDD 100 2:16 layer (upstream), i.e. we now have contributions from
Dd max two layers. At the next layer, we have three layers contribut-
where D(d) is the measured dose at depth, d, and dmax the ing, the one we are in and two upstream. At each successive
depth of maximum dose. Example PDD curves for mega- deeper layer, the number of upstream layers contributing
voltage photon beams are shown in Figure 2.21. An impor- electrons increases, so the total absorbed dose rises, or
tant feature of these curves is that fact that the maximum builds up. This process continues until we are at a depth
dose is not reached at the surface, but at a depth, dmax, beyond the range of electrons set in motion in the surface
which is dependent on the energy of the beam. This pro- layer, at which point we have reached full build up, at dmax.
vides the skin-sparing effect of megavoltage photon beams. The depth of dmax, then, corresponds to the average range of
The dose build-up effect is explained by considering the secondary electrons set in motion by the incident photon
photon interactions taking place in tissue at the energies beam, which increases with photon beam energy, as shown
involved. Table 2.3 shows us that the Compton effect in Figure 2.21 in moving from 6 to 15 MV. In practice, this
27
Walter and Millers Textbook of Radiotherapy
28
Chapter |2| Radiation interactions with matter
Given a square field of side, s1 at distance, f1 the size, s2, at distance, f2 is given by:
s2 = s1 x (f2 / f1) [1]
f1
Field areas are related by:
s22 = s12 x (f2 / f1)2 [2]
f2
D1 In the absence of photon interactions, the number of photons over each field is constant
S1 (=n, say) and the number per unit area (intensity) is therefore:
I1 = n/s12 and I2 = n/s22
Figure 2.23 Illustration of field size scaling and derivation of the inverse-square law.
Table 2.4 Proton range variation with energy (csda range Clinical use of proton beams
quoted, calculated using PSTAR [1]) In order to deliver a uniform radiation dose over defined
target dimensions, at a required depth, the full energy
ENERGY (MeV) RANGE (cm) (or pristine) Bragg peak shown in Figure 2.24A must be
broadened and range-shifted as in Figure 2.25A. Broaden-
60 3.1
ing the Bragg peak can be achieved either by varying beam
100 7.7 energy directly or by passive scattering of a single energy.
The latter is simply achieved by placing different thick-
150 15.8 nesses of attenuator in front of the patient to vary the depth
that protons penetrate. Figure 2.25B shows a Perspex mod-
200 26.0
ulator wheel. There are a number of available thicknesses
250 37.9 in the wheel, the proportion of each is determined so that
the total dose summed over all steps is uniform within the
target region.
normal tissue. The Bragg peak is also a characteristic of other
heavy charged particle beams, such as carbon ions and
pions.
Carbon ions and pions
While interactions with atomic electrons is the domi-
nant process by which clinical proton beams (50 In addition to protons, heavier nuclei and other particles
250 MeV) lose energy and so deposit dose, an incident may offer potential advantages for radiotherapy due to
proton beam may also interact with the atomic nucleus the physical characteristics of their dose deposition in mat-
through elastic or non-elastic scattering. In elastic scattering ter and their relative biological effectiveness (RBE). Beams
events, kinetic energy is passed from the incident proton of carbon ions and pions, in particular, have been applied
and the internal structure of the nucleus is unchanged. clinically for radiotherapy. In order to reach deep-seated
In non-elastic scattering, the nucleus may be fragmented tumours, the energies of heavy ion beams need to be
or left in an excited state, in which case kinetic energy is significantly higher than that of protons. For example,
not conserved. Charged particles (secondary protons, while 150 MeV protons have a range of approximately
alpha particles etc.) produced during these events will 16 cm in water, the same penetration depth for carbon ions
deposit their energy close to the site of interaction, requires a beam energy of close to 3600 MeV, or 300 MeV
whereas neutrons and photons, being uncharged, may for each of the 12 nucleons (6 protons and 6 neutrons) in
carry energy a significant distance away. the ion (often denoted 300 MeV/u).
29
Walter and Millers Textbook of Radiotherapy
5
100
60
3
40
2
20
1
0
0 5 10 15 20 25
A
0 Depth in water [mm]
0 1 2 3 4
A
Depth in water [cm]
1000
Total stopping power [MeV cm2 g1]
100
10
B
0
0 50 100 150 200 250 300 Figure 2.25 Creation of a spread-out Bragg peak (SOBP) for
B a single proton beam. In (A) the solid line represents the total
Proton energy [MeV] dose. The uniform dose across the target (circle) is achieved by
summing dose contributions from a number of range-shifted
Figure 2.24 (A) Bragg peak for 60 MeV protons in water and Bragg peaks (dotted lines). (B) an example of a perspex
(B) proton stopping power in water (data from PSTAR [1]). modulator wheel, designed to provide the appropriate weighted
Notice how the shape of the stopping power curve is reflected in range-shifting.
the observed depth-dose curve.
(Reprinted with the permission of the Clatterbridge Centre for Oncology
NHS Foundation Trust: Douglas Cyclotron)
The LET of carbon ions in the Bragg peak is significantly
higher than in the plateau region which leads to an particles over alternatives is the star effect which enhances
increased RBE across the target region relative to the sur- the dose deposited in their Bragg peak due to their capture
rounding low dose region. Hence, in addition to a lower by atomic nuclei. This capture process causes the nucleus to
physical dose, normal tissue is spared further due to a lower become unstable and disintegrate into a number of frag-
biological effect. This increased LET in the Bragg peak is ments, each of which has a high LET and very short range
a result of nuclear fragments being produced in colli- in tissue.
sions, which leads to a dose tail following the Bragg peak,
illustrated in Figure 2.26A.
Pions, negatively charged particles with a mass approx-
imately 15% of that of a proton and a half-life of NEUTRON INTERACTIONS
26 ns (2.6 108 s) can be produced by bombarding car-
bon or beryllium targets with protons. Pion beams have been Clinical beams of fast neutrons, of the order of 60 MV, were
used clinically to treat over 500 patients at a small number the subject of particular interest during the 1970s and
of centres world-wide. The potential advantage from these 1980s. Being uncharged, they show similar depth-dose
30
Chapter |2| Radiation interactions with matter
9 100
8 195 MeV/u 62 MV neutrons
270 MeV/u 80 6 MV photons
7 350 MeV/u
6
60
5
4 40
3
2 20
1
0
0
0 5 10 15 20 25
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280
A Depth [mm] Depth in water [mm]
31
Walter and Millers Textbook of Radiotherapy
REFERENCES
[1] Berger M, Coursey J, Zucker A, additional substances of dosimetric [5] Baker C, Peck K. Reconstruction
Chang J. ESTAR, PSTAR, and ASTAR: interest. National Institute of of 6 MV photon spectra from
Computer programs for calculating Standards and Technlology; 1996. measured transmission
stopping-power and range tables for NISTIR 5632. including maximum energy
electrons, protons, and helium ions [3] Berger MJ, Hubbell JH, Seltzer SM, estimation. Phys Med Biol
(version 1.2.3), Gaithersburg, MD: et al. XCOM: Photon cross sections 1997;42:204151.
National Institute of Standards and database. National Institute of [6] IPEM Report 78 . Catalogue of
Technology; 2005.http://physics. Standards and Technology; 1998. diagnostic x-ray spectra and other
nist.gov/Star. NBSIR 87-3597. data. Institute of Physics and
[2] Hubbell JH, Seltzer SM. Tables of [4] Mayles P, Nahum A, Rosenwald J-C, Engineering in Medicine; 1997.
X-ray mass attenuation coefficients editors. Handbook of radiotherapy [7] Attix F. Introduction to radiological
and mass energy-absorption physics, theory and practice. Taylor physics and radiation dosimetry.
coefficients from 1 keV to 20 MeV for and Francis; 2007. John Wiley & Sons Inc; 1996.
elements Z 1 to 92 and 48
FURTHER READING
32
Chapter |3|
Radiation detection and measurement
James E. Shaw, Colin Baker
Polarity effect 45
CHAPTER CONTENTS
Alternative dose measurement systems 45
Introduction 34 Film dosimetry 45
Kerma 34 Radiochromic film 46
Absorbed dose 34 Band theory of solids 46
Units of kerma and dose 35 Impurity bands 47
Measurement and standardization of dose 35 Semiconductor detectors 47
Dose standards 35 Diode detectors 47
Traceability of measurement 35 MOS-FET detectors 48
Standard calorimeter 36 Diamond detector 49
The free air chamber 38 Summary of direct reading radiation
Charged particle equilibrium 38 detectors 49
Practical ionization chambers 39 Thermoluminescent dosimetry (TLD) 49
Bragg-Gray cavity theory 39 Chemical and biochemical detectors 51
Dose determination based on calibrated Fricke dosimetry 51
instruments 39 Ceric dosimetry 51
Requirements for practical ionization Gel dosimetry 51
chambers 40
Fricke gels and FXG gels 52
Thimble ionization chamber 40
Polymer gels 52
Measurement of dose and dose rate 42
Alanine-EPR dosimetry 52
The parallel plate ionization chamber 42
Biological dosimetry 53
The beam monitor chamber 42
Biological molecules 53
Intercomparisons with secondary standard
instruments 43 Genetic structures 53
It may be seen from Figure 3.1 that for the Compton inter-
INTRODUCTION action illustrated:
1. the energy of an incident photon is shared between a
Chapter 2 described the various processes by which scattered photon and the ejected electron. The scattered
photons interact with matter. These interactions produce photon carries its energy away from the immediate
charged particles (electrons and possibly positrons) which region of the interaction. The term terma represents the
then travel through matter, losing energy by collision total energy removed from the beam per unit mass of
processes (ionization and excitation of atoms) and through matter, including that given to the charged particles
radiative processes (production of bremsstrahlung), as and that scattered as photons. Terma is therefore
illustrated in Figure 3.1. always greater than kerma
For photon beams, the transfer of energy from radiation 2. the electron travels through matter losing energy
to matter may be seen in two distinct stages: continually until its kinetic energy is exhausted
3. the travelling electron may lose some energy by
1. transfer of energy from the radiation to emitted charged
bremsstrahlung, producing photons which, like the
particles
scattered photon, carry energy away from the
2. deposition of energy by the emitted charged particles
immediate vicinity. The term collision kerma refers
through collision processes.
to that proportion of kerma that is deposited via
The first stage is governed by the interaction coefficients for collision processes only. Kerma and collision kerma
photons in matter as discussed in Chapter 2. The second differ only in accounting for the energy that is
stage is dependent upon the energies of the emitted charged re-radiated. In body tissues, the energy re-radiated is
particles and their subsequent patterns of energy deposi- small, being less than 1%, so these two quantities
tion as determined by their stopping powers. Together, are almost equal.
these determine the differences in deposition of energy
for differing photon energies and materials. For charged
particle beams only the second stage is relevant. Absorbed dose
The travelling electrons deposit energy in matter through
which they pass, and so the energy deposited by these
Kerma electrons is displaced in distance from the site of initial
transfer of energy from the photon beam. The amount
The term kerma, an acronym for the kinetic energy released
of energy deposited in a small mass of the material
per unit mass, is used to quantify the first of the above stages.
is termed the absorbed dose, which is defined by
It is defined by ICRU (1) as:
ICRU [1] as:
K DEtr=Dm D DEd=Dm
where Ed is the total energy deposited by these charged
where Etr represents the energy transferred from photons particles in a volume element of mass m.
to charged particles and is the sum of initial kinetic energies The absorbed dose is similar in value to collision kerma,
of all the charged particles liberated by uncharged ionizing but displaced due to the motion of the secondary charged
radiation from an amount of material of mass m. particles. Absorbed dose equals collision kerma if one of
two conditions are met:
1. the distance travelled by secondary charged
particles is sufficiently small for it to be neglected,
Energy radiated away from
the region of the interaction such that energy may be considered to be absorbed
Scattered does not contribute to the by the matter at the point where it is transferred
Photon local deposition of energy. from photons to the charged particles a condition
Point of
Interaction known as point deposition of dose. This occurs for
Bremsstrahlung low energy photons, where the emitted electrons
Electron Photon
Incident Photon
can travel only short distances, as detailed in
Chapter 2
Energy deposition 2. the energy lost from the region of initial transfer
by ionisation Deposited energy appears by the movement of charged particles away from
and excitation ultimately in the form of heat, that region is exactly compensated for by energy
chemical products or long
brought into the region by other travelling electrons
lived excited electron states.
produced elsewhere a condition known as energy
Figure 3.1 Schematic diagram of energy deposition arising equilibrium, or more generally as charged particle
from Compton interaction in a matter. equilibrium.
34
Chapter |3| Radiation detection and measurement
35
Walter and Millers Textbook of Radiotherapy
As per
Reference Level protocol
Instruments
Strontium
Consistency
System Monitor Instrument
Figure 3.2 Traceability to the National Standard is assured through a chain of intercomparisons, some of which are carried out at the
National Standards Laboratory and others are carried out in local radiation beams. Between intercomparisons, calibration is assured
using a consistency system.
For the transfer of calibration from instrument to instru- Note that the specific heat may also be expressed in calories
ment down the chain to be reliable, the method of calibra- rather than joules, in which case an additional numerical
tion must be strictly controlled. This is achieved by the multiplier of 4.18 is necessary in the above equation.
adoption of calibration protocols which specify: The rise in temperature is extremely small e.g. a beam
the basis for the standard dose measurement of x-rays delivering a dose of 5 Gy to soft tissue causes a
the instrumentation and methods for transfer of dose temperature rise of only 103 C. Such a small rise in tem-
to field instruments by a series of intercomparisons, perature is very difficult to measure accurately and extreme
including specification of any equipment used and precautions are necessary to prevent heat loss outside the
any conditions that must exist for the intercomparison irradiated vessel.
to be reliable The national standard calorimeter is based on the irradi-
instructions for use of the calibrated dosimeter in ation of a known mass of graphite (the core of the NPL high
routine practice. energy photon calorimeter measures approximately
20 mm diameter by 3 mm thick) within a graphite phan-
Each protocol is specific for an energy range and type of
tom. The design of the calorimeter, a photograph and sche-
radiation: the protocols for calibration of field instruments
matic drawing of which are shown in Figure 3.3, has the
are covered in a later section.
core shielded by three jackets, each separated by vacuum
in order to minimize heat loss. Temperature measurements
Standard calorimeter are carried out using thermistors embedded in the graphite
core, the resistances of which change with temperature. In
In situations where all the absorbed energy is manifest solely
practice, since the amount of heat energy lost from the core
as heat, i.e. no energy is lost to form new chemicals or
to surrounding structures is not negligible and may be dif-
stored in excited electron states, the relationship between
ficult to determine, the rise in temperature resulting from
radiation dose and change in temperature is given by:
irradiation is compared with the rise in temperature pro-
Dose Gy C dT duced by heating the core using a known amount of elec-
where C is the specific heat of the irradiated matter (the trical energy, allowing absorbed dose to be determined
amount of energy needed to raise the temperature of unit directly instead of using the above equation.
mass of a substance through 1 degree, expressed in units Graphite has the advantage of having no chemical defect
of in J.kg1. C1) and dT is the change in temperature (i.e. all the absorbed energy appears as heat) and a specific
in degrees Celsius. The equation above assumes no loss heat that is one-fifth that of soft tissue or water, thereby
of heat to the surrounding environment or structures. producing greater changes in temperature per unit dose.
36
Chapter |3| Radiation detection and measurement
6
5
2 1
4
50 mm
7
Figure 3.3 Photograph and simplified schematic drawing (redrawn from [2]) of the national standard high energy photon
calorimeter, showing the graphite core (C) surrounded by three insulating graphite jackets (1, 2 &. 3). The entire device is
housed within a Perspex evacuation vessel (6) which has a thin aluminized mylar front window (5) and which is evacuated via
a port (7). A plate (4) suitable for the energy to be measured can be added to the front face. Electrical connections to the core
pass through the device (8).
The absorbed dose to water may be calculated from the Table 3.1 Photon beam qualities used for therapy level
absorbed dose to graphite using the correction factors absorbed dose to water calibrations
determined by Nutbrown [6].
Measurement by calorimetry is largely independent of BEAM QUALITY EQUIVALENT REFERENCE
whether the radiation is delivered continuously or in pulses (TPR20/10) BEAM ENERGY DEPTH (cm)
and of the pulse intensity. It is therefore ideal for measuring
0.568 60 Co 5
radiation from constant-output sources, such as cobalt
units, as well as pulsed output from linear accelerators. 0.621 4 MV 5
The pattern of temperature rise (from irradiation) and fall
(from leakage of heat away from the core) may be used to 0.670 6 MV 5
determine both the peak and mean dose rates for pulsed 0.717 8 MV 5
radiation sources.
As the standard calorimeter cannot be used in a water 0.746 10 MV 5
tank, a number of specially constructed ionization cham-
bers termed reference standard instruments are calibrated 0.758 12 MV 7
annually against the graphite calorimeter in a common 0.779 16 MV 7
graphite phantom. These reference instruments are then
used to calibrate in turn the secondary standard instru- 0.790 19 MV 7
ments using a water phantom. The calibration factor
The quantity TPR20/10 is the ratio of tissue-phantom ratios at depths
provided for each secondary standard instrument is specific
of 20 cm and 10 cm respectively, used by Standards Laboratories as
to a stated beam quality and depth of measurement, the lat- the specifier of beam quality (see Chapter 2).
ter being important as the spectral content of a radiation A number of Standards Laboratories have developed water
beam changes with depth. Table 3.1 shows those photon calorimeters that directly measure the rise in temperature of a known
beam qualities at which calibration factors based on mass of water. These avoid uncertainties with the national standard
absorbed dose to water as determined by the standard graph- instrument in moving from a graphite phantom to a water phantom.
Such instruments have been used to confirm doses specified using other
ite calorimeter are provided by the National Physical Labo-
systems of dosimetry for photon and charged particle beams and are
ratory, UK [7, 8]. When used as a basis for calibration in a being increasingly developed as national dosimetry standards [4448]
radiation beam in the users department, the beam quality
37
Walter and Millers Textbook of Radiotherapy
for that beam must be determined and the appropriate cali- plate while electrons will move towards the other. All ions
bration factor obtained by interpolating from the results of one charge sign are collected on one electrode, termed
provided by the standards laboratory. Calibrations in mega- the collecting electrode. The charge reaching this electrode is
voltage photon beams are carried out at the depths shown in measured and, from this, the number of ions produced
Table 3.1 which are beyond the range of contaminating elec- may be calculated, since the charge carried by each electron
trons in the radiation beam that have been ejected from the is constant (equal to 1.6021019 coulomb). The average
head of the treatment machine [9]. energy expended by electrons in creating an ion pair, that is
allowing for energy lost in exciting atoms as well as energy lost
in ionizing them, is well determined from experimental work.
The free air chamber
Hence, since the number of ions may be determined using
The free air chamber is the primary standard instrument the free air chamber and the average energy necessary to pro-
for kV beams, and is shown schematically in Figure 3.4. duce each one is known, the total energy transferred to sec-
The free air chamber effectively determines the energy trans- ondary electrons by photon interactions can be calculated.
ferred to secondary electrons as a result of interactions of a Figure 3.4 shows the physical arrangement. The metal
photon beam within a defined mass of air, i.e. air kerma (ka). plate that forms the electrode which carries the high ten-
A well-defined beam of radiation, confined by external col- sion (HT) polarizing voltage runs the full length of the
limators, is incident upon a volume of air located between chamber, whereas the other plate has the collector elec-
metal plates that act as electrodes. The radiation causes ioni- trode as the central part only, separated and electrically
zation of the air, resulting in electrons being ejected. These isolated from adjacent metal plates called guard rings,
electrons in turn cause further excitation and ionization as which are held at the same electrical potential as the collec-
they interact with air molecules: the electrons lose kinetic tor electrode. This arrangement ensures that the electric
energy with each interaction and will travel an irregular, tor- field within the region of the collector electrode is uniform
tuous path until they come to rest. Each ejected Compton- or and perpendicular to that electrode. Any ions produced in
photo-electron can produce several hundred ion pairs. An air within the region ABCD on the diagram will be collected
essential requirement of the free air chamber is that the elec- on the collector electrode, whereas any ions produced
trons produced by photon interactions lose all their kinetic outside this region will be collected on the guard rings
energy in air and do not reach the metal electrodes. This and will not be included in the measurement.
requirement determines the minimum separation between
the metal electrodes, and the overall size of the chamber.
For example, measurement of x-rays generated at 200 kV
Charged particle equilibrium
will require a separation of at least 20 cm. The shaded region in Figure 3.4 indicates the volume of air
A potential difference, the polarizing voltage, is applied of interest irradiated by the photon beam, being specified
between the metal electrodes. This causes positively and neg- by the cross-sectional area of the photon beam and the
atively charged ions produced in the air to separate, such length of the collector electrode. The mass of air within this
that positive ions will move towards the negative potential volume depends upon atmospheric conditions (tempera-
ture and pressure). Correction for different atmospheric
HT polarizing voltage conditions is covered in a later section.
Some electrons (such as trajectory 1) emanating from
A B this region will lose all their kinetic energy within region
ABCD and will have the ions collected by the collector elec-
1 2 trode. Other electrons (such as trajectory 2) emanating
3
from the air volume will pass beyond the boundaries of
region ABCD such that some of their ions will be lost to
the collector electrode, thereby reducing the measurement
1 of ionization. However, other electrons emanating from
outside the air volume may cause ionization within region
D C
Collecting Guard ring ABCD that will be collected and measured as indicated by
electrode trajectory 3, thereby increasing the measurement of ioniza-
tion. Charged particle equilibrium is said to exist when the
Electrometer ionization lost from region ABCD is exactly matched by
the ionization gained.
Figure 3.4 The free air ionization chamber. Irradiation of the
Under the conditions of charged particle equilibrium,
mass of air shown shaded, defined by the cross-sectional area of
the radiation beam and the length of the collecting electrode, the total sum of ion pairs generated by the Compton-
results in emission of electrons that lose their kinetic energy by and photo-electrons ejected from the shaded volume will
ionization of air. Those ions created within the region ABCD are be equivalent to that determined by measuring the charge
collected and measured. collected on the collector electrode.
38
Chapter |3| Radiation detection and measurement
For charged particle equilibrium to exist, the path in air Where the medium is irradiated by a photon beam, then
before the shaded region is reached must be at least equal to photon interactions produce secondary electrons which
the range in air of the Compton- and photo-electrons. Col- cause ionization within the air cavity. Provided that inter-
limation devices must be sited beyond this range, so that actions of photons with air molecules is negligible, such
photo-electrons ejected from them cannot reach the mea- that all electrons crossing the air cavity arise as secondary
surement region. There must similarly be an equivalent electrons from within the medium and that the above con-
path length of air beyond the distal end of the measure- ditions relating to constancy of electron fluence are met,
ment volume before any exit portal is reached. The whole then the air volume can be regarded as a Bragg-Gray cavity.
instrument is therefore very large and unwieldy. Further- The above equation then still holds.
more, it is susceptible to interference from externally gen- In practice, when using ionization chambers, the air
erated electric fields and stringent measures have to be volume is enclosed by a wall of material which differs
adopted to minimizse any such influences. slightly from both air and the medium. The construction
of the chamber may introduce perturbations both to the
fluence of electrons crossing the air cavity and to the pho-
PRACTICAL IONIZATION CHAMBERS ton beam itself. A wall of infinitesimally small thickness
may be considered as having no impact on either, such
that the chamber is effectively an air cavity within the
The Primary Standard instruments described above are medium. As the wall increases in thickness, then an
complex, sophisticated and sensitive instruments that are increasing percentage of secondary electrons crossing
unsuitable for routine use within a hospital environment the air volume will be from the wall rather than the
where small, relatively robust, simple instrumentation is medium until, in the extreme, all electrons crossing the
needed. air volume originate from within the wall. In this situa-
One such instrument is the ionization chamber. tion, the electron fluence across the air volume is the same
as the fluence within the wall, and the dose to the wall
Bragg-Gray cavity theory (Dw) is given by:
Dw Ja W S=rw a
The absorbed dose within any medium cannot generally be
measured directly and so a surrogate has to be used. Ioni- Assuming the photon field is not perturbed by the pres-
zation chamber dosimetry is based upon replacing a small ence of the chamber, then the dose deposited by photons
volume of the medium by an air cavity within which the in the medium is related to that deposited in the chamber
ionization of air by the radiation can be measured and wall:
from which the dose to the medium can be determined. Dm Dw m=rm w
When a medium is irradiated uniformly by electrons, where (m/r)mw is the ratio of mass absorption coefficient
then the fluence of electrons (i.e. the energy carried across for the medium divided by that for the chamber wall.
unit cross-sectional area) will be the same at all points The conditions for the above to be strictly valid are not
within the medium. If a small air cavity is introduced of size met in practice. For measurement of charged particle
such that it does not perturb the electron fluence (i.e. does beams, the fluence of particles may vary with depth and
not introduce changes to the energy spectrum or numbers the introduction of the chamber may cause perturbations
of electrons), then the fluence of electrons in the air is the to this fluence. In measurement of photon beams, the wall
same as in the medium and the cavity is termed a Bragg- of the chamber may be insufficient to stop electrons from
Gray cavity. Under these conditions, the energy per unit outside it reaching the air volume, and the wall of the
mass (absorbed dose) imparted to the air (Da) is given by: chamber differs from the medium in its attenuation and
Da Ja W scattering of photons. Energy dependent correction factors
where Ja is the ionization produced per unit mass of air, W is need to be applied to the above to adjust for these effects.
the average energy lost by the electrons per ion pair formed in
the air. If the air is now to be replaced by medium, the energy
per unit mass imparted to the medium (Dm) would equal Dose determination based on
the absorbed dose to air multiplied by the electron mass stop- calibrated instruments
ping power for the medium divided by that for air (S/r)ma
(averaged over the energy spectrum of the electrons), i.e.: The above correction factors are not necessary when ioniza-
tion chambers are used solely as instruments which are cali-
Dm Ja WS=rm a brated in terms of absorbed dose to water against a suitable
This is the basic equation governing the use of ionization primary standard where their effects are taken into account
chambers in the dosimetry of electron beams. For other as an intrinsic part of the calibration process. They are
charged particle beams, the stopping power ratio for those required where calibration is in terms of air kerma. Such
particles must be used. calibrations are by a series of intercomparisons that are
39
Walter and Millers Textbook of Radiotherapy
traceable directly to the national standard instruments of beam energies and to remain consistent in response
described above. The absorbed dose is determined using between recalibrations by the Standards Laboratories
an instrument calibrated in terms of absorbed dose to (i.e. 3 years). They must be fully transportable so that they
water (the UK standard for megavoltage photon beams) can be used to transfer calibrations to other instruments in
is given by: beams from different treatment machines, or even across
D R:ND different hospital sites. These chambers maintain an accu-
racy of calibration around 1%. Guidelines covering second-
where D is the dose, R is the mean corrected reading and ND
ary standards instruments have been published [5].
is the absorbed dose calibration factor.
Field instruments are used in daily measurements within
For kV energy photons in the UK, the chamber calibra-
hospitals. Different types of instrument exist, depending
tion (Nk) is in terms of air kerma. A factor, [(men/r)wair],
upon the nature of those measurements. Thimble chambers,
the ratio of mass energy absorption coefficients for water
described in detail in the following section, are generally
and air, needs to be included to calculate the dose to water,
used for calibration of megavoltage photon beams. Cham-
and a perturbation factor (k) as described above needs to be
bers based upon the design of the Farmer chamber [10] fea-
applied. The equation becomes:
ture an air cavity of about 0.6 ml, providing a reasonable
D R:Nk: k: men =rwair balance between the response to radiation and smallness
The nature and magnitude of the correction factor k depends of size, are adequate for measurements in relatively uniform
on whether calibration is carried out in air (for low energy radiation beams with an accuracy of 12%. Chambers which
x-rays) or in water. Similar expressions may be derived for have much smaller internal dimensions are used to measure
other modalities of radiation. variations in dose distributions, which can be very rapid at
beam edges. Here, chambers of 0.1 ml or less may be used,
with a trade-off between accuracy of response and spatial
Requirements for practical ionization resolution. Where there is a rapid variation in dose deposi-
ted with depth, such as for measurements in the build-up
chambers
region of photon beams or in the fall-off region of electron
Radiation dosimeters based upon ionization chambers beams, parallel plate chambers are used to ensure good
have two basic components: the detector chamber which depth resolution for the measurements.
produces electrical charge when irradiated and an asso- Both thimble ionizations chambers and parallel plate
ciated electrometer, which is an electronic amplifier to ionization chambers are used widely for routine beam cali-
which the chamber is connected which is designed specifi- bration and radiation distribution measurements. Other
cally for the purpose of measuring charge. The response of types of detector systems are useful in particular circum-
the dosimeter represents the response of the chamber to stances and may be used as alternatives to ionization cham-
radiation together with the accuracy and consistency of bers. In particular, in vivo measurements use systems which
the electrometer in measuring the charge. do not require the application of polarizing voltages,
Practical instrumentation needs to have a well-determined thereby reducing electrical risks to the patient. These
and predictable, slowly varying response to different ener- various forms of radiation detectors are described within
gies of radiation, and must be consistent over time. the following sections. Some forms, such as thermolumi-
In addition, other dosimeter requirements are necessary nescent dosimeters (TLD) have no definitive, maintained
depending upon type of radiation and the nature of the calibration and are suitable only for comparative measure-
measurement being carried out. ments of a radiation dose against a known radiation
Dosimeter chambers used within Standards Laboratories dose, while other forms (e.g. ionization chambers) do
are specially constructed or selected. Materials used in their maintain a definitive calibration and can be used as
construction are fully investigated to determine chemical absolute dosimeters.
content and each chamber is meticulously assessed in terms
of its assembly and response to radiation. Electronic equip-
ment used to measure the electrical charge is equally care-
fully designed, constructed and calibrated. The prime THIMBLE IONIZATION CHAMBER
requirements here are the elimination of sources of inaccu-
racy in response and the consistency of that response. A thimble chamber is an ionization chamber that has a cen-
The overall accuracy of calibration of these instruments tral electrode (the collector electrode) in a volume of air
depends upon uncertainties in fundamental parameters that is contained by a thimble-shaped cap which forms
being measured and to the extent that systematic uncertain- the HT electrode which fits closely onto a metallic stem.
ties can be avoided. Overall consistency of calibration is The central electrode passes through the inside of the stem
between 0.5 and 1%. and is insulated from the metallic stem by a suitable high-
Secondary standard instruments are constructed to less quality insulator material such as amber or polythene. This
stringent standards, but are required to operate over a range is schematically shown in Figure 3.5. The cap is generally
40
Chapter |3| Radiation detection and measurement
Air volume Aluminium stem chamber [10] have a wall thickness of about 1 mm. This
is sufficient to produce electronic equilibrium for photons
Guard ring generated at kV energies, but is insufficient for megavoltage
Polarizing HT energies when an additional tight-fitting build-up cap is
needed to increase the effective wall thickness. This is par-
ticularly important when measurements are made in a
phantom constructed from material that differs markedly
To electrometer from the wall material.
The calibration factor of a thimble chamber varies
Thimble Central Insulator with photon energy. This calibration corrects for wall atten-
cap electrode uation, differences in the mass attenuation coefficient
between the wall material and water, and perturbations
Figure 3.5 Thimble ionization chamber. Ionization produced
to the photon beam caused when the chamber (and its
within the air volume in the thimble cap is collected by the
associated build-up cap, where applicable) are inserted into
central electrode. The aluminium stem transmits the polarizing
voltage to the thimble cap. The guard ring minimizes charge a water phantom, thereby displacing water. A typical cali-
leakage between the outer (HT) and the inner (signal) elements bration curve for such an instrument in terms of air kerma
of the interconnecting cable. A thimble chamber of the Farmer for photon beams of kV energies is shown in Figure 3.6. The
type has the chamber linked to the outside via a venting aperture calibration factor rises sharply at low photon energies
(not shown). which limits the lowest energy to which this type of instru-
ment may be used, as small variations in photon energy
made of a low atomic number low-density material such as spectrum for low energy beams can give rise to considerable
graphite, although various plastic materials have been used uncertainties in calibration factor.
where the plastic has been manufactured to be conductive The effective point of measurement for the instrument is
(e.g. Shonka plastic: [11]) or has been coated with graphite taken within UK protocols for photon beam calibrations as
to be conductive. The central electrode may be made of alu- the chamber centre. The effective point of measurement is
minium or conductive plastic. forward of the chamber centre for calibration of electron
A potential difference (the polarizing voltage) applied beams. Some international photon calibration protocols
between the outer cap and the inner electrode drives apart are derived for the effective point of measurement being
any ion pairs produced in the trapped air and prevents ion displaced from the chamber centre.
recombination, but which is insufficiently large to cause ion- Ionization of the air volume within the cap of a thimble
ization of the air itself so that in the absence of ionizing radi- chamber results in a flow of charge onto the collecting
ation no current flows. A voltage gradient of a few hundred electrode. The rate of flow of charge will depend upon
volts per millimetre is generally sufficient for this purpose. the mass of air within the cavity and on the radiation beam
In the presence of ionizing radiation, ionization within the intensity. A balance must be made between the physical
air results in the ion pairs being separated, and with the ions size of the chamber and on the ability to measure the
of one sign (depending upon the polarity of the polarizing charge with sufficient accuracy. Chambers with large air
voltage) being collected on the central electrode. The elec- volumes (2002000 ml) must be used to measure the very
trometer is generally floating, in that the input to it can low dose rates associated with radiation protection mea-
be at any voltage level with respect to ground without this surements. Chambers with volumes of 1060 ml are
affecting the reading. In use, the aluminium stem is held at
ground potential and the electrometer is floated to the level Nk
of the polarizing voltage, so that exposed conductive parts
carry no electrical risk to operators. This arrangement allows 1.15
easy reversal of polarizing voltage as required.
When the chamber is introduced into a photon beam, 1.10
photo-electric and Compton interactions in the walls of
the chamber generate electrons that traverse the air cavity, 1.05
causing ionization of the air. The wall of the thimble must
be sufficiently thick to ensure that all the electrons crossing
the air cavity originate in the wall and not in the surround- 1.0 Beam
ing material. The wall must therefore be at least as thick as 0.01 0.1 1.0 energy
the range of the electrons produced by the photon interac- mm Cu HVL
tions. However, the wall of the chamber will also attenuate Figure 3.6 Typical variation in air-kerma calibration versus
the photon beam and this attenuation will need to be taken beam energy for a thimble chamber for photon beam energies
into account. If the wall is thick, the attenuation will be within the kV range expressed in terms of their half-value layer
large. Practical ionization chambers such as the Farmer (see Chapter 2).
41
Walter and Millers Textbook of Radiotherapy
1-2 mm
Measurement of dose and dose rate Air volume
While the thimble chamber described above is suitable for THE BEAM MONITOR CHAMBER
many dosimetry situations, there are circumstances that
require alternative chamber designs: Linear accelerators and higher energy kV x-ray units have
1. for the measurement of low energy photons, the wall of inbuilt ionization chambers to monitor and control the
a thimble chamber causes too much attenuation such amount of radiation being emitted. For these units, the
that the calibration factor is large and varies rapidly amount of radiation emitted is specified in terms of monitor
with energy. This may lead to considerable units, i.e. by the quantity of radiation measured by the in-
uncertainties in measurement of dose built monitor chamber. The sensitivity of these monitor
2. the wall of a thimble chamber will also produce too chambers must be adjusted to give the correct amount of
much build up for dose measurements close to the radiation dose per monitor unit a process known as
surface for megavoltage radiation calibration.
3. in measurement of electron beams, the cylindrical air Monitor chambers are forms of parallel plate ionization
volume of a thimble chamber causes significant chamber that sample the entire radiation beam emitted
perturbation of the beam that must be corrected for. from the treatment unit. In linear accelerators, each
42
Chapter |3| Radiation detection and measurement
43
Walter and Millers Textbook of Radiotherapy
44
Chapter |3| Radiation detection and measurement
always potential for the seal to fail, allowing some flow of subtract from the ionization charge being collected,
air between the chamber and the environment. If a cham- depending upon the charge on the particle and on the
ber is unsealed, allowing free passage of air between the direction of the polarizing voltage (whether the collector
inside of the thimble and the general environment, then electrode is collecting positive ions or electrons). The effect
the mass of air within the thimble will fluctuate with atmo- is particularly important when using parallel plate cham-
spheric temperature and pressure and a correction to any bers to measure proton or electron beams, and can be over-
reading will be required to compensate for these changes. come by averaging measurements taken with both positive
As the temperature increases, so the air density falls and and negative polarizing voltage.
the mass of air within the thimble will reduce thereby A related problem is that, if measurements are carried out
reducing the chamber sensitivity. As atmospheric pressure in a solid insulating material such as polystyrene, then par-
rises, so too the density of air increases, increasing the mass ticles stopped within the material will result in a build up of
of gas within the thimble, thereby increasing the chamber charge there which will perturb the radiation beam being
sensitivity. If the assumption is made that air affected by measured. To avoid this, an insulating phantom should
temperature and pressure changes in the same way as an be made of thin sheets of material which allows charge
ideal gas, then the ideal gas laws can be applied to deter- built up in this way to leak away.
mine the magnitude of variation in response. If measure-
ments are made at a temperature of T Celsius ( C) and a
pressure of P kilopascal (kPa) using an unsealed instru- ALTERNATIVE DOSE MEASUREMENT
ment, the response may be corrected to what it would have
been at a standard temperature of 20 C (293 K) and pres-
SYSTEMS
sure of 101.25 kPa by applying the correction factor:
Correction 101:25=P T 273=293 In the sections above, the primary processes for detection
of radiation and measurement of dose centred around
Most practical field instruments are designed and con- calorimetry and ionization of air. National standard and
structed to be unsealed. The design of such an instrument secondary standard instruments are based on these pro-
has to ensure that the thimble does not distort with changes cesses, and field instruments of the thimble or parallel-plate
in temperature or pressure so that the volume remains con- chamber design are recommended for routine measurement
stant. Water vapour can affect the chamber response and of radiation output from therapy machines. There are, how-
the above correction for atmospheric conditions, produc- ever, other techniques that are suitable for measurement
ing a variation of about 0.7% for change in relative humid- of dose or dose rate for different circumstances. These are
ity from 10% to 90%. To minimize the impact of relative briefly described below and a selection of such devices repre-
humidity changes, the secondary standard calibration fac- sented schematically in Figure 3.13.
tor is specified for a humidity value of 50%: variations in
chamber response in normal use due to relative humidity
changes may generally be ignored. Film dosimetry
Film has been used as a system for measuring radiation
Chamber stem effect throughout the whole history of radiotherapy. It is particu-
If the stem of the ionization chamber is within the radia- larly useful for measurement of radiation distributions,
tion field, it may perturb the radiation beam and may gen- having applications in phantom measurement of simple
erate scatter into the air volume of the chamber, thereby and complex radiation beams, in verification of field place-
affecting the reading (termed the stem effect). ments on individual patients, in establishing geometrical
During absolute calibration, the chamber is irradiated accuracy of light beams that delineate radiation beams,
with a specific field size and a correction is applied for and in determination of leakage patterns around the head
the stem effect with this field size. It is therefore taken into of a treatment unit.
account whenever the calibration factor is applied. There is, Film consists essentially of a transparent polyester mate-
however, potential for the effect to increase or decrease for rial (the base) on which is deposited a layer of silver bromide
other field sizes. trapped in a gel (the emulsion). The emulsion may be
With well-designed ionization chambers, such as the deposited on one side or on both sides of the base. The
Farmer chamber, the stem effect is small and variations emulsion is sensitive to light and so must be used in a
in it can generally be ignored. light-tight packaging or housing. The silver bromine is in
the form of small crystals, each crystal being formed as a
lattice of negative bromine and positive silver ions. When
Polarity effect
irradiated, some lattice bonds are broken and electrons
When an ionization chamber is used to measure charged are transferred from the bromine to the silver ions, neutraliz-
particles, some of the charged particles may come to rest ing those atoms. The presence of neutral silver atoms at key
on the collecting electrode. These will either add to or positions of the lattice within a crystal makes the whole
45
Walter and Millers Textbook of Radiotherapy
Conduction band
Conduction band Conduction band
Conduction band
Forbidden zone
Energy
A B C D
Figure 3.10 Simplified energy level diagram for materials: the shaded regions shows those levels that are normally occupied
by electrons for (A) an insulator; (B) a conductor; (C) a semiconductor (undoped); (D) material with impurity levels within the
forbidden zone.
46
Chapter |3| Radiation detection and measurement
The outermost energy bands within the solid material (e.g. arsenic, selenium) that introduces free electrons into
are termed the valence band and the conduction band. the conduction band. p-type material is doped by an elec-
Electrons within the valence band are considered as linked tron acceptor (e.g. aluminium, gallium) that effectively
to the chemical bonds between individual atoms and are introduces additional vacant levels into the valence band.
therefore bound in place, although the term bound is used These unfilled levels are termed holes. If electrons are intro-
loosely as at normal temperatures such bonds may be con- duced into p-type material, they will fill vacant holes and
tinually being broken and reformed. At an energy level become trapped.
slightly above the valence band is the conduction band.
Electrons within this band are surplus to any requirements
for chemical bonding. At normal temperatures, these elec-
Diode detectors
trons are not associated with specific atoms and chemical When adjacent p-type and n-type doping occurs in a single
bonds, but migrate readily through the material. In some crystal of silicon, a pn junction is formed. Conduction
materials, there are insufficient electrons to fill the available electrons in the n-type region will diffuse into the p-type
energy levels of the valence band, such that the conduc- region and become trapped, as shown in Figure 3.11. This
tion band is empty. Where a large forbidden zone exists, results in:
these materials are classed as non-conductors or insulators
the region around the interface being devoid of free
(see Figure 3.10A). Other materials may have more outer
electrons and unfilled holes. This region is called the
electrons than the valence band can accommodate, such
depletion layer
that the lower levels of the conduction band are also occu-
a transfer of electrons (and hence charge) from the
pied. In these materials, the conduction band overlaps n-type to the p-type side of the interface. This transfer of
with the valence band and the forbidden zone disappears,
charge generates a small potential difference across the
as shown in Figure 3.10B. These materials will generally be depletion layer.
good conductors of electricity. There are some materials in
which the valence band is just filled, but the conduc- When this depletion layer is irradiated, electrons are
tion band is effectively empty, and a small but significant released by ionization creating electron-hole pairs as
forbidden zone exists. These materials are classed as semi- shown in Figure 3.11C. These drift in opposite directions
conductors, illustrated in Figure 3.10C. Any charges under the influence of the potential difference across the
injected into a semiconductor will be free to travel through depletion layer. Electrons will be drawn towards the n-type
the material. It is to be stressed that this description is material while holes will be drawn towards the p-type,
overly simplistic but serves as a basis for understanding causing charge to flow through the circuit in which the
the principles of solid-state dosimeters.
47
Walter and Millers Textbook of Radiotherapy
MOS-FET detectors
The source and drain regions may be considered as pn
The structure of a MOS-FET is shown schematically in junctions which are linked by the SiO2 channel onto which
Figure 3.12 which illustrates a device based upon p-doped the gate is deposited.
silicon substrate material onto which layers of heavily The device operates essentially like a voltage-controlled
n-doped material and SiO2 are formed. There are three elec- switch. If a small voltage is generated between the source
trical contacts, which are termed the source, gate and drain. and the gate with the drain held at the same potential as
48
Chapter |3| Radiation detection and measurement
the gate, then no current flows initially between source and are low atomic number devices with electron stopping
drain until the applied voltage exceeds a specific value power values similar to those for water [24].
(called the threshold voltage), whereupon the device
switches and a current starts to flow. The application of Summary of direct reading radiation
the applied voltage causes holes to be drawn to the
oxide/silicon surface from both the substrate and from
detectors
the source and drain regions. A conduction channel Various types of radiation detectors have been described in
between source and drain is formed once the concentration the previous sections. Each type of detector has particular
of holes becomes sufficient. applications for which it is ideally suited. Cylindrical ionisa-
When the device is irradiated, electron-hole pairs are gen- tion chambers (Figure 3.13A) are particularly useful as instru-
erated within the SiO2. The mobility of the electrons allows ments for calibration of megavoltage photon beams. Parallel
them readily to migrate away, while the holes become plate ionisation chambers (Figure 3.13B) are useful when
trapped at the oxide/silicone surface. These traps, which measuring in regions of high dose gradient, such as in the dose
can survive for a long time, reduce the threshold voltage fall-off region of an electron beam. Diodes (Figure 3.13C) are
necessary for the device to switch. The change in threshold useful for in vivo dosimetry. The small size of their detection
voltage is almost linearly related to the radiation dose region makes these devices also useful when measuring in
received by the device. small radiation fields or within beam penumbral regions.
MOS-FET devices are extremely small (<0.1 mm) and Cylindrical forms of these dectectors which include correc-
are easily fabricated in various shapes and geometries tions within the design of the device for enhanced low energy
such that individual detectors can be used for point doses photon response are readily available. Diamond detectors
or planar distributions of detectors to measure complex (Figure 3.13D) may be used as an alternative to diode detec-
dose profiles. No electrical connections are necessary dur- tors and are especially resistant to radiation damage.
ing irradiation and the electronic equipment needed for
readout is relatively simple, making these devices ideally
Thermoluminescent dosimetry (TLD)
suited to in vivo dosimetry. They do, however, suffer from
the same energy response effects as diode detectors. We have seen in the section on the band structure of solids
that some materials have a normally empty conduction
band. When such a material is irradiated, some electrons
Diamond detector
within the valence band may be given sufficient energy to
Carbon in the form of diamond is an intrinsic semiconduc- excite them into the conduction band, leaving a hole in
tor with a large energy gap between the conduction and the valence band. These electrons will eventually lose their
valence bands (5.5 eV). At normal room temperatures, extra energy and fall back to the valence band to fill the vacant
there are very few electrons in the conduction band. If a energy level (hole) there. In doing this, the electron has to
voltage is placed across a diamond crystal, a tiny current lose the energy difference between the two energy levels.
will flow because of these electrons, the magnitude of The energy lost in this transition may be a few electron-
which is dependent for any given crystal on the applied volts. In some materials, this energy loss is in the form of
voltage. The diamond therefore behaves as a resistor. emission of electromagnetic radiation, akin to the emission
When irradiated, ion pairs generated within the material of characteristic x-rays from an x-ray target but at much
increase the number of carriers, and so the resistance falls. lower energies. This process appears simple, but may actu-
The radiation-induced current increases with increasing ally involve complex energy level changes for both the elec-
dose rate. Certain impurities within the diamond can tron and the hole that are beyond the scope of this book.
improve the linearity of response between current and dose The result for some types of material is that it is transparent
rate, but the doserate response has to be taken into to the electromagnetic radiation released by these transi-
account when using these devices. tions, which is then emitted. The energy of the radiation
A diamond detector consists of a diamond crystal onto emitted may be within the visible spectrum in which case
which metal contacts have been deposited and to which the irradiated material emits light. Materials of this type
a voltage of about 100 V is applied. The radiation-induced are said to be luminescent in general. When the electrons
current is considerably larger than the natural current and excited into the conduction band fall back and emit light
so can be measured with precision. Under these conditions, immediately, the material is said to be fluorescent. Fluores-
the response is largely independent of temperature. The cent screens are used to enhance the response of x-ray
detector is not readily damaged by radiation so the device film to radiation and are used within some types of portal
has a long operational life. Diamonds may be selected nat- imaging devices. In luminescent processes, additional
ural diamonds or grown using chemical vapor deposition energy levels within the forbidden zone as shown in
processes. They are small detectors and so are useful in Figure 3.10D, formed either from impurities or as a result
measuring in high radiation gradients, with good angular of discontinuities in the crystal structure, play a part both
response characteristics. Being comprised of carbon, they in trapping the excited electrons and in the emission of light.
49
Walter and Millers Textbook of Radiotherapy
IV
Trap
levels
0.5 III
Valence band Valence band
II
I VI
A B
50
Chapter |3| Radiation detection and measurement
the radiation history of the material radiation- In some materials, the altered chemical make-up remains
induced damage may alter the energy band structure of and can be detected. Where the effect is stable and propor-
the material tional to dose, this may be used in chemical and biochemi-
the surface condition of the crystalline material marks cal dosimetry. If the chemical yield is known (number of
and scratches attenuate and scatter the light chemical molecules formed per unit of energy absorbed)
the detailed nature of the readout cycle. then chemical dosimetry could be used as a primary stan-
Some of the above cause differences in response between dard. Fricke dosimetry was used for a short period in the
different dosimeters, while others cause differences in past in this way to provide a definitive calibration of elec-
response of a single dosimeter from use to use. In addition, tron beams for which the yield was well established.
the response is not strictly linear with dose but increases
with increased dose, a feature known as supralinearity. Fricke dosimetry
TLD is not used as an absolute dosimeter (i.e. where the cal-
ibration is stable and constant). To address these issues, Fricke dosimetry is based upon conversion of ferrous
TLD dosimeters are used in batches, where the dosimeters sulfate ions (Fe2) to ferric ions in a weak sulfuric acid solu-
in each batch have the same handling and general history tion [26]. The concentration of ferric sulfate is determined
and where some are selected as measuring dosimeters while by measuring the attenuation of light passing through
others are irradiated to known doses in order to calibrate the solution. Light of a particular wavelength (304 nm) is
the batch response in a traceable manner. used as this is attenuated differentially by ferrous and ferric
Lithium fluoride is the most commonly used TLD mate- ions. The instrument used for accurate measurement of
rial and is available in various forms that include: powder; attenuation at a particular frequency of light is a spectro-
single crystal chips (size 4 mm4 mm1 mm approxi- photometer. The ferrous sulfate solution has to be carefully
mately) and rods (size 6 mm long by 1 mm diameter); sin- prepared and handled to avoid chemical contaminants that
tered chips, disks and rods; and Teflon embedded disks and can affect the result.
rods. The effective atomic number is slightly greater than The dose is given by:
that of water leading to over-response of between 1.3 D kDA=e d r G Fe3
and 1.7 for photon energies of less than 100 KeV, but the where k is a constant, A is the change in absorption (opti-
response is virtually uniform for megavoltage radiation. cal density), d is the optical path length, r is the Fricke
The detector response does not vary with dose rate up to density, e the difference in molar extinction coefficient,
dose rates of greater than 106 Gy/min. Other materials and G(Fe3) is the chemical yield.
are available, including lithium borate which has a more This system is not very sensitive such that doses of greater
uniform energy response at low energies, and calcium sul- than 10 Gy are required to produce sufficient concentra-
fate which has a high sensitivity to low energy photons. tion of ferric ions, but accuracies of better than 2% are read-
TLD materials are currently used as in vivo dosimeters for ily achievable. The process is effectively insensitive to dose
both surface dose and interstitial measurements. For mea- rate and can be used to determine doses up to 400 Gy. The
surements on the patient surface in order to estimate the detector is 96% water and is therefore essentially water
dose at the depth of dose maximum, care must be taken equivalent. It can be used over a wide range of energies
to ensure that appropriate build-up is used, both for the and modalities. Fricke dosimetry has been used in the past
patient measurement and also for calibration irradiation. by Standards Laboratories to confirm measurements of
Despite the variations in response described above, TLD absorbed dose using other dosimetric techniques.
is used to provide a traceable postal calibration service both
to centres without access to a primary or secondary Stan-
dards Laboratory and to check on the accuracy of calibra- Ceric dosimetry
tion across various centres as part of clinical trial quality
Similar to Fricke dosimetry above, ceric dosimetry relies of
control procedures.
the reduction by radiation of ceric ions (Ce4) to cerous
ions (Ce3) in a mixture of ceric and cerous ions in
0.4 M sulfuric acid. The concentration of cerous ions is
Chemical and biochemical detectors determined by spectrophotometry using 320 nm light.
Energy deposited in matter may be manifest ultimately in var-
ious forms, one being altered chemistry, as indicated in
Gel dosimetry
Figure 3.1. Radiotherapy relies upon this to a large extent in
the process of damaging and destroying tissue cells. In some The techniques described previously are suitable for pro-
cells, direct interaction of the radiation with DNA causes irrep- ducing single point measurements of dose (e.g. ionization
arable damage leading to death of those cells. In others, radi- chambers) or measurements of two-dimensional distribu-
ation-induced chemical changes within the cells produce tions (e.g. film). In contrast to these, gel dosimeters allow
active free radicals that cause similar damage to DNA. measurement of three-dimensional distributions. These are
51
Walter and Millers Textbook of Radiotherapy
ideally suited to determination of distributions arising using an optical CT device, as radiation induces white
from complex treatments such as intensity modulated opacity in an otherwise transparent material. Because
radiotherapy (IMRT). In addition, gel dosimetry is proving cross-linkage of monomers stabilizes the material, there
useful in situations where other forms of measurement are is no migration away from irradiated areas, such that these
difficult, such as in dosimetry of very small radiation fields devices are stable over time.
(e.g. stereotactic radiotherapy and proton beams) and mea- BANG gels have to be produced and sealed while under a
surements around brachytherapy sources where the radia- nitrogen atmosphere to avoid oxygen-induced polymeriza-
tion dose varies rapidly with position relative to the source. tion affecting the results. This necessity has been removed
Phantoms to hold the gel material can be made to reflect in newer gel formulations (e.g. MAGIC) in which oxygen in
anatomical shapes. the gel is bound into a chemical matrix which prevents it
There are currently two forms of gel detectors in use, from causing polymerization, making the production of
Fricke gel and polymer gel. For each, various ways of gels for dosimetry far simpler [32].
reading out the signal have been developed, the most com-
mon of which are magnetic resonance and optical com-
Alanine-EPR dosimetry
puted tomography (CT). Gel detectors in general are
insensitive to dose rates, are effectively water equivalent, Alanine is a polycrystalline amino acid (chemical formula
and the signal is relatively linear with dose. Overall accu- CH3CH(NH2)COOH). When irradiated, stable free radi-
racy is limited (typically around 5%), although spatial cals are formed within the material. These radicals can exist
resolution is excellent. unchanged for long periods of time, allowing separation of
irradiation from the readout process [33]. Some of these
free radicals have a single unpaired electron attached to
Fricke gels and FXG gels one of the atoms of the radical. The single unpaired elec-
In 1984, Gore proposed the use of magnetic resonance tron exists in one of two energy states. When subjected to
(MR) techniques on Fricke solutions [27] and Fricke- a magnetic field, these energy states equate to spin parallel
infused gels in which ferrous ions are held within the gel and spin anti-parallel states, the difference in energy
matrix. When reduced by radiation to ferric ions, the between them being proportional to the strength of the
spinspin (T2) relaxation times of linked protein atoms magnetic field.
changes. This change in relaxation times in each small The electron normally occupies the lower state, but may
volume of the material can be measured using a magnetic be excited into the higher state by absorbing a specific res-
resonance scanner. Each measurement is accompanied by a onant wavelength of electromagnetic radiation of photon
test irradiation that is used to determine the sensitivity of energy (hu) equal to the energy separation between the
each detector batch to different dose levels. two states, for magnetic field strengths of 300 mT the fre-
Although able to produce accurate dose distributions, quency of about 9 MH, which is within the microwave part
the process has two main drawbacks. First, measurement of the electromagnetic spectrum. The concentration of free
is time-consuming and requires ready access to an MR scan- radicals can be assessed by measuring the degree of absorp-
ner. Secondly, the ferric ions migrate through the gel matrix tion of this resonant radiation, a process know as electron
with time, so that measurements have to be undertaken paramagnetic resonance (EPR or traditionally electron
shortly after irradiation [28]. spin resonance, ESR) [34]. A number of free radicals are
A development of this technique led to the introduction involved, the most important one involving the loss of
of Xylenol Orange into the gel mix [29]. This material is the NH2 group.
photochromic and has the property of changing colour Dosimeters are formed by mixing known quantities of
from orange to purple when the mix is irradiated. This alanine with one or more binding agents to produce a com-
change in colour can be determined by measuring optical pact, solid detector which has both density and atomic
attenuation of filtered light. A set of two-dimensional slice number values that differ only slightly from water and
readouts can be obtained using an optical CT device. which is suitably sensitive to radiation. The dose response
is almost linear from 10 Gy to 104 Gy and is largely inde-
pendent of dose rate. Lower doses down to below 1 Gy
Polymer gels can be measured provided that the device is calibrated to
Polymer gels are based upon the polymerization of mono- account for non-linearity of response at these dose levels.
mers embedded in the gel matrix which produces long Accuracies of better than 2% are achievable under con-
polymer chains and cross-linkage of polymers [30]. These trolled conditions. The combination of accuracy and stabil-
reduce the T2 relaxation time which can be determined ity has led to their being used by a number of Standards
using a magnetic resonance scanner. A common polymer Laboratories as a basis for a remote calibration service
gel in current use is the BANG gel of Maryanski [31] which which rivals the use of thermoluminescent dosimetry. Ala-
is based upon polymerization of the monomer acrylamide. nine dosimetry systems are also available commercially.
This may be produced in forms that allow optical readout A number of research groups are currently investigating
52
Chapter |3| Radiation detection and measurement
53
Walter and Millers Textbook of Radiotherapy
ve
+ Thin anode
(i)
Pulse size or current (log scale)
wire at high
(ii) +ve potential
(iii)
Metal cathode
+ve at ground
potential
(i) Radiation ionizes the gas
producing an initial ion pair.
Low pressure
The electron is accelerated
gas filling
towards the +ve electrode.
Gas container
(ii) The electron causes further
ionization, producing further
A B C D E F electron which are accelerated.
54
Chapter |3| Radiation detection and measurement
between different types of radiation. Further, the dead time scintillator crystal. Thus, a 300 keV gamma ray will, on
has implications for use in high intensity or pulsed radia- average, produce a pulse that is twice as large as that pro-
tion fields. As the radiation intensity increases, so the rate duced by a 150 keV gamma ray provided that in both cases
of events increases and the chance of missing pulses the total energy of the gamma ray is absorbed in the
because of the extended dead time increases, resulting in crystal.
under-recording. Similarly, in the pulsed radiation field A pulse-height analyzer is a device that has a number
of a linear accelerator where the pulse lengths are less than of counters each representing one channel. Each channel
the dead time of the detector, the most that a Geiger counts the pulses that occur only with a narrow band of
counter will record will be one count per pulse, regardless pulse heights. Successive channels are set to count increas-
of the actual radiation intensity. Hence, Geiger counters ingly larger pulses. Hence, small pulses will appear in the
cannot be used to measure the intensity of a linear acceler- lower channels and large pulses will be counted in higher
ator beam and great care must be exercised when using channels. When a scintillation detector is connected to a
them to monitor radiation levels around a linear accelera- pulse-height analyzer, the spectrum of counts produced
tor installation. represents the spectrum of energies deposited in the scin-
The pulse height from a Geiger counter varies only slowly tillator crystal. When measuring monoenergetic radiation
with increasing voltage, as shown in Figure 3.17, making (such as gamma rays from a gamma source), those inter-
the device relatively insensitive to small changes. At higher action events that result in all the photon energy being
voltages, however, the electric field strength can be suffi- absorbed in the crystal will have similar pulse heights
cient in itself to ionize the gas, resulting in continued elec- and will be counted together in a narrow series of chan-
trical discharge, or breakdown. nels that represent this photon energy level. Interactions
that result in less energy being deposited in the crystal
(such as detection of Compton-scattered photons) will
Scintillation devices
be counted in the wide range of channels below the
Some materials, such as thallium-doped sodium iodide, photopeak channels, as shown in Figure 3.19. Since the
are known as scintillator materials which are a form of positions of peaks in the spectrum represent specific
fluorescent material described earlier that emit light when energy levels, scintillation counters are able to differenti-
irradiated. Scintillator materials are transparent to the ate between different energies of incident photons.
light emitted, and so photon interactions cause short By matching measured energy levels and their rates of
flashes of light in the material. The amount of light decay against tabulated energies of emissions and half-
emitted is proportional to the energy deposited in the lives of known radioactive materials, specific radioactive
crystal. These short flashes of light can be detected by a substances can be identified in any given sample. This pro-
photomultiplier tube a device that converts very low cess is called gamma spectroscopy. This process also under-
levels of light into measurable electrical pulses. Sodium lies the principles of operation of the gamma camera used
iodide is hygroscopic and is housed within a container in nuclear medicine.
that encompasses the material, prevents ingress of water
vapour and reflects light back into the crystal the inner
surface of the container being covered in a reflective coat-
ing of titanium dioxide or magnesium oxide. One surface
Count rate per channel
55
Walter and Millers Textbook of Radiotherapy
The pulse from a sodium iodide/photomultiplier detector Small plastic scintillators connected to distant pho-
has a pulse length of a few microseconds. Additional signals tomultiplier tubes via long fibre-optic light guides have
that occur within this time period combine together and been used to measure dose distributions in radiotherapy
appear as an enlarged signal. These will fall outside the main [41]. The high sensitivity of the device allows use of
photopeak channels. The chance of two interactions occur- tiny detectors that are of particular use in the measurement
ring within the short time period will increase as the overall of rapidly varying intensities, such as in the penumbra of
count rate increases, i.e. where the radiation is more intense, megavoltage beams or in the measurement of distributions
resulting in an underestimate of the true radiation intensity. from radioactive eye plaques [42]. More recently, tomo-
Some plastic scintillators can have much shorter pulse graphic reconstruction techniques have been applied to
lengths and can be constructed with large surface areas. These the optical signals from liquid scintillators to reconstruct
can be used to measure higher radiation intensities or to full three-dimensional dose distribution maps around
detect and measure radiation distributed over a large area. brachytherapy sources and eye plaques [43].
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and Measurement; 1980. dosimetry. National Physical 25MeV based on an absorbed dose
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[7] Rosser KE, Owen B, DuSautoy AR, potential. Phys Med Biol [22] Shi J, Simon WE, Ding L, Saini D.
Pritchard DH, Stoker I, Brend CJ. 2005;50:273948. Important issues regarding diode
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Chapter |3| Radiation detection and measurement
diodes. Phys Med Biol [32] Fong PM, Keil DC, Does MD, [41] Beddar AS, Mackie TR, Attix FH.
1983;28:12617. Gore JC. Polymer gels for magnetic Water-equivalent plastic
[24] Khrunov VS, Martynov SS, resonance imaging of radiation dose scintillation detectors for high-
Vatnitsky SM, et al. Diamond distributions at normal room energy beam dosimetry: 1. Physical
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photon, electron and proton 2001;46:310513. considerations. Phys Med Biol
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Dosimetry 1990;33:1557. Crawford GW, Spelzler HAW. The [42] Fluhs D, Heintz M, Indenkampen F,
[25] Kron T. Thermoluminescence use of alanine as solid dosimeter. Wieczorek C, Kolanoski H, Quast U.
dosimetry and its applications in Radiat Res 1962;17:11. Direct reading measurement of
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[29] Appleby A, Leghrouz A. Imaging of non-stochastic effect of very low purity 4 calorimeter for absorbed
radiation dose by visible colour dose whole body exposure, a dose determinations in high-energy
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1991;18:30912. 1982;41:13950. [47] Ross CK, Seuntjens JP, Klassen NV,
[30] Maryanski MJ, Gore JC, Kennan RP, [39] Bender MA, Awa AA, Brooks AL, Shortt KR. The NRC sealed water
Schulz RJ. NMR relaxation et al. Current status of cytogenetic calorimeter: correction factors and
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and cross-linked by ionizing previous exposures to radiation. Rosser KE, editors. Proc NPL
radiations: a new approach to 3D Mutat Res 1988;196:10359. Workshop on Recent Advances in
dosimetry by MRI. Magn Reson [40] Prosser JS, Lloyd DC, Edwards AA. Calorimetric Absorbed Dose
Imaging 1993;11:2538. A comparison of chromosomal and Standards. NPL Teddington; 2000.
[31] Maryanski MJ, Schuklz RJ, micronuclear methods for radiation p. 90102.
Ibbott GS, et al. Magnetic resonance accident dosimetry. In: [48] Willaims AJ, Rosser KE, Thomson NJ,
imaging of radiation dose Goldfinch EP, editors. Radiation DuSautoy AR. Recent advances in
distributions using polymer gel protection: theory and practice. water calorimetry at NPL. In: Proc
dosimeter. Phys Med Biol New York: Institute of Physics; 22nd Annual EMBS International
1994;39:143755. 1989. p. 1336. Conference. Chicago; 2000.
57
Intentionally left as blank
Chapter |4|
Radiation protection
Mike Dunn
Ionising radiation
Stochastic somatic effects
These effects are expressed in the exposed individual in the
Energy absorbed form of cancer induction. Again, cancer has a number of
causes, radiation being only one. About one in four of
the population is likely to have a cancer in their lifetime.
Ionisation and excitation Chemical changes
The probability of this being caused by radiation increases
Direct Indirect with dose. The current risk estimated by ICRP 60 [1] of a
cancer from radiation is one in 13 000 for a radiation dose
Biological changes of 1 mSv (see below). The extra cancer risk from very low
doses is extremely small and, in practice, undetectable in
the population. However, the extra cancer risk at higher
Hereditary effects Somatic effects doses may be detectable using statistical methods. Even
(Stochastic) (Stochastic)
after high dose exposure, it is rarely possible to be certain
that radiation was directly responsible for a cancer arising
Somatic effects in an individual. There are a number of scientific uncertain-
(Non-stochastic) ties in making these estimates of cancer risk at low doses.
In 2000, the highly respected United Nations Scientific Com-
Figure 4.1 Effects of radiation. mittee on the Effects of Atomic Radiation (UNSCEAR) [2]
60
Chapter |4| Radiation protection
61
Walter and Millers Textbook of Radiotherapy
BACKGROUND RADIATION
dramatically than others. To take this effect into account,
the ICRP have developed a list of tissue weighting factors,
denoted WT, for a number of organs and tissues that most We are all exposed to radiation, regardless of our occupa-
significantly contribute to an overall effective biological tion, from natural radiation sources in the environment
damage to the body. It should be noted that areas of the and from man-made sources. We have no control over
body with a high cell turnover are more radiosensitive than the level of exposure to these sources of natural radiation
areas with a slower cell turnover and thus have a larger other than by choosing a particular lifestyle. For example,
weighting factor. Table 4.3 presents values of the tissue- cosmic rays from outer space are attenuated by the Earths
atmosphere and the more atmosphere there is the more the
attenuation. This means that people who live at high alti-
tudes or travel in high flying aircraft will get a greater radi-
Table 4.3 WT values
ation dose from cosmic rays. Other sources of natural
radiation and the proportions that they contribute to the
TISSUE OR BODY PART WT overall dose are shown in Figure 4.3.
Gonads 0.20 The major sources of natural radiation are the radioactive
gases radon and thoron. Together they contribute over 50%
Bone marrow 0.12 of the average background radiation dose in the UK. These
gases are generated in granite rock and, as a consequence,
Colon 0.12 the intensity of the radon exposure varies considerably
Lung 0.12 around the world, being higher in areas were there is more
granite rock. In addition, if the rock is cracked the gas can
Stomach 0.12 escape into the environment more easily leading to higher
levels in the environment. Such a situation exists in Corn-
Bladder 0.05
wall where the level of radon gas is up to three times the
Breast 0.05 national average. This has consequences in terms of the
gas entering the homes of people living in these areas. Since
Liver 0.05 the trend is to insulate homes more rigorously, this can
have the effect of trapping the gas in the homes, leading
Oesophagus 0.05
to elevated doses to the inhabitants. Constructing well-ven-
Thyroid 0.05 tilated houses and incorporating a special membrane into
the foundation of new houses can alleviate this. Installing
Skin 0.01 extraction fans and increasing under floor ventilation may
improve older properties. These natural sources contribute
Bone surface 0.01
an average dose of about 2.3 mSv per annum to a member
Remainder (adrenals, brain, upper large intestine, 0.05 of the UK population.
small intestine, kidney, muscle, pancreas, spleen, Another 0.3 mSv per annum is contributed to by artificial
thymus, and uterus) or man-made sources, such as discharges from nuclear power
stations, making the average total dose 2.6 mSv. However,
Total 1.00 the biggest contribution is from the diagnostic uses of radia-
From [1]
tion where, although the individual doses are small, a large
number of x-rays are performed with, on average, every
62
Chapter |4| Radiation protection
Table 4.4 Effective dose from a chest x-ray with a skin entrance dose of 500 mGy
Stomach 5 25 25 0.12 3
On the basis of the above ICRP figure of 1 in 13000 cancer incidences per mSv, this implies an additional risk of 1 in 493358
63
Walter and Millers Textbook of Radiotherapy
64
Chapter |4| Radiation protection
of about 2 mSv and is the limit that the employer has to Comforters and carers
apply for the declared term of the pregnancy. As such, A special case is made in the regulations for members
the period of time for the dose limit to be exceeded starts of the public who are comforters and carers of patients
when the worker declares herself to be pregnant to her undergoing or who may have undergone a medical expo-
employer. Secondly, there are three groups of people with sure, e.g. a parent who holds a child while being x-rayed or
different dose limits, classified workers, unclassified work- a member of the family of a patient treated with radioac-
ers and members of the public. Classified workers are those tive material who is discharged from hospital with rela-
workers who, by virtue of the work they undertake, are tively large amounts of radioactive material still in their
likely to exceed the dose limits for unclassified workers. bodies. To fall into this category, the carer has knowingly
Before a worker can be classified, they are required to be and willingly to accept the risks in providing comfort and
declared fit to do so by an appointed doctor. This is a support to the patient. This means that the carer must be
registered medical practitioner who has been appointed provided with information about the risks by the hospital
in writing by the Health and Safety Executive (HSE). Once treating the patient. In this case, there are no specific dose
a worker has been classified, the employer is legally obliged limits for the carer, however, information should be given
to issue the worker with an individual radiation dosimeter to them regarding steps to be taken to control as far as rea-
and keep a cumulative dose record for 50 years of the last sonably practicable the dose they receive. The National
entry in it. This must be undertaken by an HSE approved Radiological Protection Board (now part of the Health
dosimetry and record keeping service. An annual report Protection Agency), a body set up by Government to pro-
is sent to a body known as the Central Index for Dose Infor- vide impartial advice on radiation protection matters, has
mation (CIDI) of the doses received by all classified per- recommended that, in this context, the exposure received
sons, with the intention of being able to undertake by persons acting as comforters and carers should not in
epidemiological studies in subsequent years and to provide general exceed 5 mSv from their involvement in one series
a central record of doses received by a classified worker or course of treatment. Normally, it should be possible to
which, if the worker changes employers, is passed onto design procedures that will keep doses received by carers
their new employer. The reports of any investigation into below this level.
a real or suspected overexposure of a member of staff or There will also be occasions when members of the pub-
a patient must also be kept for 50 years. The Health and lic who are not comforters and carers and therefore
Safety Executive has defined an exposure significantly more cannot knowingly or willingly be exposed to radiation,
than intended as being the reporting criteria to be used come into contact with patients who have undergone
in determining if a patient has been overexposed due to a therapeutic administration of a radiopharmaceutical,
equipment failure. This information is given in Appendix e.g. sharing public transport or accommodation. In such
2 of the Guidance Note PM77 [8] Equipment used in con- cases, an effective dose limit of 5 mSv in any period of 5
nection with medical exposure. This specifies that notifica- consecutive years is used. In practice, sufficient action is
tion to the HSE should be made if the dose given to normally taken by hospitals following accepted practice
a patient from beam therapy or brachytherapy exceeds on release of such patients from hospital for this not to
1.1 times the intended dose for a whole course or 1.2 times be a problem.
65
Walter and Millers Textbook of Radiotherapy
Controlled and supervised radiation areas into a passbook carried by the classified worker.
This gives an estimate of the dose received by the
If the dose limits are to be adhered to, it is necessary to
classified worker while working in the controlled
impose strict controls on how and where radiation generat-
area [9]
ing equipment and radioactive materials are used. Such
3. unclassified radiation workers and others who have
equipment and material should be housed in areas where
been issued with written schemes of work which, if
sufficient protection is afforded by the surrounding struc-
followed, ensure that they do not receive a dose greater
tures so that people in adjacent areas will not get a significant
than any applicable dose limit
exposure. Where persons are required to enter radiation areas
4. regulatory inspectors, who enter to inspect the area for
or adjacent locales then engineering controls and design con-
checking compliance with requirements.
siderations must be used to protect them. For example, con-
crete walls and door interlocks to terminate an exposure if A supervised area is any area where a person is likely to
entry to the treatment room is made, are preferable to mobile receive an effective dose of greater than 1 mSv per year
lead screens, which may be placed incorrectly or written (publics dose limit) or an equivalent dose greater than
instruction prohibiting entry, which may not be obeyed. one-tenth of any relevant dose limit. If a supervised area
Radiation areas are defined under UK legislation as being has been defined, it is necessary to keep the conditions
either a controlled or a supervised radiation area. These of the area under review to determine if the area needs to
should have been identified as part of the prior risk assess- be designated a controlled area. Supervised areas should
ment (see above). be suitably signed to indicate the nature of the radiation
A controlled area is any area where persons entering are source and warning that a supervised area exists and the
required to follow special procedures to limit the risk of a risks arising therein.
significant exposure contained within local safety rules,
(see below) or where they are likely to receive an effective Local rules, radiation protection advisers
dose of greater than 6 mSv per year or an equivalent dose and supervisors
greater than three-tenths of any other applicable dose limit. Once a controlled or supervised area has been defined, then
A controlled area must, wherever possible, be defined with it is necessary to have written local safety rules, referred to as
reference to physical boundaries, e.g. the whole of an x-ray local rules. These should be drawn up taking into account
room must be defined as a controlled area, even though the the findings of the prior risk assessment. These rules must
dose definition of a controlled area would mean that the be drawn to the attention of any worker who needs to enter
controlled area perhaps does not extend more than 2 meters a controlled or supervised area. Among other things, they
from the x-ray tube and patient. Once a controlled area has should contain written schemes of work for safe entry into
been defined, access into it must be controlled, wherever the controlled areas and contingency plans for any foresee-
practicable radiation warning signs and notices are able accident, e.g. radioactive source spillage. They should
required to be placed on entrances to the area, explaining also contain the name of the Radiation Protection Adviser
the nature of the radiation, e.g. x-rays, gamma rays etc, (RPA), who needs to be appointed by any employer who
and the control measures to help avoid the risk, e.g. do has set up a controlled area. Their duty is to advise the
not enter when red light is on. An example of such signing employer on compliance with the regulatory requirements,
is given in (Figure evolve 4.4 ). the correct identification of controlled and supervised areas
Where a source of radiation is mobile, e.g. mobile x-ray and the prior examination of plans for radiation installa-
unit used on several wards, then such signing would be tions and the acceptance into service of new or modified
impracticable and is therefore not used. However, a con- sources of ionizing radiation. In the Health Service, an
trolled area is still defined and controlled by the radiogra- RPA is normally an experienced radiation physicist. An
pher, e.g. 2 metres around the x-ray set and patient and RPA is required to have a certificate of competence to act
anywhere in the main beam until it is sufficiently attenu- as an RPA, which is issued by an HSE approved certification
ated by a solid object or distance. body every 5 years to candidates who can provide evidence
In a medical situation, access to a controlled area is lim- of their suitability to act as an RPA.
ited to four groups of people; these are: In addition, the name of the Radiation Protection
1. the patient undergoing the exposure, for whom there Supervisors (RPS) for the area should be included in the
are stringent controls both on the equipment that is local rules. Their responsibility is to supervise that the
used and the process. These are governed by the work with radiation that is being undertaken on a day-
Ionising Radiation (Medical Exposure) Regulations to-day basis is in compliance with the local rules. They
2000 (see below) should also be involved in the preparation of the local
2. classified workers who are subjected to individual rules for the area that they supervise in order to ensure that
monitoring. Where a classified worker of another they are both practical and not prohibitive. To act as an
employer enters someone elses controlled area, then RPS, the person must have received training in a core of
the owner of the controlled area must make an entry knowledge that has been specified by the HSE. They
66
Chapter |4| Radiation protection
67
Walter and Millers Textbook of Radiotherapy
given for particular examinations. A local series of by the employers procedures to undertake this role. Their
diagnostic reference levels should be set for each legal duty is to justify a medical exposure on the basis of the
standard radiological examination, including information provided to them by the referrer, taking into
interventional procedures, nuclear medicine account the specific objectives of the exposure, the total
investigations and radiotherapy planning procedures potential benefits and risks to the individual undergoing
procedures for the conduct of medical research the exposure and the possibility of using alternative techni-
involving the exposure to ionizing radiation of the ques which do not employ ionizing radiation but which
participating individuals where no direct medical would attain the same objective.
benefit is expected from the exposure. This should In radiotherapy applications, there will normally be
include the use and setting of dose constraints that are only one IRMER practitioner, for both the treatment expo-
levels of dose associated with the research, which are sures and any concomitant exposures as part of the
not allowed to be exceeded planning process, e.g. simulation, CT scans and verifica-
procedures for giving written information and tion images. The number of concomitant exposures is
instruction to patients undergoing treatment or likely to increase as the developing technical capabilities
diagnosis with radioactive materials in order for for conformal, image-guided radiotherapy make target
information to be given on how the exposure from the and critical organ definition an increasingly important
patient can be restricted so as to protect persons in aspect of radiotherapy. Estimation of doses and risks to
contact with the patient following discharge from the critical organs in the body from all sources is thus neces-
hospital (see comforters and carers above) sary to provide the basis for adequate justification of the
procedures for the carrying out and recording of an exposures as required by IRMER. Although negligible
evaluation of each medical exposure including factors in comparison with the target dose, realistic numbers of
relating to patient dose. That is a procedure to ensure concomitant exposures give a small but significant contri-
that no exposure is undertaken without a net benefit bution to the total dose to most organs and tissues outside
to the patient, e.g. if x-ray images were not examined the target volume. Generally, this is in the range of 510%
by a radiologist, no benefit would ensue from the of the total organ dose, but can be as high as 20% for bone
exposure surfaces [11].
procedures to ensure that the probability and
magnitude of accidental or unintended doses are
reduced as far as reasonably practicable. This should The operator
include things such as routine servicing and post- The operator is any person recognized by the employers
servicing quality assurance checks on the equipment. procedures who carries out any practical application of
The employer is also legally obliged to keep training the medical exposure. This covers a range of functions, each
records of those identified as undertaking practitioner or of which will have a direct influence on the medical expo-
operator roles. They must also draw up and keep up to date sure. Some of these will be undertaken in the presence of
an inventory of the radiation equipment at each radiologi- the patient, e.g. making the exposure, identifying the
cal installation they control. They are also responsible for patient. Other aspects are performed without the patient
establishing referral criteria for medical exposures and for being present, e.g. machine calibration and radiotherapy
making these available to the referrers. planning. Anyone who evaluates a medical image and
records the result of this evaluation is also considered to
be an operator.
The referrer A requirement of the legislation is that practitioners and
operators are adequately and appropriately trained and
The referrer must be a registered medical or dental practi- that they undertake continuing education in radiation pro-
tioner or other health professional entitled to act as a refer- tection of the patient. Medical and dental practitioners who
rer under the employers procedures (see above). The legal act as referrers do not require any additional training,
responsibility is to provide sufficient detail on the referral although other health professionals performing this role
request to allow for the correct identification of the patient should be trained in the clinical aspects of a patients pre-
and, where relevant, their menstrual status. They are also sentation that would warrant an exposure.
required to provide sufficient details of the clinical problem
to allow justification and authorization of the radiation
exposure. Medical physics expert (MPE)
An MPE is defined as a state registered clinical scientist
with corporate membership of the Institute of Physics
The practitioner and Engineering in Medicine (MIPEM) or equivalent
The IRMER practitioner is a registered medical or dental and at least 6 years of experience in the clinical specialty.
practitioner or other health professional who is entitled An MPE is a legal requirement for radiotherapy practices.
68
Chapter |4| Radiation protection
They must be full-time contracted to the radiation High Activity Sealed Radioactive
employer and available at all times for radiotherapy prac- Sources and Orphan Sources
tices. Their roles in radiotherapy are, among other things,
to provide consultation on the suitability of treatment Regulations 2005
techniques, with responsibility for the dosimetry and These regulations were introduced in an effort to reduce the
accuracy of treatment, optimization of treatments by loss of such sources either through a terrorist act or incorrect
ensuring that equipment meets adequate standards of disposal. A special registration is required for sources which
accuracy and the definitive calibration of radiotherapy are designated as High Activity Sealed Sources (HASS). This
equipment and dosimeters. designation is dependent on the radionuclide involved and
its activity and form. If a source falls into an HASS category,
additional security arrangements are required to be put in
Legal liability place and the source owner must demonstrate that they have
IRMER requires that any cases of exposures significantly adequate financial provisions in place for its subsequent
more than intended be reported to the Department of future disposal. Without this a registration will not be
Health in order for them to carry out an investigation. granted.
The employer should of course also perform such investi-
gations. In so doing, it should be possible to determine if Administration of Radioactive
the IRMER procedures are correct or if they were not
adhered to. By failing to adhere to the employers proce-
Substances Advisory Committee
dures, individuals take on the legal liability which, in cer- (ARSAC)
tain circumstances, may lead to a criminal prosecution of Regulation 2 of the Medicines (Administration of Radioac-
that individual. tive Substances) Regulations 1978 [13] (MARS Regulations
1978) and as amended in 1995 [14], requires that any doc-
tor or dentist who wishes to administer radioactive medici-
Radioactive Substance Act 1993 [12] nal products to humans should hold a certificate issued by
In order to keep, use and dispose of radioactive materials Health Ministers. The Regulations also established a com-
in the quantities used in a hospital that performs radio- mittee to advise Ministers on applications. This is known
therapy and diagnostic applications of radionuclides, the as the ARSAC and issues certificates to medical staff (nor-
above Act requires that the premises are registered to keep mally of Consultant status) who wish to administer radio-
the material and authorized to dispose of any waste aris- active materials to patients. In order to become certificated,
ing from its use. The Department of the Environment a practitioner is required to demonstrate that they have
pollutions inspectorate regulates this. Registration will received IRMER training and an apprenticeship with an
detail the maximum activity and number of sources that ARSAC certificate holder. The certificates issued are hospital
may be held on the premises of individually named location, radionuclide and treatment-type specific.
radionuclides. Authorization for keeping and disposal
of radioactive waste will be given providing the radiation
user has performed an environmental impact assessment, PROTECTIVE MEASURES
which shows that, in the worse case scenario, doses to
members of the public and others who come into contact There are a number of protective measures that may be
with the radioactive waste are acceptable and that the employed, either singularly or, more commonly, in combi-
disposals follow the best practical means for the environ- nation to reduce or limit the amount of radiation personnel
ment. Authorizations will indicate the maximum activity are exposed to. By minimizing the radiation dose people
of individual radionuclides that may be kept and subse- receive, you will minimize the risk of stochastic effects
quently disposed of over noted time periods by various occurring and eliminate the risk of deterministic effects.
routes.
Allowed routes of disposal are:
Time
in general domestic refuse providing that it is to be
disposed of by land filling and that it is below certain The dose someone receives when exposed to radiation
very low activity limits and concentrations depends on the dose rate of the source and the time
by incineration via a similarly authorized incinerator spent exposed to it, since high dose rates will give a higher
disposal of liquid waste in the sewage system, this is by dose in a shorter time. As a consequence, anything that can
far the most common route in terms of the activity be done to minimize the time exposed to a radiation source
disposed will minimize the exposure. For complex procedures,
gaseous disposal of radioactive gases normally from a staff should carry out practice runs with dummy sources until
discharge point on the top of a building. they become proficient in the procedure; for fluoroscopic
69
Walter and Millers Textbook of Radiotherapy
screening procedures, such as simulation, the use of a last comparing one absorber to another at a given radiation
image hold device will minimize the exposure time. energy. At diagnostic x-ray energies, the photoelectric absorp-
tion in lead is significant, since attenuation due to photo-
electric absorption is proportional to the atomic number of
Distance
the material cubed and the density. For higher energy radia-
Radiation arising from a point source reduces in intensity tion where Compton scatter starts to predominate as the
in proportion to the square of the distance from the source. attenuation process, the reduction in radiation is propor-
That means doubling your distance would quarter your tional to the density of the material. As a consequence, as
exposure, quadrupling your distance would reduce the the energy of the radiation increases, the advantage of lead
exposure to a sixteenth. As such, this is a relatively easy over other absorbing material diminishes because of the
way of reducing exposure and, importantly from the strong interdependence of photo-electric absorption on
employers point of view, does not usually cost anything. energy. With radiation above about 1 MeV in energy, where
The use of long-handled forceps when dealing with the Compton process predominates, there is no real advan-
radioactive sources will significantly reduce exposure, par- tage in using lead since all materials show very similar atten-
ticularly to the hands. However, in radiotherapy installa- uation properties depending solely on their density.
tions, e.g. linear accelerators, as the original source
intensity is usually high, the distance required to move to
in order to reduce the intensity to an acceptable level makes Contamination
this method of protection unusable by itself, as the distance
Where unsealed radioactive materials are used, either in the
required would be in the order of kilometres. Distance
gaseous or liquid state, the possibility of contamination of
is very often employed as a protective measure in linear
the surfaces and the environment in which the material is
accelerator installations by the installation of a maze type
being used needs to be considered. Such contamination
entrance into the treatment area which requires scattered
may be subsequently internalized within the body either
radiation generated within the treatment area to undergo
through inhalation, ingestion or absorption through the
a number of scattering interactions along the maze corridor
skin or wounds in the skin. Such absorptions will then
before reaching the maze entrance or door, thus increasing
counter the protective measures noted above as it will not
the distance the radiation travels and reducing the dose
minimize the exposure time, it will minimize the distance
rate. A correctly designed maze can mean no requirement
from the source to the tissues and no barriers could be
for a radiation protective door to be used at the entrance.
put in place. As a consequence, other controls are essential
when unsealed sources are used. These are, source confine-
Barriers ment, using trays, fume cupboards, glove boxes etc; ensuring
that the environment in which the sources are being used is
By placing an appropriate protective barrier between the
well ventilated and easily decontaminated and good basic
radiation source and the area you are trying to protect, the
hygiene standards such as wearing gloves and protective
level of the radiation reaching that area will be attenuated
clothing and washing hands after dealing with such sources.
and reduced. However, care must be taken in choosing
These simple precautions will help to reduce the risk of inter-
the correct material for the radiation type you are shielding
nal exposure rather than eliminate it altogether. Adequate
against. If dense materials are used as the initial attenuator
contamination monitoring with a radiation detector such
for beta particles (electrons), then x-rays will be generated
as a Geiger counter should also be undertaken.
from the attenuating material due to bremsstralung or brak-
ing radiation. As a consequence, beta particles should be
initially shielded by low-density material, such as Perspex,
Building materials
followed by a denser outer shield, such as lead. The thickness
of shielding required is dependent upon the initial dose rate, The correct choice of building material is essential for ade-
the dose rate that is required after passing through the atten- quate protection of surrounding areas at the least possible
uator and the energy of the radiation, thickness increasing cost. Various factors need to be taken into account when
with any of these. As a consequence, lead aprons, with a specifying the level of protection required and the material
thickness of approximately 0.25 mm of lead that are success- with which to protect. The radiation beam itself can consist
fully used for shielding personnel using diagnostic x-rays, of three components, primary beam radiation, that is radi-
with a typical energy of 3060 keV, would be completely ation that is in the main beam of the radiation source, this
inadequate to provide protection from the radiation from will be the most intense and energetic. Scattered radiation
a cesium-137 radiation source (energy 662 keV). originating from objects such as the patient that the pri-
Since lead is the most common radiation shielding mate- mary beam has struck, this is less intense than the primary
rial, it is normal to quote the amount of protection afforded beam radiation but is taken to be of the same energy and,
by different materials in terms of the lead equivalence of finally, for x-ray tubes, linear accelerators and sealed source
that material. The lead equivalence thus forms the basis of units, leakage radiation originating from the radiation
70
Chapter |4| Radiation protection
source housing. This is limited to certain maximum levels is not compromised. Occasionally, breaches in the pro-
by regulatory requirements and typical leakage levels are tection are essential in order to supply room services such
less than 10% of the maximum allowed. Those factors that as air conditioning and electrical supply. In such cir-
need to be taken into account in determining the levels of cumstances, thought needs to be given as to how this is
barrier thickness required are such things as: achieved. Such breaches should never occur in primary bar-
riers and the use of mazes and careful angulations of the
the attenuation properties of the material at the ducting passing through the wall will retain the protective
energies of radiation to be used
ability. Whenever possible, it is better to take the services
the area you are trying to protect, i.e. is it going to through a wall below the level of a solid floor. This is nor-
contain radiation sensitive material such as film?
mally tested during room commissioning with the use of a
the occupancy of the area to be protected radioactive source and radiation detector. With increasing
the energy of the radiation that is to be used, the higher energy and the photoelectric effect becoming less predomi-
the energy the greater the penetration
nant, lead becomes less favourable as the attenuating
the possibility of neutron production (see below) medium due to the large amounts that would be required
the beam use factors, i.e. is the area to be subjected to the and its tendency to creep or pool under its own weight. As
primary radiation beam at any time and if so for how long,
a consequence, for radiotherapy applications, concrete is
or is it only exposed to scattered and leakage radiation?
the usual attenuating medium with occasionally barium
the amount of radiation that is going to be used in a
concrete being used in areas subjected to the primary beam,
week, more commonly called the workload, e.g. beam
particularly where space is at a premium. This type of con-
on time
crete is relatively expensive and because of its higher density
what is above, below and surrounding the area where
much heavier than normal concrete. The typical wall thick-
radiation is being generated
ness (primary barrier) for a 10 MeV linear accelerator is of
what is the acceptable exposure level to the areas you
the order of 1.2 meter dense concrete. Lapped steel plate
are protecting, such areas should be designed to
can also be used in conjunction with concrete for an instal-
conform to the As Low As Reasonably Practical
lation where space needs to be conserved, but it is best
requirement but, for public areas, should not exceed
avoided where neutron production is likely. Such activa-
1 mSv per year.
tion is brought about when linear accelerators are operated
Having taken the above factors into consideration, calcula- above 1015 MV, by photonuclear reactions of the high-
tions are made to determine the lead equivalence that is energy photons or electrons in the various materials of
needed to protect the areas to the required degree. For diag- the target, flattening filter collimator and other shielding
nostic x-ray and radionuclide uses, the level of protection materials [19]. Neutron contamination increases rapidly as
required varies from about 0.5 mm to 2 mm of lead depen- the energy of the beam increases from 10 to 20 MV and then
dent on whether the barrier is subjected to the primary remains approximately constant above this. Measurements
beam. This is usually achieved either by using sheet lead have shown that, in the 1625 MV x-ray therapy range, the
or concrete. Other material may be used but care must neutron dose equivalent along the central access is about
be taken since the design and density of alternative build- 0.5 % of the applied x-ray dose and falls off to about 0.1% out-
ing materials vary. For example, clay bricks come in various side the field. If concrete has been used to shield from the
densities ranging from 1600 to 2000 kg m3. In addition, photons then sufficient protection from the neutrons will
they may be designed to reduce their weight by introducing be provided by these structures. However, great care needs
cavities into the brick. In practice, because of these vari- to be taken if iron or lead is used for part of the shielding
ables, it is advisable to perform transmission measure- as not only is the neutron attenuation poorer but neutron
ments on the intended material before construction with interactions in such material produce gamma radiation.
it is undertaken, in order to verify the lead equivalence Indeed gamma production can arise in dense concrete which
provided by it. Many lightweight building blocks are avail- has metal bearing aggregate and care must be taken to avoid
able with densities of less than 1000 kg m3 but, by them- this type of aggregate. In such cases, it is necessary to use a
selves, they are unsuitable for use in a radiation area and combination of shielding materials with a sandwich con-
need to be used in conjunction with other protective mate- struction of lead, steel, and polyethylene or concrete. Polyeth-
rial such as barium (barytes) plaster or lead lining. Conven- ylene is used as an efficient attenuator of neutrons and the
tional plaster is made with calcium sulfate. Replacing the steel or lead is then used as a photon attenuator.
calcium sulfate with barium sulfate to plaster x-ray room If designing an area where unsealed (e.g. liquid) radio-
walls, significantly increases the attenuation of the wall nuclides are to be used, then thought needs to be given
owing to the relatively high atomic number of barium (56) to ensuring that the floors and walls are constructed and
compared to calcium (20), indeed this is the reason why finished in such a way as to make them easy to decontami-
barium is used in barium meals and enemas. Care needs nate. Decontamination is usually achieved by a washing
to be taken with wall and door furniture, such as handles process, occasionally using caustic solutions. As a conse-
and coat hooks, to ensure that the protection of the barrier quence, providing the surfaces are easily washable without
71
Walter and Millers Textbook of Radiotherapy
degradation and are impermeable to the cleaning solu- detecting surface contamination in radionuclide laborato-
tions, then they will be suitable for use. Care should be ries; their chief disadvantage is that they are energy depen-
taken in ensuring that joints between benches, etc. are dent, their response varying with the energy of radiation
sealed. Thought also is required in the correct selection being measured. As such, unless the monitor has been cali-
of the material used for drains as some radionuclides are brated with the energy of radiation being measured the
absorbed preferentially by plastics. reading will not be correct. Such instruments can be used
In conclusion, a number of factors need to be taken into in diagnostic x-ray installations, together with a radioactive
account in designing a radiation room; its walls and bar- source such as Americium 241 to check the integrity of
riers must be such that the levels of radiation received by barriers, at positions such as handles and light switches.
staff, waiting patients and members of the public are kept Mains operated radiation detectors are often placed at exits
to a minimum. This can be achieved by the correct use of and other strategic places in radiation areas where either the
shielding material. A certified and appropriately experi- level of radiation may fluctuate or the radiation sources are
enced Radiation Protection Adviser should always be con- mobile and a warning is required if the source leaves the area.
sulted in any design process involving radiation. Detectors with either an audible or visual indication of a high
reading are often placed on exit doors of the rooms of
patients being treated with radioactive materials such that,
MONITORING OF RADIATION LEVELS if they try to leave the area, an alarm will alert the ward staff.
Similar alarms are required in radiotherapy departments, to
Monitoring of radiation levels can be performed in a number provide independent confirmation that the source(s) on
of ways. The Ionising Radiations Regulations only require gamma beam generators or remote after loading units have
employers to provide personal radiation dosimeters to their returned to the safe position.
classified radiation workers and to demonstrate that non-
classified workers do not need to become classified. One
way of avoiding issuing personal radiation monitors to
Personal radiation dosimeters
non-classified staff is to perform environmental monitoring There are a number of different types of personal radiation
and then making a judgment as to the probability of workers dosimeters which can be used to assess the dose individual
requiring to become classified. Environmental monitoring staff members receive as part of their work activity; these
must also be carried out on all new or modified protective are detailed below, together with their relative advantages
structures to ensure that they meet with the radiation pro- and disadvantages. These must be worn when at work and
tection specification required by the design specification not be exposed to radiation when the person is not at work,
worked out taking into account those matters described in as these monitors are used to determine the exposure a per-
the above section. A number of different instruments can be son receives as part of their work. This includes those cases
used to perform this monitoring, each with their own advan- where the person undergoes a medical exposure to radiation
tages and drawbacks, some of these are now described (see as part of their care pathway. The dosimeters are usually worn
also Chapter 3). at waist level and changed on a regular basis, normally
Ion chambers can be used for such measurements; they monthly. If a protective apron is being worn, the dosimeter
have the advantage that they have a relatively uniform should be worn underneath, since the whole-body radiation
response over a wide range of energies and can be used to exposure to the trunk is the quantity to be measured. Occa-
make both dose and dose rate measurements. The lower sionally, dose is assessed to other areas of the body and
the level of dose that is to be measured the larger the ioniza- providing the dosimeter is small enough can be placed on
tion chamber needs to be in order for there to be sufficient the fingers, wrists, legs or forehead. These are used to demon-
ionization current to make a measurement. Doubling the strate that the doses these areas receive are within the dose
volume of an ion chamber, will double its sensitivity, all limits for the individual organs noted in Table 4.5. In order
other things being equal. Ion chambers with volumes in to carry out definitive measurements of dose, which will be
excess of 1 litre are available to measure transmission accepted by the regulators, the dosimeters used must be of
through protective walls. Smaller volume ion chambers are a Health and Safety Executive approved type. To meet this
used to measure radiation output in the primary beam of type approval the dosimeters have to meet certain minimum
an x-ray unit ranging in volume from about 0.5 to 6 ml. performance and measurement specification.
One disadvantage of such devices is that they have a relatively
long time constant, which means they do not respond
quickly to changes in the incident radiation intensity. Direct readout dosimeters
Instruments involving Geiger counters or scintillation These have a radiation detector associated with an elec-
detectors are more sensitive than ionization chambers, tronic display so that a direct readout of the dose received
respond more quickly and use detectors of smaller size. can be made at any time. More sophisticated devices allow
This is because the signals that are initially generated are interrogation of the dose time profile via connection to a
further amplified. Such instruments are more often used in computer, to help establish when peaks of dose have
72
Chapter |4| Radiation protection
occurred, and also recording of the dose received. A picture The advantages and disadvantages of film badge dosi-
of such a device is shown in (Figure evolve 4.5 ). meters are as follows:
The advantage of such dosimeters is that there is no delay use highly sensitivity silver halide film, but not tissue
in knowing what dose has been received as the equipment equivalent in its absorption properties, which are
provides a direct readout; the disadvantages are that they energy dependent
are relatively expensive (200400), susceptible to damage fitted with a range of filters which can fall out of the
and some are energy dependent so different readings will holder
be obtained on them for the same received dose. Less distinguishes beta, x-ray, gamma and thermal neutrons
expensive versions also have the disadvantage that there provides permanent record of an individuals dose which
is no permanent record of the dose received unless logged can be reread if there are any doubts about the result
by the user. adverse effects of light and heat can give an indication
that a radiation dose has been received
Film badge dosimeters relatively short shelf-life (months)
require dark room facilities (development chemicals)
These consist of an envelope of film placed into a small significant manual handling during assessment
holder. The holder consists of different thicknesses of differ- not washing machine proof, the film emulsion melts
ent types of material e.g. tin/lead, Dural and different thick- making the dosimeter unreadable
ness of plastic. The blackening under the different filters is a density patterning subject to fading over a period of
function of the quality of the radiation to which the whole time and so should be processed within a relative short
badge has been exposed. As such, different energies and period after exposure (a month or so)
types of radiation produce different density patterns on doses down to 0.2 mSv accurately readable.
the film. For a given radiation quality, the film density is
roughly proportional to the exposure, if the exposure is
small. The used films are developed with a set of suitable cal- Thermoluminescent dosimeters (TLD)
ibration films previously exposed to a range of known doses
of gamma rays, together with unexposed films to estimate The TLD consists of a crystal or powder (e.g. calcium sulfate or
background and fog effects. A number of empirical methods lithium boride), which is able to record the dose of radiation
are adopted by different laboratories to deduce the exposure it is exposed to and store this information. When heated
from the densities measured under the various filters. Film (thermo), the material gives off light (luminescent), the
badges are suitable for monitoring doses from photons amount of light being given off is proportional to the radia-
(15 keV3 MeV) and beta (Emax >500 keV) radiations and tion dose to the material. The material is usually placed in a
with the addition of different filters, they can be used to holder which enables the dosimeter to distinguish between
measure neutron radiation dose. They are ideal for workers penetrating and non-penetrating radiations; this is done by
who encounter x-ray fields and have a dose range of 0.1 mSv placing a portion of material underneath a dome of plastic
to 10 Sv for Hp(10), that is the penetrating radiation dose at and another portion merely under a thin protective envelope.
10 cm depth in tissue. Due to the technique they employ to Used as personal and environmental dosimeter
monitor dose, film monitors provide the ability to detect if Use thermoluminescent (TL) materials
radioactive contamination of the dosimeter has occurred. In Electrons are raised/trapped at higher energy levels
order to extend the range of exposure covered by the film, The energy is released as light when heated
one side is coated with a thick sensitive emulsion and the Light emitted is converted into an electrical signal
other side has a thinner, less sensitive emulsion. In normal Light emitted is proportional to incident radiation
use, the density through both emulsions is measured and Lithium (LiF:Mn) based TLDs for personal dosimetry:
the doses of a few percent of the dose limit estimated. High because they are tissue-equivalent
doses make the sensitive emulsion too black for measure- Calcium (CaF2:Dy, CaSO4:Dy) based TLDs for
ment, but it can then be stripped off and a measurement environmental monitoring: due to their high sensitivity
of the density of the thin emulsion alone can be made lead- Lithium borate (Li2B4O7:Mn) TLDs for high dose range
ing to estimates of up to about 10 Sv. dosimetry
A typical film badge is shown in (Figure evolve 4.6 ). It TL materials are available in many different forms: e.g.
will be noticed that there is an open window in the front of powder, hot pressed chips, pellets, impregnated Teflon
the badge which allows the badge identification number to disks
be observed. This is stamped onto the badge with sufficient Read-out instruments (reader) are required
pressure for the number to be visible on the developed film. Method to heat the TLD material: electrical, hot gas
Each person monitored will have a number associated with or a radiofrequency heater, heated in an inert gas
him or her. As a consequence, one should only ever wear during read-out
the badge issued to you and not one issued to someone else Device to convert the light output to an electrical pulse
since the dose records will not be correct. Light signal is amplified using a photomultiplier
73
Walter and Millers Textbook of Radiotherapy
Small size (only milligram quantities of TL material is Equipment checks and calibration
needed)
On an annual basis, contamination monitors, dosimeters
TLDs can be reused
and dose rate meters require to be calibrated and the results
Doses down to 0.1 mSv accurately readable
of this calibration logged. The calibration of such equip-
The disadvantages of TLDs are: ment needs to be traceable back to a national calibration
only one reading during heating, cannot be repeated standard so that it can be assured that what is measured
subject to fading (due to temperature or light effects) at one centre will be the same as measured at another. This
requires careful handling to avoid dirt on the is often arranged by sending one instrument away for cali-
dosimeters interfering with light emission. bration by a national calibration service, such as the
National Physical Laboratory, and then cross calibrating
other equipment held with the one that was sent away.
Optically stimulated luminescent Having calibrated the measurement equipment, these can
(OSL) dosimeter then be used with a degree of confidence for carrying out
These measure radiation through a thin layer of alumin- dose measurements on radiotherapy treatments machines,
ium oxide. During analysis, the aluminium oxide is stimu- diagnostic x-ray equipment and for contamination and dose
lated with selected frequencies of laser light causing it to rate measurements. Such measurements in radiotherapy
become luminescent in proportion to the amount of radi- form part of a comprehensive quality assurance programme
ation exposure. This is very similar in principle to the com- that is required to be in place in every radiotherapy depart-
puted radiography imaging plates that are replacing film ment to help ensure that the risk of incorrect or inaccurate
in diagnostic radiology. The dosimeters give accurate read- treatments being given is minimized.
ings down to 0.01 mSv, representing another revolution
in dosimetry. This new degree of sensitivity is ideal for
employees working in low-radiation environments and
Other requirements
for pregnant employees. Another advantage is that they A number of other matters some of which do not directly
can go through a washing machine cycle without being relate to radiation will now be discussed, all of them are
affected (Figure evolve 4.7 ). however safety related and are therefore worthy of note.
74
Chapter |4| Radiation protection
keep it for reference throughout the life of the equipment. structures. Where megavoltage equipment is concerned,
The critical examination should be repeated after any major merely rotating the gantry from one position to another
upgrade or repair to the equipment, which may affect the involves the acceleration and retardation of several tonnes.
radiation output or other safety critical factors, e.g. source Care should be taken in moving such equipment, ensuring
or x-ray tube change. that there is nothing in the intended path of travel as a lot of
Once the installer has performed a critical examination, damage can be caused quite easily if such weights crash into
the user should carry out an adequate number of tests and something, e.g. a trolley left beside the treatment couch.
measurements to establish a quality control baseline and Even low voltage electrical equipment has the potential
ensure that the equipment is working within the purchas- to kill. The voltages that radiotherapy and x-ray equipment
ing specification. All safety related features of the equip- work at ranges from a few volts to hundreds of thousands
ment should be checked including those associated with of volts, as a consequence, such equipment should never
the room containing the equipment. be operated with wet hands or in wet conditions. All
A Medical Physics Expert should be responsible for major components of any installation should be visibly
acceptance testing of the equipment. For radiotherapy connected to earth using either a continuous copper tape
equipment, compliance with the Guidance Notes [5], or a single core wire covered with a green or green and
HSG 226 [15], and the appropriate sections of BS EN yellow sheath. These connections should all be brought
60601 [16], relevant to equipment safety should be together at a common earth reference terminal (often
checked. Further guidance on the acceptance testing and labelled as ERT), which is normally a large copper bar
commissioning of radiotherapy equipment can be found placed close to the control console or x-ray generator. All
in IPEM 54 [17] Commissioning and Quality Assurance areas of the equipment that is potentially electrically haz-
of Linear Accelerators and IPEM 81 [18] Physics Aspects ardous will be housed in cabinets either behind fixed
of Quality Control in Radiotherapy. panels or locked doors. These must always be kept secure
and only opened by authorized personnel after they have
isolated the electricity supply. In addition, large capacitors
Personal protective equipment (PPE)
may be present and are likely to hold their charge even after
A range of PPE (lead aprons, gloves, thyroid shields and eye the mains supply has been switched off and special precau-
protectors) should be provided in all diagnostic x-ray tions need to be taken to discharge them safely before
rooms and for use with mobile x-ray equipment. When maintenance work is undertaken.
not in use, these should be stored appropriately so as to Due to the high voltages employed in radiotherapy and
avoid damaging their protective properties. Lead aprons x-ray equipment, there is an increased risk of fire. Due to
for instance should never be folded but should be hung the requirement for radiotherapy installations to have a min-
on dedicated hangers or rails of sufficiently large diameter imum number of entrances/exits, such rooms normally only
to prevent creasing. have the one. As such, it is important that any fires starting in
All PPE should be visually examined at frequent intervals such rooms are detected as early as possible and fire detec-
and any defective items removed from use. Protective cloth- tion devices, such as smoke alarms, are essential. In some
ing must be examined at least annually to ensure that no situations, patients undergoing treatment will be immobi-
cracks in the protective material have developed. This has lized on the treatment table by securing them to it with treat-
to be done by radiographic or fluoroscopic examination ment moulds. This makes the release of these patients time
if the protective material is not directly visible. The results consuming in an emergency situation such as fire. Rehear-
of the inspection should be recorded and the protective sals of removing patients from treatment rooms should be
devices themselves should be individually identifiable, undertaken regularly so staff are aware of problems that they
e.g. by a serial number. may face. Fire extinguishers should be of a type suitable for
tackling electrical fires, the use of water being avoided, as this
would present a potential electrocution hazard. Procedures
Mechanical, electrical and fire hazards should be in place to provide advice to the fire brigade if a
In addition to the hazard from the radiation being generated fire occurs in radiation areas and a list of the location of
from radiotherapy and diagnostic x-ray equipment, hazards radioactive material should be provided to the fire service
also arise from the mechanical structure of the equipment in on an annual basis. In a fire situation, if the fire brigade
the form of the weight associated with the equipment. see a radiation warning sign they will err on the safe side
Radiotherapy equipment, in particular, normally has a large until the nature of the hazard has been established.
amount of high-density material (lead or depleted uranium) By complying with all the regulatory requirements and
surrounding the radiation source to ensure that radiation is guidance, it is possible to remove the risk of acute radiation
only directed to the area intended and leakage radiation effects and limit the probability of stochastic effects occurring.
from the x-ray tube or around the radiation source is mini- As such, anyone working routinely with radiation should be
mized. The overall weight of the equipment is also increased made aware of what is expected of them in terms of protecting
by the need for counterbalancing weights in supporting both themselves and others from the use of radiation.
75
Walter and Millers Textbook of Radiotherapy
REFERENCES
[1] ICRP 60. Ann ICRP 1991;21(13). 1999 Statutory Instrument 1999 Regulations 1978Statutory
ICRP Publication 60. 1990 No. 3242. HMSO. Instrument 1978 No. 1004.
Recommendations of the [7] Ionising Radiation (Medical HMSO.
International Commission Exposure) Regulations 2000. [14] The Medicines (Administration of
on Radiological Protection. Statutory Instrument 2000 Radioactive Substances)
Pergamon Press. No. 1059. HMSO. Amendment Regulations 1995
[2] United Nations. Sources and effects [8] Guidance Note PM 77. Equipment Statutory Instrument 1995 No.
of ionising radiation, vols. 12. used in connection with medical 2147. HMSO.
UNSCEAR 2000 Report to the exposure. 3rd ed. Health and Safety [15] HSG 226. Radiation equipment
General Assembly with scientific Executive; 2006. used for medical exposure. Health
annexes. United Nations sales [9] HSE. Protection of outside workers and Safety guidance Note 226.
publications E.00.IX.3 and E.00. against ionising radiation. HSE Health and Safety Executive.
IX.4. United Nations, New York; information sheet Ionising [16] BS EN 60601. Medical electrical
2000. Radiation Protection Series 4. 2000. equipment British Standard. From
[3] The Ionising Radiations Regulations [10] The Ionising Radiation (Medical British Standards online at:http://
1999 Statutory Instrument 1999 Exposure) (Amendment) bsonline.techindex.co.uk.
No. 3232. HMSO. Regulations 2006Statutory [17] IPEM 54. Commissioning and
[4] Work with ionising radiation. Instrument 2006 No. 2523. HMSO. quality assurance of linear
Approved Code of Practice and [11] Harrison RM, Wilkinson M, accelerators. IPEM Report No. 54.
Guidance. HSE; 2000. Shemilt A, Rawlings DJ, Moore M, IPEM; 1988.
[5] Medical and Dental Guidance Notes. Lecomber AR. Organ doses from [18] IPEM 81. Physics aspects of quality
A good practice guide on all aspects prostate radiotherapy and control in radiotherapy. IPEM
of ionising radiation protection in associated concomitant exposures. Report No. 81. IPEM; 1999.
the clinical environment. Institute of Br J Radiol 2006;79:48796. [19] Axton E, Bardell A. Neutron
Physic and Engineering in Medicine [12] Radioactive Substances Act 1993. production from electron
(IPEM); 2002. Chapter 12. HMSO. accelerators used for medical
[6] The Management of Health [13] The Medicines (Administration of purposes. Phys Med Biol
and Safety at Work Regulations Radioactive Substances) 1972;17:293.
Figure evolve 4.2 Radiation damage to Figure evolve 4.5 Direct readout
hands of early radiation worker dosimeter
Figure evolve 4.4 Radiation warning Figure evolve 4.6 Film badge dosimeter
signs Figure evolve 4.7 OSL dosimeter
76
Chapter |5|
Imaging with x-ray, MRI and ultrasound
Geoffrey P. Lawrence, Carl Tivas, Sarah Wayte
Practical configurations 86
CHAPTER CONTENTS
Multislice CT 86
Introduction 78 Cone beam CT 86
X-ray imaging 78 Dynamic imaging 86
Overview of x-ray imaging process 78 Gated imaging 87
Production of x-rays for imaging 78 Dedicated radiotherapy systems 87
Information from absorption/scattering 79 Simulator 87
Differential attenuation in the primary beam 79 CT virtual simulator 87
Contrast media 80 Treatment verification systems 87
Scatter as unwanted background 80 Magnetic resonance imaging 87
Anti-scatter grid 80 Overview of magnetic resonance
Planar imaging 81 imaging process 87
Film/screen detection 81 Producing a signal 87
Characteristic curve 82 Returning to thermal equilibrium 88
Digital (computed) radiography using Imaging sequences 89
photostimulable phosphors 82 How contrast is altered in an MR image 89
Fluoroscopic imaging with image How positional information is encoded
intensifier/TV chain 83 in the signal 89
Digital fluoroscopy and radiography using MRI scanners 91
solid state detectors 83
Spectroscopy 91
Assessment of image quality 84
Clinical applications of MRI in oncology 92
Magnification/distortion 84
Brain tumours 92
Resolution/unsharpness (geometric/movement) 84
Body tumours 92
Image signal and noise 85 Ultrasound imaging 92
Dose 85 Overview of ultrasound imaging process 92
Tomographic imaging 85 Ultrasound scanners 93
Aims: contrast improvement/localization in 3D 85 Clinical applications 94
CT Reconstruction from projections 85 References 95
X-ray, magnetic resonance imaging (MRI) and ultrasonic Overview of x-ray imaging process
images play a key role in the diagnosis, staging, planning
and delivery of treatment and follow up of patients with The energy source in medical x-ray imaging is usually an
cancer. x-ray tube and electrical generator though, in the case of
In everyday language, an image is a picture and, more radiotherapy portal imaging, it is the linear accelerator.
generally, it is a representation of the distribution of some As the x-ray beam passes through the patient, some radia-
property of an object. It is formed by transferring infor- tion is absorbed or scattered. The intensity of the emerging
mation from the object to an image domain. In practice, primary beam varies with position and carries information
this requires the ordered transfer of energy from some about the interactions that have occurred in the body. The
source via the object of interest to a detector system. The emerging beam can be detected by a variety of devices,
detected signal may be processed in some way before being e.g. film/screen cassette, image intensifier, solid state elec-
displayed and stored by suitable devices. tronic detector. These are typically large area devices and
Medical imaging modalities covered in this chapter are the image is a two-dimensional shadowgraph of the inter-
classified according to the type of energy used to carry infor- vening anatomy. Radiographic film is unique in combining
mation: x-rays, radiofrequency waves and high frequency all three roles of image detection, recording and display.
sound waves. Image intensifiers are usually coupled to a television
X-ray imaging enables tumours to be localized with camera and display monitors: static images or dynamic
respect to normal anatomical structures and to external (i.e. moving) series may be stored on analogue video media
markers. Because x-rays travel in straight lines until they or digitized for storage on DVD or other computer-based
are absorbed or scattered, they can produce images which media. Digital fluoroscopy and radiography systems use
faithfully represent spatial relationships within the body. digital computers and their storage and display devices as
It is principally for this reason that x-ray images of vari- integral components of the imaging system, as does com-
ous kinds are essential to the planning and delivery of puted tomography (CT). In CT, the x-ray beam is colli-
radiotherapy. A further reason is that interactions of ioniz- mated in the longitudinal direction to a narrow slit and
ing radiation with matter are an essential feature of both this is aligned with an arc of solid state detectors. The tube
imaging and therapy, so that information on properties and detectors are mounted on a gantry which rotates about
of tissues relevant to treatment planning, such as electron the patient. Essentially one-dimensional projection images
density, may be obtained from suitable images. are acquired from many angles and the data are processed
Magnetic resonance imaging is an excellent technique in a digital computer to form images of transverse slices
for imaging soft tissue, and is often used to diagnose through the patient.
and stage cancer in the head, neck and body. It can also
be used to monitor the response to treatment. The extent
Production of x-rays for imaging
of the cancer can be seen on anatomical images. Other
specialized MRI techniques, such as diffusion weighted The general topic of x-ray production is covered in
imaging and dynamic imaging with a contrast agent can Chapter 2. This section highlights some aspects of specific
also be used to refine the diagnosis and cancer staging. relevance to imaging.
Magnetic resonance spectroscopy provides information X-rays are generated by causing electrons, which have
regarding the metabolism of the tumours and can also be been accelerated to high energies in a vacuum tube, to col-
used to monitor treatment response. lide with a metal target. The electrical supply is normally
Diagnostic ultrasound imaging has several advantages from a generator, which takes power from the mains three
over other imaging modalities [1]. It is relatively cheap, phase alternating current (AC) supply and converts it, using
safe, gives real time images and has good soft tissue con- a transformer and associated circuits, to an approximately
trast. As well as anatomical detail, ultrasound can exploit constant kilovoltage (kV) direct current (DC) output. Older
the Doppler effect to give information about blood flow models employed rectification and smoothing circuits
and the vascularity in tissues. The distortion of tissue under which resulted in appreciable ripple on the kV waveform,
pressure in ultrasound images can give images related to the i.e. the output voltage varied by several per cent over a
elasticity of tissues. mains cycle. For this reason, the kilovoltage is specified
Radionuclide imaging, including PET-CT, which is pri- as the peak value, denoted by the abbreviation kVp. Mod-
marily concerned with the function of organs and tissues ern generators employ converters, operating at a frequency
is dealt with in Chapter 6. of several kHz, which produce voltage waveforms with very
78
Chapter |5| Imaging with x-ray, MRI and ultrasound
little ripple. Diagnostic imaging work mostly uses acceler- Characteristic radiation
ating potentials in the range 50 to 150 kVp, though lower
values are used in mammography.
At megavoltage energies, as in linear accelerators used Bremssrtahlung
79
Walter and Millers Textbook of Radiotherapy
0.8
are, however, much smaller and special techniques such
as CT are needed to reveal them.
0.6
Primary
Contrast media
0.4 Scatter
Some structures may be made visible by deliberately intro-
ducing contrast agents, such as air or liquids containing
iodine or barium, which have a very different value of m 0.2
from the surrounding tissues.
0
Scatter as unwanted background 0 5 10 15 20 25
Distance from patient to detector /cm
Scattered radiation generally contributes a more or less
uniform background signal to the image, which does Figure 5.4 Diagram showing fall off in scatter reaching
not convey useful information but which reduces detector with distance.
80
Chapter |5| Imaging with x-ray, MRI and ultrasound
Scatter
81
Walter and Millers Textbook of Radiotherapy
X-ray photon
Flourescence
(light protons)
Optical density
Film emulsion
Phosphor
Relective layer
Base
82
Chapter |5| Imaging with x-ray, MRI and ultrasound
X-rays
Slow response (y)
Image
Caesium lodide
input phosphor TV camera
83
Walter and Millers Textbook of Radiotherapy
possible to produce higher quality fluoroscopic and radio- (a) X-ray focal spot size
graphic images. Diagnostic x-ray tubes usually offer a choice of two focal spot
sizes: fine (typical diameter 0.4 to 0.8 mm) or broad (typical
Assessment of image quality diameter 0.8 to 1.5 mm). Figure 5.13 shows how such a
source gives rise to a penumbra when imaging a sharp edge.
Magnification/distortion The penumbra is wider for a larger focal spot. Because of the
Because x-rays diverge from a small focal spot and travel bevelled angle of the rotating anode, the apparent size of the
in straight lines through the patient before reaching the focal spot, and hence the degree of blurring, varies across the
image detector, the image is magnified as shown in image in the direction of the axis of rotation of the anode.
Figure 5.12. Object features which lie in a given plane, parallel The blurring is also increased for detail lying in planes with
to the image detector, are magnified by the same factor. Planes greater magnification. This is especially important for the
closer to the x-ray source have a higher magnification factor; image of field defining wires in a simulator as these are
planes nearer to the image detector have a lower magnifica- located relatively close to the x-ray source and are thus greatly
tion factor. It is often said that a particular image is taken at magnified (Figure 5.14). Sometimes, especially if the broad
a certain magnification: strictly this only applies to one spe- focus is used, a double image may be produced: this results
cific plane, usually that passing through the isocentre. Any from the fact that the focal spot in fact often consists of two
anatomical feature which does not lie in a single plane parallel relatively intense linear sources of x-rays, separated by a
to the detector will appear distorted in the image, since differ- region of lower intensity.
ent parts of it will be magnified to different degrees.
(b) Patient movement
If the patient moves during the exposure, then features
Resolution/unsharpness will be blurred in the image. This can be minimized by
(geometric/movement) using short exposure times, by asking the patient to keep
The resolution of an imaging system is a measure of its abil-
ity to represent separate features in the object as separate
features in the image. Because no imaging system is perfect, Unsharp image Sharp object Extended
the image of a point in the object is to some degree blurred source
and sharp edges are rendered unsharp. The image of a point
is called the point source response function for the system.
There are several sources which contribute to the unsharp-
ness of an x-ray image: (a) the finite size of the x-ray focal spot,
(b) patient movement and (c) resolution of the detector.
Penumbra
X-ray source Imaging plane
Single
image Fine focus
Field wire
Small object
Double
image
Patient
Images of
identical
Broad focus
structures
Imaging plane
Figure 5.12 Magnification of objects lying in different planes. Figure 5.14 Magnification of the field wires in the simulator.
84
Chapter |5| Imaging with x-ray, MRI and ultrasound
still and to hold his/her breath and, if necessary, by using Ionising Radiation (Medical Exposure) Regulations [2] that
patient immobilization devices. the doses from medical imaging exposures should be kept
as low as reasonably practicable consistent with the
(c) Detector resolution intended purpose. Doses from different procedures can
The detector resolution is inherently related to the num- be measured or calculated in various ways. For a given
ber of distinct and independent samples which are patient, it is often convenient to combine these into an esti-
detected within the image. This can be thought of as the mate of the total effective dose received, which may be
spatial sampling rate of the detector. For film, the sam- regarded as an index of the total radiation risk from the
pling rate is directly related to the grain size, so for exam- imaging procedures.
ple, if a grain size was 1.0 mm by 1.0 mm, a 1 mm2 area of
film would contain 1 000 000 samples. Hence the sam-
pling rate can be expressed as one million samples per
Tomographic imaging
mm2. With digital systems, the sampling rate is depen- Aims: contrast improvement/
dent upon the density of sensitive electronic devices localization in 3D
which can be manufactured per square mm. This is con-
stantly being increased in order to improve image quality Planar x-ray imaging is limited in its ability to show low-
as it is recognized that to ensure adequate detection of a contrast features, especially in soft tissues, and to allow accu-
small medical abnormality at an early stage, high resolu- rate localization of features in all three spatial dimensions.
tion is important. This results from the fact that it projects a 3-dimensional
object onto a 2-dimensional image domain, coupled with
limited ability to reject scattered radiation. Tomographic
Image signal and noise imaging addresses these limitations by imaging selected
An ideal x-ray image would represent the distribution of planes of the patient separately, i.e. 2-dimensional sections
attenuation coefficient in an object with perfect fidelity. of the patient as 2-dimensional images.
In practice, even the image of a homogeneous object of Historically, so-called conventional tomography emp-
uniform thickness is not perfectly uniform. The signal exhi- loyed linked movements of the x-ray tube with planar
bits variations about its mean level and these are called detectors to image selected longitudinal planes of the
noise. Noise can make it difficult to distinguish signal levels patient in focus, with more distant planes increasingly
which only differ by a small amount, i.e. areas of low blurred out into a more or less uniform background. Inge-
contrast in the image. nious methods were devised to optimize the use of these
There are various sources of noise but one which is systems and there is continuing interest in digital proces-
always present to some degree is quantum noise, or mottle. sing of the component images, e.g. in the technique called
This results from the fact that any image is made using tomosynthesis. Although these techniques can improve
a finite number of x-ray photons (quanta) and the pro- localization and contrast, they do not reduce the effect of
cesses of interaction in the patient and of absorption in scattered radiation.
the detector are random. This means that there is a statisti-
cal variation in the number of photons detected even over
CT Reconstruction from projections
an area of uniform attenuation. If the average number of
photons per unit area is N, then the statistical uncertainty Computed tomography (CT) uses the principle of mathe-
in the number detected in any particular unit area is N. matically reconstructing the internal structure of an object
Expressed as a percentage of the average number this is from a set of images of the object taken from different pro-
100 N/N% or 100/N%. So, relative to the detected sig- jections. To acquire data from which to reconstruct a single
nal, the noise decreases as the number of x-ray photons slice, the x-ray beam is collimated to a narrow slit and this is
increases, but it is never quite equal to zero. aligned with an arc of solid state detectors. The tube and
Other sources of image noise can be the finite size of detectors are mounted on a gantry which rotates about the
the fluorescent crystals in intensifying screens, the finite patient (Figure 5.15). With this set-up it is possible to reject
size of silver grains in radiographic film and electrical noise a large proportion of the scatter while detecting the transmit-
in various components of a TV imaging chain or digital ted primary beam with high efficiency. Essentially, one-
detector system. dimensional projection images are acquired from many
angles and the data are processed in a digital computer to
form images of transverse slices through the patient. There
Dose are several mathematical techniques which can be employed
All x-ray imaging procedures, including those discussed to do this, including Fourier analysis and iterative methods,
below, give some radiation dose to the patient. This is but most commercial systems use some variant of filtered
believed to entail a (usually small) risk of harmful effects, back projection (FBP). The way in which this works is out-
such as future cancer induction. It is a requirement of the lined in Figure 5.16.
85
Walter and Millers Textbook of Radiotherapy
X-ray
beam
Patient
Fan beam
Patient
Detector
Rotation of source
and detector assembly
Detector array
Figure 5.15 General construction of a CT scanner with tube,
etc. located. Figure 5.17 Diagram of a third generation of CT scanner.
Multislice CT
Image 1 Image 2 In recent years, multislice CT scanners have become avail-
able, in which several arcs of detectors are stacked together
longitudinally and the divergence of the x-ray beam can be
adjusted so as to irradiate them simultaneously. This permits
Back projection more rapid collection of projection data from a given length
of the patient and makes for efficient use of the x-rays gener-
ated by the tube, thus easing the heat loading requirements.
Cone beam CT
It is possible to acquire projection data using devices other
than a dedicated CT scanner. Using an electronic planar
imaging device and rotating this about the patient during
Image 2 data acquisition, a set of cone beam projections is obtained
Image 1 from which a set of transverse slices can be reconstructed.
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Chapter |5| Imaging with x-ray, MRI and ultrasound
By taking a time-sequence of images, a so-called dynamic data during a rotation about the patient to produce cone-
series can be acquired which represents the anatomy of beam CT images.
interest at its various positions. This can be useful for diag- Another system employs two fixed x-ray tubes mounted
nosis and staging, e.g. a barium swallow to demonstrate in the floor of the treatment room, used in conjunction
oesophageal or gastric abnormalities, or for planning treat- with ceiling mounted detectors to acquire oblique views
ment, e.g. a fluoroscopic study of the chest to demonstrate of the patient. The images can be analysed by computer
movement of a lung tumour. software to compare with reference images to indicate
required set-up corrections. It can, however, be difficult
Gated imaging for operators to interpret images taken from these angles.
One manufacturer offers a CT scanner in the treatment
Where periodic motion is present, gated imaging may be a room so that, by rotating the treatment couch by 90 from
useful option. This represents data over a typical cycle of the the usual treatment position, a CT scan can be obtained
motion as a series of images at different times or phases of with the patient set-up.
the cycle. The image acquisition is linked to some suitable
physiological gating signal, e.g. from an electrocardiograph
or respiratory monitoring device.
MAGNETIC RESONANCE IMAGING
Dedicated radiotherapy systems
Simulator
Overview of magnetic resonance
imaging process
The radiotherapy simulator is a machine which replicates
the movements and geometry of a treatment machine Magnetic resonance imaging uses a strong magnetic field
(linac) but uses a diagnostic x-ray tube to produce kV (typically 0.3 to 3.0 tesla) and radiofrequency (RF) pulses
images. It includes beam limiting diaphragms and field- to produce images of the hydrogen distribution within the
defining wires to allow accurate simulation of the treat- body. By altering the interval between the RF pulses and the
ment beam and patient geometry. The gantry and couch time at which the signals are detected, images with different
of the simulator should reproduce all the movements of tissue contrast are produced. Nuclei with odd numbers of
the treatment machine and to the same accuracy or better protons and neutrons act like tiny magnets. In the presence
(see Chapter 10). of a strong magnetic field they have a net alignment with
the field. After a pulse of radiofrequency (RF) energy is
applied, some of the nuclei will flip and align themselves
CT virtual simulator against the field. After the pulse the nuclei will float back
By acquiring a series of CT slices over a suitable longitudi- to the original alignment producing an RF signal at the
nal range, it is possible to generate a digital representation same frequency as the one applied. Images are generated
of the body in all three spatial dimensions. This can be used that reflect the distribution of these nuclei within the tissue.
as the basis of virtual simulation, in which digitally recon- So-called T1 spin lattice relaxation is when the nuclei are
structed radiographs (DRR) can be generated to provide aligned in the direction of the magnetic field. The T2
beams eye views (BEV) of the patient from arbitrary direc- spin-spin relaxation time is when the nuclei are aligned
tions for various shapes and sizes of field (see Chapter 9). at 90 to the magnetic field.
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Walter and Millers Textbook of Radiotherapy
B0 z M0
Precessing anti-parallel
high energy state y
A x
Precessing parallel
low energy state
M0
Figure 5.18 Protons precessing parallel or anti-parallel to the y
applied magnetic field.
B B1 x
can either precess parallel or anti-parallel to the mag-
netic field, as shown in Figure 5.18. The parallel energy state
requires less energy. At a field strength of 1.5 tesla, at body
z
temperature (37 C), the excess of parallel protons is around
4 per million. The excess of parallel protons (or spins)
in the lower energy state produces a net magnetization vec-
tor (Mo) parallel to the magnetic field. By convention,
the direction of the applied magnetic field is the z-axis.
The net magnetization vector rotates about the z-axis at
the Larmor frequency, as shown in Figure 5.19A.
Mo is of the order of microtesla, so in all MR imaging M0
y
sequences a radiofrequency pulse is applied to detect it.
The applied RF pulse needs to be at the Larmor frequency,
or it will have no effect. The motion of the net magnetiza- C B1 x
tion vector during the radiofrequency pulse in the rotating
frame and the lab frame is shown in Figure 5.19. The angle
through which Mo is rotated depends on the amplitude and Figure 5.19 (A) The net magnetization vector (Mo) rotating about
duration of the RF pulse. A 90 pulse will rotate Mo into the the z-axis at the Larmor frequency. (B) Motion of Mo in the rotating
x-y or transverse plane. frame during the application of a 90 RF pulse (B1). (C) Motion of Mo
The rotating magnetization vector induces a voltage in in the lab frame during the application of a 90 RF pulse (B1).
a receiver coil. The detected signal oscillates at Larmor
frequency, and decays exponentially, as the individual spin
components of Mo rapidly de-phase. T1 relaxation is also called longitudinal relaxation, as it
governs the rate at which the z-component of Mo recovers.
The recovery process occurs when spins which have been
Returning to thermal equilibrium excited by the RF pulse give up their energy to their sur-
Once the RF pulse is switched off, the net magnetization vec- roundings (or lattice in early experiments). Following a
tor Mo will return to its thermal equilibrium state parallel to 90 RF pulse, the Bloch equation simplifies to:
h i
the magnetic field. Felix Bloch described this process, called
Mz t Mo 1 e t T1 5:6
relaxation, using two different time constants, T1 and T2.
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Chapter |5| Imaging with x-ray, MRI and ultrasound
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Walter and Millers Textbook of Radiotherapy
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Chapter |5| Imaging with x-ray, MRI and ultrasound
applied along the slice, perpendicular to the frequency The RF coils can be used both to transmit the RF pulses
encoding gradient. For a 256256 matrix image, the phase and to detect the voltage signal produced. The most com-
encoding gradient is applied with 256 different amplitudes. mon design of coil which both transmits and receives
In Figure 5.24, some different amplitudes of phase encod- RF pulses is a birdcage coil, Figure 5.28. This coil design
ing gradient are shown, and it can be seen that these dif- produces a uniform RF field with good penetration, and
ferent amplitudes rotate the angle of the lines of equal is often used in head and knee coils. Frequently, the RF
frequency in the image. The different amplitudes of phase pulses are transmitted through a body coil which is inside
encoding gradient can be thought of as analogous to the the bore of the magnet, and the signal is picked up by a ded-
different back projections obtained at different tube angles icated receiver coil. At its simplest, this receiver coil is a loop
in CT. An RF pulse and slice selection gradient, followed of wire, orientated perpendicular to the main magnetic
by one of the 256 amplitudes of phase encoding gradient field. An MRI scanner would typically have five or more dif-
and the frequency encoding gradient, are applied for each ferent coils dedicated to imaging different body parts, for
signal collected. The signals produced are digitized and example head, knee, spine, body, heart and breast coils,
stored in turn in a computer. This complete data set (called and a few general purpose coils for imaging the remaining
the k-space data) undergoes a two-dimensional Fourier parts of the body.
transform to produce the final MR image of the slice.
Figure evolve 5.25 shows the k-space data and Spectroscopy
corresponding MR image.
Single voxel magnetic resonance spectroscopy (MRS) is a
technique which produces a spectrum of the metabolites
MRI scanners present in a voxel. Most MRS is performed on hydrogen
The main components of an MRI scanner are the main nuclei as they are the most abundant nuclei and MRI sys-
magnetic, x, y and z gradient coils, a radiofrequency trans- tems and coils are already tuned to hydrogens resonant
mitter coil and a receiver coil. A computer controls the frequency. MRS can also be performed on 23Na and 31P.
timings of the RF pulses and currents through the gradient In the limited space available here only hydrogen MRS will
coils. Image reconstruction may be performed by the main be discussed.
computer or an additional specialized computer. The voxel which produces the MRS spectrum is normally
The majority of clinical MRI scanners use super- selected using RF pulses and gradient. For single voxel spec-
conducting magnets. These currently have field strengths troscopy, two techniques called PRESS [6] and STEAM [6]
between 0.5 and 3.0 tesla, but there are 7 and 8 T research are commonly used. An Fourier transform of the signal
systems. (The signal to noise ratio increases with field detected from the voxel gives the spectrum (Figure evolve
strength, but so does the potential for RF burns and scan- 5.29 ). A spectrum is produced because each metabolite
ner cost.) The super-conductivity (no electrical resistance) has a slightly different local magnetic field strength, due to
is achieved by cooling the wire coils which produce the its chemical environment. Therefore, each metabolite reso-
magnetic field to around 269 C using liquid helium. nates at a slightly different frequency. The area under each
These magnets have a cylindrical design, with the patients peak is proportional to the amount of metabolite present.
lying inside the bore (or tunnel), and the magnetic The water peak has to be suppressed, or this would dominate
field direction aligned with the bore. Figure evolve 5.26 the spectrum.
shows a commercial MRI scanner with a super- Chemical shift imaging (CSI) is another spectroscopic
conducting magnet. technique which produces a matrix of spectra from a matrix
Other types of magnet are available in commercial MRI of voxels encoded with a phase encoding gradient.
systems. For example, Figure evolve 5.27 shows an open
0.35 T permanent magnet. Although the magnet is heavy
(around 10 tonnes), running costs are low.
The remainder of this section will concentrate on the
cylindrical super-conducting magnet system, as it is by far
the most common. As the field produced by the magnet
is not completely uniform, it must be shimmed. A fixed
shim is achieved either passively using small pieces of steel
positioned around the magnet, and/or actively using com-
puter determined current magnitudes inside special super-
conducting coils called shim coils. As the patient affects
the magnetic field homogeneity, additional shimming is
also performed each time a patient is imaged. This dynamic
shimming uses the gradient coils and sometimes extra
(resistive) shim coils. Figure 5.28 Schematic diagram of a birdcage coil.
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Walter and Millers Textbook of Radiotherapy
Clinical applications of The single voxel spectrum from the glioma or meta-
MRI in oncology stasis is shown in Figure evolve 5.32 . For comparison,
a spectrum obtained from normal brain tissue was shown
Anatomical MR imaging is often used in the head, neck, in Figure evolve 5.29 . The very high level of lactate,
abdomen and pelvis for the detection of cancer, and staging and only slightly increased choline level, show that this
the disease. Contrast agents, which are gadolinium based, lesion is likely to be a metastasis.
and injected intravenously, shorten the T1 of tissue. Areas
of tumour with high vasculature are, therefore, highlighted
on T1 weighted images. Body tumours
Complete textbooks have been written on the use of MRI MRIs role in body cancer diagnosis and staging is vast.
in cancer diagnosis, staging, treatment planning and for As a purely illustrative example, we will look at the role
treatment monitoring. In this section, the application of of MRI in staging rectal cancer and the difference that it
MRI in brain tumour imaging is briefly outlined. MRI makes to treatment.
can be used to diagnose and stage cancer in most organs The very close proximity of the rectum to other organs
of the body including bladder, pancreas, bowel, and makes the very exact staging of rectal cancer critical. Figure
breasts, cervix and ovaries in women, and prostate in evolve 5.33A and B shows an early stage of rectal cancer,
men. The use of MRI in bowel cancer will be concentrated with the cancer confined within the rectum muscle
on as an example of this vast area. wall. This patient was managed by surgical resection.
Brain tumours Figure evolve 5.33C, D and E show a patient with the
later stage of rectal cancer, the cancer has extended outside
MRI scanning is unsurpassed as the ideal imaging medium the rectal muscle wall along the veins into the surrounding
for the diagnosis of brain tumours. Brain tumours make up fatty tissue (extra mural venous invasion). This patient
around 9% of all adult cancers. Approximately 80% are required combined radiotherapy and chemotherapy, fol-
primary tumours and 20% are secondary. lowed by surgery. MRI was used again at the end of the
Figure evolve 5.29 shows images of a large left fron- combined radiotherapy and chemotherapy to monitor
tal malignant glioma. Gliomas are the most common type the response of the tumour. The patient then had surgery.
(4550%) of primary brain tumour. Figure evolve 5.30A All patients with rectal cancer will have continued monitor-
shows the extent of the tumour appears as an area of hyper- ing with CT at 612 month intervals, to check for liver and
intense signal on the T2 weighted image. Pathological pro- other metastases.
cesses, such as a tumour or infarction, increase the amount MR images of tumours in the abdomen and pelvis are
of extracellular water, which can lead to cerebral oedema. occasionally fused with CT images for use during treatment
T2 weighted images (Figure evolve 5.30A ) are best at planning. The non-rigid nature of the anatomy makes
showing an increase in the amount of extracellular water, fusion more difficult than in the brain.
which also appear as hyperintense areas (white). On T1
weighted images, oedema appears as a hypointense (black)
area. A pre-contrast T1 weighted image of the glioma is
shown in Figure evolve 5.30B .
ULTRASOUND IMAGING
Discrimination between the tumour and surrounding
oedema can be helped by the use of gadolinium contrast, In this chapter, the emphasis is on the use of ultrasound in
which can enhance the tumour in the image. Gadolinium imaging. However, above the levels used for diagnosis, it is
is a rare earth metal with seven unpaired electrons. These used in various ways in the treatment of cancer and other
unpaired electrons enable nearby protons to align more conditions. These include lithotripsy, hyperthermia, drug
quickly and shortens the T1 and T2 relaxation times. activation and enhancement and high intensity focused
Usually, low grade gliomas do not enhance on T1 weighted ultrasound (HIFU) to ablate soft tissue.
images with gadolinium, however, high grade gliomas
enhance avidly, often with a heterogeneous appearance Overview of ultrasound imaging
due to haemorrhage or necrosis. Figure evolve 5.30C
process
shows areas of strong contrast enhancement where the
glioma has broken down the bloodbrain barrier. However, Ultrasound is defined as a vibration with a frequency
isolated tumours cells can penetrate beyond the tumour above the upper limit of human hearing at 20 kilohertz
margins visualized using MRI. This is significant with regard (1 hertz 1 vibration cycle per second). In fact, medical
to the margins used in planning (see Chapter 9). ultrasound most often uses much higher frequencies,
The type of brain tumour can usually be determined by usually between 1 and 20 MHz, but sometimes higher
its location and appearance. The tumour shown in Figure frequencies for applications such as acoustic microscopy.
evolve 5.31 could, from its visual appearance and Ultrasound moves as a longitudinal pressure wave
location, have been a glioma or metastasis. through soft tissue with areas of compression and
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Chapter |5| Imaging with x-ray, MRI and ultrasound
rarefraction travelling through the tissue. Considering a For interfaces between soft tissues, the amount reflected
small area of tissue this will vibrate to and fro along is usually between 0.01 and 1%. For a soft tissue to air inter-
the direction of travel of the ultrasound wave as the pres- face, 99.9% of the ultrasound is reflected. The practical con-
sure wave passes. The amplitude of the ultrasound wave sequence of this is that ultrasound cannot image beyond gas,
can be defined in various ways, such as the peak pressure, so that lung tissue cannot be imaged. Bowel gas can be a
the peak distance displaced or peak velocity of a small area problem in the abdomen. Also, the air gap between the ultra-
of tissue. sound transducer and the skin must be eliminated using
Cf w ultrasound gel when scanning. Imaging into and beyond
bone is usually difficult as bone both reflects a lot of the
where C speed of sound (m/s), f frequency (Hz) and
ultrasound and highly attenuates the ultrasound beam.
w wavelength (m).
For smooth interfaces between different tissues, reflec-
For soft tissues, the average speed of sound is 1540 m/s.
tion will be mirror like, so that the angle of reflection
So, for medical ultrasound, the wavelength is from about
equals the angle of incidence. Also, the transmitted part
0.075 to 1.5 mm. The resolution of ultrasound images
of the wave may be bent slightly (refracted) due to the dif-
is related to the wavelength, so higher frequency ultrasound,
ference in sound velocity between the materials. Usually,
which has a smaller wavelength, gives better resolution.
for soft tissues, the angle of refraction is small and is
The speed of ultrasound in tissue is related to the bulk
neglected.
modulus and the density of the tissue through which the
For rough interfaces, the ultrasound will be reflected at a
ultrasound travels. The bulk modulus is defined as the
variety of different angles. For small scatterers, which are
change in pressure divided by the fractional change in
much smaller than the wavelength, the ultrasound is scat-
volume for a material. So, for harder materials, where a
tered in all directions. This is called Rayleigh scattering and
given change in pressure will result in a small change in
occurs for instance for red blood cells.
volume, the bulk modulus is large. Higher density results
As it travels through tissue, energy will be lost from the
in a lower velocity.
ultrasound beam by scattering of ultrasound away from
C B=D 5:10 the beam direction and by energy absorption in the tissue.
where C speed of sound (m/s), B bulk modulus Energy absorption occurs when the coherent vibration of
(N/m2) and D density (kg/m3). the ultrasound wave is degraded into random motion
B dP= dV=V V dP=dV 5:11 of the tissue i.e. heat.
Attenuation of the ultrasound beam is usually pro-
where P pressure (N/m2) and V volume (m3).
portional to the frequency of the ultrasound, so higher
The speed of ultrasound in different soft tissues is
frequency ultrasound is more highly attenuated. This results
generally within about 6% of 1540 m/s. The speed of
in a compromise between attenuation and image resolution.
ultrasound in harder tissues, such as bone, is much
For superficial structures, a higher frequency is usually used
higher at about 3200 m/s. Air, which has a low bulk
to give better resolution. For deeper structures, a lower fre-
modulus and low density, has a much lower speed of
quency with poorer resolution may be needed to allow suf-
sound at 330 m/s.
ficient ultrasound to penetrate the tissues.
For diagnostic purposes, ultrasound gives us information
related to the mechanical properties of tissue. Ultrasound
is reflected from interfaces between tissues with different Ultrasound scanners
mechanical properties. The amount of ultrasound reflected
Ultrasound machines use piezoelectric materials to gener-
depends on the acoustic impedance of the material.
ate and detect ultrasound.
Considering a small area of tissue, the acoustic imped-
The piezoelectric effect was discovered by Pierre and
ance is defined as the ratio of the pressure amplitude
Jacque Curie in 1880 and occurs in some materials where
divided by the velocity amplitude of this small area of tissue
there is a polarized crystal structure. When a piezoelectric
as the ultrasound wave passes through it. The acoustic
material is compressed, it generates a voltage across the crys-
impedance can also be defined relative to the speed of
tal structure. An opposite voltage is generated if the crystal is
sound and tissue density.
subjected to low pressure. Thus, a piezoelectric crystal will
ZrC 5:12 generate an alternating voltage across it as ultrasound
where Z acoustic impedance, r density and C speed passes through it and can be used as a detector. Conversely,
of sound in tissue. if an alternating voltage is applied across a piezoelectric
The fraction of ultrasound reflected from an interface crystal, it will vibrate and hence can be used to generate
between tissues of different acoustic impedances can be ultrasound.
calculated below. The most commonly used piezoelectric material is a
ceramic material, lead zirconate titanate (PZT).
R Z1 Z2 2 = Z1 Z2 2 5:13
Originally, a focused beam of ultrasound was produced
where R fraction of ultrasound reflected. by using a flat disk piezoelectric element with an acoustic
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Walter and Millers Textbook of Radiotherapy
lens attached to the front. A curved piezoelectric element grey scale image. The colour on the image is coded according
can also produce a focused beam, but is more difficult to to the direction of the flow relative to the beam and the size
manufacture. Modern ultrasound transducers use an array of the frequency shift, which is related to the blood flow
of many small piezoelectric elements. Focusing can be velocity. Colour Doppler images can give an idea of the vas-
produced by electronically altering the delay in the pulse cularity of tissue. Figure evolve 5.36 shows a colour flow
applied to each element so that the peak of the ultrasound Doppler image of blood flow in the common carotid artery.
wave occurs at the focus for all elements. The depth of focus Encapsulated microbubbles can be injected into the
can be altered by electronically altering the amount of delay blood stream as a contrast agent to increase the reflections
applied to the elements. Likewise, a stepwise delay across from vascular tissue [7].
the elements can be used to steer the ultrasound beam. A newer technique, called elastography, can map out
To produce an ultrasound image, the SONAR (sound how hard various tissues are [8]. It achieves this by mea-
navigation and ranging) principle is used. This was origi- suring the distortion of the tissues on ultrasound images
nally used to detect submarines. A short pulse is directed with and without applying pressure to the tissue. Some-
along a narrow beam and the depth from which the echoes times, elastography can demonstrate changes in the hard-
were generated within the tissue is calculated from the time ness of tissue surrounding a mass demonstrated on the
delay between the transmitted pulse and the echoes return, B mode image. This suggests that infiltration into the sur-
knowing the speed of ultrasound in tissue. For each pulse rounding tissue has occurred and that the B mode image
transmitted, the amplitude of the echoes can be used to alone may underestimate the extent of the tumour local
modulate the brightness of the image screen along a line involvement in some cases.
in the image.
By moving the line along which the beam is directed
Clinical applications
for subsequent pulses, a 2-dimensional image of the
amplitude of echoes from the tissue can be built up. This As previously shown, the dependence of ultrasound imag-
is called a B mode image or brightness mode image (Figure ing on the transmission and reflection at tissue interfaces
evolve 5.34 ). and the poor transmission through an airtissue interface
As ultrasound travels very quickly in soft tissue limits the clinical applications of ultrasound imaging. It
(1540 m/s), each ultrasound image can be acquired very is of no value in examining the lungs or the gastrointesti-
quickly and frame rates of between 5 and 40 images per nal tract.
second can be achieved, allowing real time imaging. This Its use in obstetrics to image the fetus is widely known.
allows following movements of the heart and real time The age of the pregnancy, fetal growth and fetal abnormal-
guidance of biopsies from suspicious areas on the ultra- ities can be monitored and detected.
sound image. However, ultrasound can identify abnormal structure,
The movement of blood and tissues can be measured size or texture of many different organs in the body. It is
using the Doppler effect. The Doppler effect occurs when used widely in the diagnosis of cancer, assessment of its
a wave is reflected from a moving structure. If the struc- local extent and staging. Masses can be identified and
ture is moving towards the sound source, the wavefronts characterized, helping to differentiate solid masses from
are compressed and this increases the frequency of the benign fluid-filled cysts. Often, the ultrasound appearance
ultrasound. Likewise, the frequency is decreased when of a solid mass is not specific enough to diagnose whether
the structure is moving away from us. The most familiar a lesion is cancerous, so needle biopsy of masses is usually
everyday example of this is a car horn, which sounds higher performed under ultrasound guidance to define a lesions
pitched when the car approaches and lower as the car histology.
passes and moves away from us. Good images are produced if there is a tissuefluid inter-
Pulsed mode Doppler ultrasound uses repeated sam- face and, therefore, ultrasound is particularly effective at
pling of the ultrasound from a sample volume in a blood showing whether lumps are cystic or solid. For this reason,
vessel and gives a detailed real time blood flow velocity ultrasound is frequently used to examine the breast. Ultra-
spectrum, allowing the changes in flow during the heart sound can distinguish between solid (often malignant) and
cycle to be studied and the blood velocity to be calculated. cystic (often benign) lumps within the breast. Ultrasound
Figure evolve 5.35 shows a pulsed Doppler mode blood images are influenced by vasculature of the scanned organ
velocity spectrum in the lower half of the image. and the differences in the blood supply within that organ.
It shows the blood flow velocity spectrum (vertical axis) This difference may also be used to differentiate between
in a small sample volume as it changes with time (horizon- benign and malignant disease within the breast.
tal axis). Each peak represents high systolic flow at the start Ultrasound is a sensitive technique for detecting metas-
of each heart cycle. The small upper image shows where tases within the liver as metastases often reflect the sound
the sample volume was located. wave poorly and produce hypoechogenic areas. The use
Colour Doppler ultrasound measures the shift in fre- of gas bubbles as an ultrasound contrast agent can help
quency from moving blood and overlays this on the B mode to characterize the blood supply in liver tumours. Liver
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Chapter |5| Imaging with x-ray, MRI and ultrasound
tumours often derive their blood supply from the hepatic clearer images to be produced. Trans-rectal and trans-vagi-
artery which makes them enhance early on contrast studies. nal ultrasound probes can be used in imaging of the pros-
Liver tissue that has a blood supply from the portal vein will tate, ovary or uterus for instance. Trans-vaginal ultrasound
enhance later. can be used to measure the thickness of the lining of
Small endoscopic ultrasound probes can be used to the uterus (the endometrium) and is a sensitive measure
assess the invasion of a tumour into the bowel wall and sur- for screening for endometrial cancer in patients with
rounding tissue. post-menopausal bleeding. It also produces good images
Intracavity probes can be introduced into the body to of ovarian cysts and solid areas within these cysts can be
allow the ultrasound transducer to be as close as possible demonstrated which helps decide whether the lesion is
to the tissue of interest. This allows higher resolution, likely to be benign or malignant.
REFERENCES
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Whittingham T. Diagnostic Prince MR. MRI: from picture to Charboneau JW. Diagnostic
ultrasound: Physics and equipment. proton. Cambridge University Press; ultrasound. 3rd ed. Elsevier Mosby;
Greenwich Medical Media Ltd; 2002. 2003. 2005.
[2] Statutory Instrument 2000 No. 1059. [5] Elster AD, Burdett JH. Questions and [8] Ophir J, Alam SK, Garra B, et al.
The Ionising Radiation (Medical answers in magnetic resonance Elastography: ultrasonic estimation
Exposures) Regulations 2000. imaging. Mosby; 2000. and imaging of the elastic properties
[3] Edelstein WA, Hutchison JMS, [6] Keevil SF. Spatial localization in of tissues. Proceedings of the Institute
Johnson G, Redpath TW. Spin warp nuclear magnetic resonance of Mechanical Engineering
NMR imaging and application to the spectroscopy. Phys Med Biol 1999;213:20333.
human whole-body imaging. Phys 2006;51:R579636.
Med Biol 1980;25:7516.
Figure evolve 5.21 T1 weighted image weighted image. The contrast agent invasion. The dark arrows point to
(TR 554 ms, TE 13 ms), T2 weighted clearly defines the area of the the tumour and the light arrows
image (TR 5070 ms, TE 98 ms) glioma where blood/brain barrier to areas of extra-mural venous
and proton density (TR 370 ms, has broken down invasion
TE 15 ms) Figure evolve 5.31 (A) Axial T2 weighted Figure evolve 5.34 A B-mode transverse
Figure evolve 5.25 (A) k-space data image of a glioma or brain metastases. image of the neck showing a map
stored; (B) the two dimensional (b) Axial T1 weighted image post of the brightness of reflection of
Fourier transform of the k-space data contrast ultrasound from different tissues.
Figure evolve 5.26 An MRI system with a Figure evolve 5.32 Spectrum from the Blood vessels are dark on B mode
cylindrical super-conducting magnet metastasis showing an extremely images as blood reflects relatively
Figure evolve 5.27 An open MRI system elevated lactate peak, and slightly little ultrasound
with a permanent magnet elevated choline levels. The spectrum Figure evolve 5.35 Pulsed mode
Figure evolve 5.29 Spectrum from a was obtained using STEAM with Doppler sonogram of flow in the
voxel normal brain tissue showing a TE 30 ms internal carotid artery
high N-acetyl aspartate (NAA) peak, Figure evolve 5.33 (A) Sagittal image Figure evolve 5.36 A colour Doppler
and choline (Cho) levels below those of early stage rectal carcinoma image of flow in the common carotid
of creatine (Cr). Obtained using a (dark arrow) still contained within artery. The background B mode
STEAM sequence TE 30ms the rectal muscle wall (light arrow). information shows the echoes of
Figure evolve 5.30 (A) T2 weighted (B) Coronal image of early stage stationary tissue. Within the colour
pre-contrast axial image showing rectal carcinoma (dark arrow) still box flowing blood is colour coded
a large left frontal lobe malignant contained within rectal muscle according to the direction of flow
glioma. (B) Pre-contrast T1 weighted wall (light arrow). (C), (D) and and size of the frequency shift, which
axial image. (The same slice (E) Axial, sagittal and coronal is related to the blood flow velocity
position is shown as previous images of a stage 3 rectal cancer, and the angle of the flow relative to
image.) (C) Post-contrast axial T1 which has extra-mural venous the beam direction
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Chapter |6|
Imaging with radionuclides
Marjorie Rose, Nigel R. Williams
the ordered transfer from the object to the image. Radio- in the body. The distribution of the radiopharmaceutical
nuclide imaging is primarily concerned with the function is related to the physiology or function of an organ, tissue
of organs and tissues. The other modalities, x-ray, magnetic or tissue type; this is in contrast to x-ray, MR or ultrasound
resonance imaging (MRI) and ultrasound, primarily con- imaging which, to a large extent, images structure.
vey structural or anatomical information, though the dis- Gamma rays are imaged by a device known as a gamma
tinction between structural and functional imaging is not camera. The device used to detect annihilation photons
absolute. The detected signal is often processed in some resulting from the decay of a radionuclide emitting posi-
way before being displayed. Multimodality combinations trons is referred to as a PET camera. Gamma cameras are
of images, as in positron emission tomography and x-ray a large area detection device capable of forming an image
computed tomography (PET-CT), can provide an especially of the distribution of a radionuclide within the body.
powerful tool for discriminating between normal and The majority of devices have two detector heads, although
malignant tissues [1]. it is possible to purchase single or triple head equipment.
Nuclear medicine is the science and clinical applica- Imaging with a gamma camera can take place with the
tion of unsealed radiopharmaceuticals for diagnostic and detector heads in a stationary position, planar mode, or
investigative purposes and this includes imaging. A suitable with the detector heads moving around the body through,
radionuclide or isotope is combined with a pharmaceutical typically, 180 or 360 . This mode of acquisition is known
or a molecule which marks a particular biological function as single photon emission computerized tomography
or process. The behaviour of this radio-labelled compound (SPECT) or, dropping the reference to computerization
is monitored by radiation detectors external to the body, (SPET). PET cameras work on the basis of a series of rings
allowing the non-invasive measurement of in-vivo bio- of stationary detectors, identifying the location of a nucleus
chemical function, aspects of tissue function, and dynamic decaying via positron emission, by detection of both anni-
biological processes. Localization of functional informa- hilation photons within a predefined time (nanoseconds).
tion is increasingly becoming essential information for This is sometimes referred to as coincidence imaging.
cancer diagnosis and radiotherapy treatment. The most up-to-date gamma cameras and all PET cameras
are now manufactured with an x-ray CT imaging
device incorporated into the gantry. In both cases, the pri-
OVERVIEW OF THE RADIONUCLIDE mary purpose of this ancillary facility is to allow the use of
the structural CT (transmission) images to be converted into
IMAGING PROCESS an attenuation map [2]. This map is used to correct the func-
tional nuclear medicine (emission) images for variation in
Nuclear medicine departments routinely perform diag- body tissue thickness and density. Having the CT imaging
nostic imaging and non-imaging procedures and, in many incorporated into the cameras allows the emission and trans-
hospitals, undertake radionuclide radiotherapy treatments. mission images to be acquired sequentially in the same
However, in this chapter, only radionuclide imaging will patient imaging session. Assuming there is no patient move-
be described and therapeutic applications are dealt with ment, the data derived from the transmission image can be
in Chapter 7. A radionuclide is an unstable isotope of an accurately applied to the emission images. This process is
element that will spontaneously decay by the emission applicable to SPECT images acquired on gamma cameras
of particles and/or electromagnetic radiation. The three and all images acquired on PET cameras. Consequently,
most common emissions from radionuclides are alpha imaging techniques associated with these devices are known
and beta particles and gamma rays. There are two types as SPECT/CT and PET/CT. Initially, the CT units were not of a
of beta particle, beta minus (b) and beta plus (b), they standard comparable to the most up-to-date helical multi-
are both electrons with a negative and positive charge, slice devices and the structural images obtained were not
respectively. A beta plus is referred to as a positron. of a diagnostic quality. However, gamma cameras and PET
A gamma ray is a form of electromagnetic radiation and scanners can now be purchased with high specification CT
is the only one with sufficient penetrating characteristics units attached and the registration or fusion of high spatial
to enable it to be detected externally if originating from resolution structural images with the sensitive but poor res-
within the body. Most use is made of a relatively limited olution function images results in an imaging device that is
number of radionuclides that emit only gamma rays. How- extremely effective at identifying and localizing pathology.
ever, there is a growing use of radionuclides that decay by
emitting a positron; this particle is not penetrating but
interacts with an electron, both annihilating to form two GAMMA CAMERAS
photons travelling in opposite directions. These photons
are penetrating and can be detected as they leave the body. Gamma cameras (Figure 6.1) are imaging devices used to
A radionuclide is attached, or labelled, to a pharmaceutical, detect and record the distribution of a radiopharmaceuti-
forming a radiopharmaceutical. This is introduced into the cal within the body. Gamma rays are detected by a large
body, most commonly by intravenous injection but also by area crystal of sodium iodide doped with trace quantities
ingestion and inhalation, and has a known biodistribution of thallium (NaI(Tl)), the crystal structure has the
98
Chapter |6| Imaging with radionuclides
99
Walter and Millers Textbook of Radiotherapy
energy collimators are available with descriptions such as achieved with the aid of a CT attenuation map. A CT acqui-
high sensitivity, general purpose, high resolution and very sition represents the variation of x-ray absorption through-
high resolution. The exact characteristics of each collimator out the image volume, a direct relationship can be made
can vary immensely between manufacturers. between this and the attenuation of the emitted gamma
radiation. An example of nuclear medicine images that
have been attenuation corrected and fused with the CT
IMAGING TECHNIQUES structural images is shown in Figure evolve 6.6 . Note that
the CT device in this example is a low dose unit, not in the
Planar imaging diagnostic category.
100
Chapter |6| Imaging with radionuclides
Corrections can be made during data acquisition to over- arranged in 360 rings, with typically 15 to 30 rings con-
come some of the non-random defects in camera per- sisting of the order of 10 000 individual crystal elements.
formance. These include corrections for non-uniformity The crystal size is one of the main factors in limiting the
of sensitivity, non-uniformity of energy resolution, and spatial resolution, commonly 4 mm (FWHM) [7].
non-linearity. Although systems designed for special purposes, such as
There are additional performance characteristics to take brain scanning, can achieve 2 mm. The computer system
into account when performing SPECT imaging and still is able to reconstruct the line connecting two detected
further with SPECT/CT. SPECT imaging requires the centre events in opposite crystals as a line of response (LOR).
of rotation (COR) of the rotating camera heads to be within Millions of LORs are acquired over a period of time and
predefined limits. Failure to do so will result in artifacts on reconstructed to form cross-sectional images using appro-
the reconstructed SPECT images. It is also important that priate image reconstruction software.
the parameters defining the detector heads remain stable Attenuation of the annihilation photons within the body
at every angle of rotation. SPECT/CT relies on the accurate is an issue in the same manner as it is for SPECT imaging.
registration of the SPECT and CT images. The performance Ironically, although the 511 keV photon energy is much
of the CT is assessed as for all CT equipment, as covered by higher and therefore much more penetrating than the
IPEM Report 91 [6]. A crucial additional assessment is the Tc-99m 140 keV emission most widely used in SPECT,
alignment of the SPECT and CT data together. Phantoms attenuation effects are more pronounced on the recon-
are routinely used to assess the gamma camera SPECT capa- structed images. This is because the majority of detected
bility and SPECT/CT alignment. photons will have had to pass through the equivalent of
the total body thickness, the exception being activity
located close to the body surface. Correction for the quali-
POSITRON EMISSION TOMOGRAPHY tative and quantitative impairment of PET images due to
attenuation is achieved by the acquisition of CT attenua-
SCANNERS tion correction maps. CT was introduced for this purpose
in the early 2000s and all PET equipment now has diag-
Dedicated positron emission tomography cameras nostic quality CT units attached. As for SPECT, the primary
(Figure 6.3) are designed specifically for radionuclides purpose of the CT is for its correction function, but the
that decay by positron emission. Scintillator crystals with quality of the CT greatly enhances the diagnostic capability
high stopping power are utilized, examples are bismuth of the modality as functional and structural information is
germanate (BGO) and lutetium orthosilicate (LSO). These fused on a single set of images.
crystals, coupled to photomultiplier tubes, are positioned
in rings around a gantry. Electronic circuitry, designed to
register if two crystals detect a photon within a coinci- RADIOPHARMACEUTICALS
dence time, usually a few nanoseconds, allow true events
to be detected. Many single events will be detected. The A wide range of radiopharmaceuticals is available [8]. The
size of the crystal elements depends on the make and most common route of administration is intravenous, but
model, but is generally 3 to 6 mm. The elements are radiopharmaceuticals may be administered orally or by
inhalation. The intramuscular, intracavity and intrathecal
routes are possible, but rare.
When deciding upon the efficacy of a given radiophar-
maceutical, the physical and chemical properties of the
radionuclide, together with biochemical, physiological
and pharmacological properties of the pharmaceutical,
must be considered.
The radionuclide
The best possible radionuclide to use for any given proce-
dure will depend upon its properties, which include:
type of radiation emitted, its energy and abundance
half-life
specific activity
radionuclidic purity
chemical properties of the element.
Figure 6.3 Dedicated PET camera. Each of these properties is considered below.
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Walter and Millers Textbook of Radiotherapy
102
Chapter |6| Imaging with radionuclides
Diffusion and isotope dilution on thyroid function. Radioactive iodine introduced into
the body therefore enables iodine metabolism to be studied
Tracers may be used that distribute themselves throughout
easily. Iodine-131 and iodine-123 are two radionuclides
the space in the body into which they were introduced. Imag-
commonly used for imaging thyroid tissue (see below).
ing of their distribution can identify the extent of these areas
or demonstrate where their natural boundaries have broken
down. For example, ventilation imaging, which depends Metabolic trapping
upon the inhalation of a suitable tracer, such as krypton- Some radiopharmaceuticals become trapped within the
81m gas, into the lungs where it diffuses throughout the func- tissue into which they have been transported by metabolic
tioning air spaces, allowing them to be visualized. processes. Certain radiopharmaceuticals have been devel-
Isotope dilution is a quantitative method which depends oped specifically to exhibit this behaviour. For example,
on complete mixing of a radiopharmaceutical through- technetium-99m tetrofosmin and methoxy isobutyl iso-
out a body space. Knowledge of the administered activity nitrile (MIBI) were developed to mimic the distribution
and the radioactive concentration of a sample of the fluid of uptake of thallium-201 used in myocardial perfusion.
within the space once mixing is complete, will allow the Thallium-201 washes out of the tissues quickly but the
volume of the space to be calculated. An example is the technetium-99m-labelled analogues are trapped, allowing
determination of red cell mass. plenty of time for the distribution of tracer to be imaged.
F-18 fluorodeoxyglucose (F-18 FDG) is the most widely
Capillary blockade and cell sequestration used radiopharmaceutical in PET imaging. It is commonly
described as a metabolic marker. Its chemistry is modified
If radioactive particles in the size range 2050 mm are
by the label so that it becomes trapped with cells and
injected into the vascular system, they will partially occlude
its method of localization comes under the heading of met-
the first capillary bed they encounter (the size of capillaries
abolic trapping rather than metabolic pathway (see below).
is 810 mm). An intravenous injection of half a million
technetium-99m labelled particles of MAA will block
approximately 0.05% of the capillaries of a normal lung, Antibodies and antibody fragments
thus permitting the visualization of the vascular bed of Antibodies are large Y-shaped molecules consisting of
the lungs. A protein such as albumin is chosen for produc- proteins. They form part of the bodys immune response.
tion of the particles, as it will be broken down naturally The body manufactures them as needed to neutralize the
and removed from the lungs. threat posed to the body by foreign or harmful material.
The material that triggers the antibody response is called
Phagocytosis the antigen. Antibodies are produced in the body at the site
of need. They are not designed to be carried in the blood
The reticuloendothelial1 cells in the body have the capa-
seeking out suitable receptors but that is what nuclear med-
city to ingest bacteria and small particles in the range
icine requires of them as diagnostic or therapeutic agents.
0.0110 mm. This is known as phagocytosis. If a radio-
One possible solution to this dilemma is to split them into
labelled colloid is injected intravenously, the phagocytic
fragments which retain the functionality but are more
action of the reticuloendothelial cells, in particular the Kupf-
mobile than the whole antibody.
fer cells in the liver, will remove the colloid from the circu-
Antibodies can be raised against substances which are not
lation, enabling the organ to be visualized. Areas of non-
foreign to the body. For example, there are anti-leukocyte anti-
functioning liver tissue will not remove colloid material.
bodies. These, or fragments of them, can be radiolabeled and
used to investigate the distribution of circulating leukocytes
Metabolic pathway and sites of accumulation of them in the body (see below).
The metabolic pathway of a huge number of substances can Potentially there are an enormous number of antibodies
be investigated using radioactive techniques. They may be that could be used in nuclear medicine but only a handful
designed specifically to trace a particular body function, is available commercially.
such as technetium-99m-labelled mercapto acetyl trigly-
cine (MAG3) for the investigation of kidney function. Receptor binding
Iodine is incorporated into the hormones produced by
The experience gained in attempting to label antibodies has
the thyroid gland, and a study of the metabolic behaviour
paid dividends in the area of receptor labelling. Receptors
of iodine in the body gives valuable diagnostic information
are found in all areas of the body and their specificity has
been exploited in various commercially available products.
One example is Octreotide, a somatostatin receptor imag-
1
Reticuloendothelial cells are concerned with defense against microbial ing agent, formulated to be labelled with indium-111. It
infection and with the removal of worn-out blood cells from the blood
stream (taken from the Oxford Medical Dictionary, 4th edn, (2007), can be used to investigate and treat neuroendocrine and
Oxford University Press). other tumours (see below).
103
Walter and Millers Textbook of Radiotherapy
Production and quality control of Act and the Ionising Radiation (Medical Exposures) Reg-
radiopharmaceuticals ulations 2000 [11].
If the binding of the radionuclide to the pharmaceuti-
For the vast majority of studies, radiopharmaceuticals cal is poor, the distribution of radioactivity in the body
are bought from a supplier; either as the labelled com- may appear unusual or abnormal. Poor binding can be
pound ready for administration or as a sterile kit containing due to the radiopharmaceutical or one of its components
the chemicals to label the desired radionuclide on site. or it may be due to a fault in reconstitution. Radiophar-
The chemicals are supplied freeze dried in a vial ready to macies measure the radiochemical purity, usually by
be reconstituted when needed. The most common type is chromatography, to check the binding. Unusual distribu-
the technetium-99m cold kit. There are many examples tions in images should be reported to the radiopharmacy
of these. They all contain the pharmaceutical itself, some for investigation, although other situations can arise
form of reducing agent to pull the technetium away from that will modify the distribution. For example, a woman
its pertechnetate environment and additional material who is breastfeeding may exhibit increased uptake of
required to bulk out the contents so that they freeze-dry radioactivity due to uptake into milk. Also, prescribed
successfully. There may be additional chemicals to buffer and over-the-counter drugs may affect the distribution
the solution to ensure that it maintains the correct pH of a radiopharmaceutical.
and other substances required to ensure optimum chemical
binding between the radionuclide and the pharmaceutical.
The pertechnetate itself is obtained from a molybdenum- CLINICAL APPLICATIONS
99 generator, obtained from a manufacturer once or twice
a week, and eluted once or twice a day. Imaging of the distribution of a radiopharmaceutical
The bulk of the quality control of a radiopharmaceutical within an organ and, in some cases, how it changes with
or its components is the responsibility of the manufacturer. time, enables deductions to be made about the function
However, each nuclear medicine department is required of the organ. An abnormal distribution may appear as an
to ensure the quality of the radiopharmaceuticals it uses. increase in radioactive concentration above the surround-
For the majority of diagnostic tests, intravenous injec- ings or the expected margins, revealing lesions as hot spots;
tion is necessary so great care must be taken to produce a or as reduced activity in the visualized pattern. The appear-
radiopharmaceutical in a sterile solution of the correct ance of hot spots does not necessarily mean that a lesion is
pH value and free from foreign proteins arising from pre- larger than the minimum resolvable power of the gamma
vious bacteriological activity (pyrogens). To ensure this, camera; if the amount of activity accumulated in the lesion
they are obtained from an on-site or off-site radiopharmacy is large enough compared to its surroundings, the lesion
which is either licensed by the Medicines and Health- will be detected in the image. Cold spots are sometimes
care Products Regulatory Agency (MHRA) or can claim referred to as photopenic areas; they are more difficult to
an exemption under the Medicines Act 1968 [10]. detect than hot spots because the margins are blurred with
Specialized cabinets are used to provide an environ- respect to the surroundings.
ment that caters for the conflicting requirements of the The purpose of imaging is to investigate organ function
radiation safety of the operator and the need for aseptic rather than anatomical definition. The following provides
production. For radiation safety, it is customary to provide a brief description of some of the more important clinical
an environment at a lower pressure than its surroundings applications of radionuclide imaging, directly or closely
to contain any airborne contaminants. However, the prep- applicable to imaging cancer.
aration area must be bathed in pure sterile air at a pressure Table 6.1 is a list of commonly used radiopharmaceuti-
higher than that of the surroundings so as to avoid inward cals with notes on their more important uses, details of
leakage of non-sterile air and micro-organisms. The label- the diagnostic reference level, the absorbed dose to the
ling of a patients own cells is classed as a medical proce- critical organ and the effective dose to the whole body from
dure and is undertaken in specialized facilities with more ICRP 80 [12].
stringent requirements for protection of the operator and Table 6.2 gives comparative examples of the effective
the product. dose from some common radiopharmaceutical investi-
Prior to administration, the label on the vial, syringe gations and common radiology investigations.
or capsule, if oral administration, is checked against that
prescribed for the procedure. The activity given to the
patient is checked independently on a radionuclide cali-
Bone imaging
brator which measures the activity in MBq for the radio- Bone imaging is the most widely used investigation in
nuclide specified. The consistency of the radionuclide nuclear medicine and the majority of referrals relate to
calibrator is checked daily and its calibration is traceable patients with known primary tumours and suspected bone
to national standards. The activity is noted in the patient secondaries. Bone is made up of collagen and minerals,
record. These checks are required under the Medicines mainly calcium, phosphates and hydroxides. The minerals
104
Chapter
Table 6.1 Examples of some radionuclides in common diagnostic use with critical organ (CO), effective dose (ED) and diagnostic reference level (DRL) activity
RADIONUCLIDE CHEMICAL CLINICAL USE DRL PHYSICAL ROUTE CO DOSE TO CO FROM ED FROM
FORM ACTIVITY HALF-LIFE ACTIVITY (mSv) ACTIVITY
(MBq) (mSv)
|6|
Chromium-51 Sodium chromate Red blood cell 4 27.8 days Red cell Spleen 6.4 0.7
volume labelling and
IV
Indium-111 Indium oxide Infection and abscess 20 2.8 days Leukocyte Spleen 110 7
labelled imaging labelling and
leukocytes IV
Iodine-123 Sodium iodide Thyroid imaging 20 13.2 h Oral or IV Thyroid 90 4 for 35%
uptake
Iodine-125 Human serum Plasma volume 0.2 60 days IV Heart 0.1 0.04
albumin (HSA) measurement
Iodine-131 Sodium iodide Thyroid metastases 400 8.1 days Oral or IV Bladder 244 24 for 0%
imaging uptake
Continued
105
106
Table 6.1 Examples of some radionuclides in common diagnostic use with critical organ (CO), effective dose (ED) and diagnostic reference level (DRL) activitycontd
Xenon-133 Gas Lung ventilation 400 5.25 days Inhalation Gonads 0.5 0.4
imaging
Chapter |6| Imaging with radionuclides
Table 6.2 Effective dose from some common radiopharmaceutical and radiological examinations
107
Walter and Millers Textbook of Radiotherapy
imaging and with iodine-131 for pretreatment dosimetry and extra-hepatic metastases in colorectal and ovarian
and therapy. Normal adrenal medulla tissue will concen- cancer but its role is controversial.
trate the agent as will neuroendocrine tumours or tumours
of neural crest origin, such as phaeochromocytoma, neuro-
Imaging thyroid cancer
blastoma, carcinoid tumours and medullary carcinoma of
the thyroid. Uptake into tumour can be inhibited by many Nuclear medicine imaging of the thyroid plays a minor
drugs, including tricyclic antidepressants; therefore care role in the initial diagnosis of thyroid cancer. Ultrasound
must be taken to withdraw any potentially interfering med- and fine needle aspiration (FNA) is the first line imaging
ication well in advance. technique [13].
The normal function of the thyroid gland includes the con-
centration of iodine from the circulation, and the synthesis
Octreotide somatostatin receptor imaging
and storage of thyroid hormones. Iodine may also be trapped
Somatostatin is a 14-amino acid peptide found in brain, in the salivary glands and the gastric mucosa. Iodine-131 was
where it acts as a neurotransmitter, in the gastrointestinal once the radionuclide of choice for all thyroid imaging. How-
tract, as well as the pancreas, where it is manufactured. ever, because it delivers a relatively high radiation dose to the
It inhibits the release of neuroendocrine hormones, such patient and it has poorer imaging properties, it has been
as growth hormone and insulin. almost completely superseded by iodine-123 and techne-
Somatostatin receptors are found in normal pituitary, tium-99m pertechnetate for routine diagnostic thyroid
pancreas and upper gastrointestinal tract from stomach to imaging. Iodine-131 continues to be used for therapy (see
jejunum. They are also expressed by a variety of endocrine Chapter 7) and, in some centres, for whole body imaging
tumours, such as carcinoid, small cell lung cancer, in in patients who have previously undergone treatment for thy-
tumours of ovary, cervix, endometrium, breast, kidney, lar- roid cancer and where further disease is suspected.
ynx, paranasal sinus, salivary gland and some skin tumours, Figure evolve 6.7 shows a whole body I-131 scan on a
and tumours arising from glial cells in the central nervous sys- patient previously treated for thyroid cancer but with wide-
tem. It can be surmised that somatostatin receptor imaging spread metastases. Sometimes suspected thyroid metastases
could therefore be clinically useful in a variety of tumours. do not appear hot on the I-131 scan. In such circumstances,
However, somatostatin has a half-life of only 2 to 3 minutes they may be designated to be not iodine avid and an F-18
in the body so such imaging was not feasible until the avail- FDG study may be considered for further evaluation.
ability of Octreotide [8], a somatostatin analogue with a
much longer clearance time than the natural peptide.
Octreoscan is a kit which enables the attachment of Cardiac imaging
indium-111 via pentetate to Octreotide to form pente- The commonest cardiac investigation performed in the
treotide. Sufficient pentetreotide uptake for visualization nuclear medicine department on oncology patients is
can occur with many carcinoid tumours, pituitary tumours, gated blood pool imaging. It is correctly called equilibrium
gastrointestinal tract endocrine tumours (although disap- radionuclide ventriculography but more often termed a
pointing in insulinoma), small cell lung cancer, medullary MUGA (multiple gated acquisition) scan. It is used to eval-
carcinoma of thyroid, neuroblastoma, pheochromocy- uate cardiac function, in terms of left ventricular ejection
toma, meningioma, Hodgkins and non-Hodgkins lym- fraction, prior to and in response to the administration
phoma. Many of these tumours may be better visualized of potentially cardiotoxic chemotherapeutic drugs.
with CT and MRI, but pentetreotide imaging may be used The heart is a muscular organ divided internally by a
to demonstrate small symptomatic tumours and metastatic muscular septum into right and left sides, each side having
spread, although hepatic metastases are difficult to visua- two chambers. The right and left atria receive blood return-
lize because of uptake in normal liver. Evidence of pente- ing from the pulmonary and systemic circulations. The
treotide uptake is a guide for therapy with octreotide, right and left ventricles are pumping chambers and are
especially for carcinoid tumours. Figure evolve 6.6 shows more muscular, particularly the left ventricle (LV), which
an indium-111 Octreotide SPECT/CT image of a patient with pumps the blood to the systemic circulation.
multiple neuroendocrine tumour metastases in the liver. Left ventricular ejection fraction (LVEF) is one of the
major indicators of cardiac function. It can be investigated
by means of a MUGA scan which is taken 2030 minutes fol-
Oncoscint lowing a two-stage injection procedure. A non-radioactive
Oncoscint [8] was the first monoclonal antibody to be or cold injection of pyrophosphate is followed by 400
approved by the Food and Drugs Agency (FDA) for use 800 MBq of technetium-99m pertechnetate, both adminis-
in the USA. It is indium-111 labelled B72.3 or satumomab, tered intravenously. Due to the cold pre-injection, labeling
a murine monoclonal antibody which targets Tag-72 which of the patients red cells takes place in vivo. By using the
is a cell-surface antigen expressed by colorectal carcinoma R-wave of the patients ECG to gate (i.e. control) image
cells. It may be used for the detection of local recurrence acquisition, a series of 16 to 24 images is recorded during
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Chapter |6| Imaging with radionuclides
each cardiac cycle and stored in time order on computer. The commonest reason for renal isotope investigation in
Data collection continues for 10 to 15 minutes. Images of oncology patients is to investigate suspected obstruction to
adequate spatial resolution for the purpose are obtained urine drainage down the ureters caused by primary tumour
by summing images of identical time segments in several masses, such as gynecological pelvic malignancy or bladder
hundred cardiac cycles. The MUGA images can be processed and prostate carcinomas, or by secondary metastatic disease
to produce amplitude and phase images that aid the delin- spread to lymph nodes in the para-aortic or iliac chains,
eation of the left ventricle and the demonstration of para- which lie adjacent to the ureters. The non-imaging test, glo-
doxical motion. Amplitude refers to the magnitude of the merular filtration rate (GFR) is also common in oncology
change of the LV image intensity, while phase refers to the patients; as part of the algorithm for the prescription of car-
timing of the intensity change within the cycle. The LVEF boplatin or to investigate kidney function prior to and in
is derived from the maximum counts (Cmax) and minimum response to any potentially nephrotoxic drug.
counts (Cmin) in the left ventricle over the cardiac cycle, The most widely used radiopharmaceuticals for kidney
Equation 6.1, and is usually expressed as a percentage. All function imaging are technetium-99m tiatide (MAG3)
counts are corrected for background. and pentetate (DTPA). They are suitable for the assessment
of individual kidney function, and investigation of drain-
LVEF C max C min =C max 6:1
age. With the kidneys and bladder in the field of view of
The technique is recognized as the gold standard [14] for the gamma camera, up to 80 MBq of technetium-99m
LVEF estimation among competing modalities as it does MAG3 is injected intravenously. For the following 20 min-
not rely on geometrical approximations to the shape of utes a series of images (generally 20 s frames) is acquired.
the heart chamber but derives its values from the entire Regions of interest are defined around the kidneys and
ventricle, including any effect due to paradoxical motion. bladder and, after suitable background correction, time
Figure evolve 6.8 shows images from a patient with a nor- activity curves can be generated for each region. This set
mal LVEF. of curves is termed a renogram. Often, the term is also used
MUGA scans image radioactive labeled blood within the to denote the entire investigation.
heart. Blood flow to the heart muscle itself (myocardial Figure evolve 6.9 shows the renogram results from a
perfusion) can be imaged using technetium-99m methoxy patient with one normally functioning kidney and one
isobutyl isonitrile (MIBI) or tetrofosmin. Thallium-201 obstructed kidney.
was once the most common agent but, due to its higher radi- Other renal agents include technetium-99m dimercapto
ation dose, more limited availability and less favorable imag- succinic acid (DMSA), used primarily in the investigation
ing characteristics, has been superseded in popularity. All of of renal scarring, often in children.
these radiopharmaceuticals distribute themselves within the
heart muscle according to blood flow through the coronary
arteries. Tomographic images are taken under stress and at
Infection imaging
rest and the results used in the differential diagnosis of nor- A patients own leukocytes (white cells) will accumulate at
mal myocardial perfusion, ischemia and infarction. These the site of infection, so one method of localizing infection
studies have an important role in diagnosis of heart disease is to label autologous white cells with a suitable radio-
in patients with low to medium probability and in progno- nuclide. Two are available: indium-111 and technetium-
sis. The LVEF can be derived from gated myocardial perfu- 99m. Both labelling processes involve taking up to
sion tomography but the results are not as reliable as those 200 ml blood from the patient and leaving it to settle under
from the MUGA, particularly where the position of a sub- gravity for about an hour. This enables reasonable separa-
stantial part of the myocardial wall must be inferred because tion of white cells from the rest of the blood. The cells
there is no blood flow within it. MUGA scanning is used are incubated with either indium-111 as oxine or tropolo-
extensively in patients being treated for breast cancer, partic- nate or technetium-99m as HM-PAO marketed as Ceretec,
ularly those receiving Herceptin and the anthracycline group which was originally developed for cerebral perfusion
of cytotoxic agents that can be cardiotoxic. studies. The labelling technique is not available in many
centres as it is labour-intensive, requiring skilled experi-
enced staff and specialized aseptic facilities. An alternative
Kidney imaging
is technetium-99m labelled Leukoscan, or sulesomab, an
The kidney produces urine and disposes of metabolic waste anti-leukocyte antibody fragment.
products. It is divided into an outer cortical and an inner The use of gallium-67 citrate in the localization of
medullary region. Urine drains from the medullary region infection is discussed under its general entry above.
via the renal pelvis into the ureter and thence into the blad-
der. Several radiopharmaceuticals are available for imaging
Sentinel node mapping
the kidney and investigating renal function. The choice of
pharmaceutical depends on the specific renal function mea- Lymphatic vessels receive cellular waste and discharge it
surements required and the clinical condition being studied. from the body. The waste is filtered through nodes within
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Walter and Millers Textbook of Radiotherapy
the vessels. Metastatic spread from some tumours is carried Therefore, determination by PET of the uptake of FDG
by the lymphatics and sites of disease are found within the during and after antineoplastic treatment may be used as
lymph nodes. an early indicator of response to treatment. The reaction
Breast cancer is known to spread in this way and almost to radiotherapy or chemotherapy treatment may be an ini-
all of the associated lymph nodes are located in the axilla. tial rise in FDG-uptake, followed by a decrease, the magni-
A widely used approach by breast surgeons was to perform tude of which can serve as a marker of treatment response.
a full axillary clearance of lymph nodes along with surgical However, FDG is also taken up in inflammatory lesions
removal of the breast in patients with breast carcinoma. giving rise to a non-specificity which presents limitations,
Should histology have subsequently failed to find any evi- and requires caution, in the interpretation of the PET/CT
dence of metastatic spread in the nodes, this signalled a scan. The optimal timing of post-treatment evaluation by
good prognosis for the patient. Unfortunately, some of PET/CT is not established and is the subject of current
these patients went on to suffer the morbidity associated research, probably depending on tumour type and treat-
with the removal of the nodes, including severe oedema ment modality.
of the arm. A growing body of literature has now led to FDG-PET
A technique has been developed to locate the node(s) being used routinely in the clinic for the detection and
nearest to the tumour site; this is referred to as the sentinel staging of malignant tumours, determining the extent of
node(s). In a subgroup of breast tumour patients a Tc-99m spread of disease (including assessment of the suitability
labeled nanacolliod is injected sub- or intra-dermally in the of patients for radical surgery), differentiation of mass
peripheral areola region of the breast quadrant containing lesions, establishing response to therapy, and long-term
the tumour. Many centres will image the breast on a gamma follow up for detection of recurrent disease.
camera post-injection and identify the number and general A great number of other compounds have also been labelled
location of the sentinel nodes. Figure evolve 6.10 shows with fluorine-18, such as fluorofatty acids, fluoroamino acids,
the sentinel lymph node images of a patient immediately spiperone derivatives, fluoromisonidazole (FMISO), and
prior to surgery. Injection and imaging, if performed, take fluoroaltanserin. More recently, a fluorine-18 labeled pyrimi-
place either on the morning of the surgery or the previous dine analogue, 30 -deoxy-30 -fluorothymidine (FLT) has shown
afternoon. Patients will have the sentinel nodes located in promise as a marker of tumour cell proliferation. This has the
theatre with the aid of an intra-operative probe system potential to provide more specific and effective PET/CT
(Figure evolve 6.11 ). Histological evaluation of the sen- measurements for monitoring response to therapy. Previ-
tinel nodes will influence the patients subsequent treat- ously, work on cell proliferation using the equivalent car-
ment pathway. The technique is now also used for bon-11 labelled compound, carbon-11 thymidine, has been
melanoma and vulva tumours and other tumour sites are published by a number of research groups, but it is anticipated
being investigated. that FLT will be superior due to its longer half-life (110 min for
fluorine-18, 20 min for carbon-11), allowing simpler metab-
olite corrections, and longer, more practicable, image acquisi-
PET/CT imaging
tion times.
The increased glucose metabolism of malignant cells A number of other medium half-life, inorganic posi-
compared to healthy tissue makes the positron emitting tron emitting radionuclides are becoming available. Their
tracer, fluorine-18 fluorodeoxyglucose (FDG) particularly half-lives of several hours offer considerable advantages
useful in oncology. Detailed descriptions of clinical PET for supply from regional distribution centres. Iodine-124
and PET/CT can be found in Barrington et al [15] and (t 100 h) or iodine-120 (t 1.4 h) may be used to
Lin et al [16]. The increased metabolism of glucose in label tracers and ligands that have been labelled with
malignant cells is due to upregulation of the enzyme hexo- iodine-123 or iodine-131. 5-Iododeoxyuridine (IUdR),
kinase and increased levels of the membrane transport offers potential as a radiotracer for functional imaging of
proteins GLUT1 and GLUT3. Overexpression of GLUT1 cell proliferation. Bromine-176 (t 16 h) has also been
and GLUT3 is primarily seen in the rim of hypoxic tumour used as a PET label for a variety of compounds, including
tissue. The production of ATP is maintained by upregula- deoxyuridine deriviatives as proliferation markers and anti-
tion of glucose transport and glycolysis even in the pres- bodies. Macromolecules, such as peptides (e.g. octreotide)
ence of hypoxia. The metabolism of glucose is partly and proteins (e.g. monoclonal antibodies), are also amena-
regulated by the transcription factor hypoxia-inducible ble to radiolabelling with such radionuclides. Perfusion
factor 1 (HIF-1). HIF-1 stimulates the expression of more and permeability clinical studies have been demonstrated
than 40 genes, including vascular endothelial growth factor using copper-64 (t 12.7 h) as a label for the perfu-
(VEGF), insulin-like growth factor 2 (IGF-II), GLUT 1, and 3, sion/flow marker copper-64 PTSM (Cu(II)-pyruvalde-
and several glycolytic enzymes, e.g. hexokinase 1 and 3. hyde-bis(N4-methylthiosemicarbazone)).
It has been demonstrated that the activity of tumour cell Further opportunities are possible using positron emitter
hexokinase, which can be indirectly measured by FDG- generator systems, where the parent radionuclide has a
PET, is correlated to the growth rate of tumours. much longer half-life than the daughter. A germanium-
110
Chapter |6| Imaging with radionuclides
68/gallium-68 generator is already available with parent/ generator system may be used as a ready supply of radioiso-
daughter having half-lives of 268 days and 68 minutes, tope for phantom and calibration studies.
respectively. Apart from the demonstrated use of gallium- Figure evolve 6.12 shows an F-18 FDG PET/CT image
68 for labelling a variety of tracers and ligands, this of a patient with a lung tumour.
REFERENCES
[1] Lowe VJ, et al. Prospective diagnostic x-ray imaging systems. [12] ICRP Publication 80. Radiation
investigation of positron emission IPEM Report 91. IPEM. 2005. dose to patients from
tomography in lung nodules. J Clin [7] Bailey DL, Townsend DW, Valk PE, radiopharmaceuticals. Ann ICRP
Oncol 1998;16:107584. Maisey MN, editors. Positron 1998;28(3).
[2] Dendy PP, Heaton B. Physics for emission tomography. Springer- [13] Schoedel KE, Tublin ME, et al.
diagnostic radiology. 2nd ed. Verlag; 2005. Ultrasound-guided biopsy of the
Institute of Physics; 2003. [8] Welch MJ, Redvanly CS, editors. thyroid: a comparison of
[3] Cherry SR, Sorenson JA, Phelps ME. Handbook of technique with respect to diagnostic
Physics in nuclear medicine. 3rd ed. radiopharmaceuticals, accuracy. Diagn Cytopathol
Saunders; 2003. radiochemistry and applications. 2008;36:7879.
[4] Institute of Physics and Engineering Wiley; 2003. [14] Bartlett ML, Srinivasan G, et al. Left
in Medicine (IPEM). Quality [9] Baath M, Kolbeck K, et al. ventricular ejection fraction:
control of gamma camera systems. Somatostatin receptor scintigraphy comparison of results from planar
In: Bolster A, editor. Institute of with 99mTc-depreotide (NeoSpect) and SPECT gated blood-pool
Physics and Engineering in in discriminating between studies. J Nucl Med
Medicine. 2003. malignant and benign lesions in the 1996;37:17959.
[5] National Electrical Manufacturers diagnosis of lung cancer: a pilot [15] Barrington SF, Maisey MN, et al.
Association (NEMA). Performance study. Acta Radiol 2004;45:8339. Atlas of clinical positron emission
measurements of gamma cameras, [10] The Medicines Act 1968. HMSO; tomography. 2nd ed. Hodder
NU-1. 2007. 1968. Arnold; 2006.
[6] Institute of Physics and Engineering [11] SI 1059, The Ionising Radiation [16] Lin EC, Alavi A. PET and PET/CT.
in Medicine (IPEM). (Medical Exposure) Regulations Thieme; 2005.
Recommended standards for the 2000. HMSO; 2000.
routine performance testing of
Figure evolve 6.4 Normal bone scan Figure evolve 6.7 Whole body Figure evolve 6.10 Sentinel lymph node
Figure evolve 6.5 Bone scan with I-131 scan images of a patient immediately prior
secondary deposits Figure evolve 6.8 MUGA images from a to surgery
Figure evolve 6.6 Indium-111 patient with a normal LVEF Figure evolve 6.11 Intraoperative lymph
Octreotide SPECT/CT image of a Figure evolve 6.9 Renogram images and node probe system
patient with multiple neuroendocrine clearance traces Figure evolve 6.12 F-18 FDG PET/CT
tumour metastases of the liver image of a patient with a lung tumour
111
Intentionally left as blank
Chapter |7|
Therapy with unsealed radionuclides
Marjorie Rose, Sue Owens, David Hastings
where Teff, Tbiol and Tphys are the effective, biological and (thyrotoxicosis and non-toxic goiter) and in thyroid carci-
physical half-lives. The effective half-life is the important noma. It has no role in medullary thyroid cancer. There are
parameter when estimating radiation dose as it determines specific guidelines [46] from the Royal College of Physi-
the duration and rate of delivery of radiation dose. cians (RCP) in the UK, as well as from Europe and the
Radionuclide therapy has been in use since the 1940s USA for using radioiodine in the management of hyperthy-
and some treatments have been relatively unchanged for roidism and of thyroid cancer. The characteristics of 131I are
several decades. However, more recently, there has been shown in Table 7.1. As specified by the European Associa-
much research effort dedicated to improving strategies tion of Nuclear Medicine (EANM) and the Society of
for treatment, developing new radiopharmaceuticals and Nuclear Medicine (SNM) [5,6], it is essential that, before
looking at alternative radionuclides to take advantage of any treatment, all thyroid hormones, iodine-containing
different properties. This is ongoing, but has resulted in preparations and supplements and any other medications
introductions such as iodine-131 labelled m-IBG in the that could suppress thyroid uptake are discontinued for a
1980s, samarium-153 EDTMP in the 1990s, and now radi- sufficient length of time. Almost all thyroid treatments
olabelled monoclonal antibodies for non-Hodgkins lym- are given orally, as a capsule or as a liquid.
phoma (NHL).
The subject is growing and this text has been limited to
products with licences or marketing authorizations, but Thyrotoxicosis
it should be noted that there are many interesting areas of In thyrotoxicosis, or hyperthyroidism, the thyroid gland is
development, such as the use of yttrium-90-labelled somato- over-producing thyroid hormones. The possible approaches
statin analogues for neuroendocrine tumours [13]. to radionuclide therapy have included giving sufficient
Please note that where a product is unique to a particular radioiodine to render the patient hypothyroid and giving
company, the trade name has been given. low activities of 131I in combination with anti-thyroid
drugs. However, the RCP recommend that the aim of treat-
ment should be to render the patient euthyroid, while
IODINE-131 IN THE TREATMENT OF accepting that there will be a moderate rate of hypothy-
roidism [4]. For a standard case of hyperthyroidism, the
THYROID DISEASE RCP suggest a guide activity of 400 to 550 MBq at first pre-
sentation. An alternative is to use pretreatment thyroid
Iodine-131 (131I) is the radionuclide most widely used uptake measurements, with tracer activities of 131I, to calcu-
therapeutically. Iodine is readily concentrated in the thy- late the activity to be administered to deliver a prescribed
roid gland and using 131I, emitting beta particles with a radiation dose. Such calculations require knowledge of
maximum range of 3 mm in tissue, allows a high radiation the thyroid mass, the percentage uptake and the rate
dose to be delivered to the thyroid and a low dose to the rest of clearance from the gland, requiring repeated measure-
of the body. It is most commonly used in the form of ments over a period of several days. Some centres may
sodium iodide[131I] for treatment of benign thyroid disease use measured uptake and thyroid mass but assume a
BETA GAMMA
114
Chapter |7| Therapy with unsealed radionuclides
standard turnover rate. There have been studies looking at requirement for an in-patient stay. The most common indi-
the effectiveness of different treatment schedules and cation is the treatment of polycythaemia rubra vera (PRV),
corresponding rates of hypothyroidism [7, 8]. Most treat- although the treatment may also be used in essential
ments in the UK are administered to outpatients, although thrombocythaemia, a rare disorder. In the opinion of the
this will depend on the amount of activity prescribed, the EANM, the use of 32P for this indication is declining. How-
patients home circumstances and national regulations. ever, there seems to be some agreement that it has a role
in patients over 70 who are resistant to other treatments
such as venesection and conventional chemotherapy [12].
Thyroid tumours Treatment regimens vary and are a matter for clinical
There is also a role for 131I in the treatment of well- judgment, with typical activities in the range 150
differentiated thyroid cancer, when it is administered both 250 MBq. The EANM Guideline suggests two regimens in
for the ablation of thyroid remnant after surgery and for current use, based on using either an activity per surface
the treatment of metastases. Following total thyroidec- area or a fixed starting activity which is incremented. The
tomy, the aim of remnant ablation is to destroy any use of 32P to treat PRV was first reported in 1955 [13],
remaining normal thyroid tissue and any microscopic but Parmentier [12], in a review in 2005 stated: Few data
deposits of thyroid carcinoma [9]. The RCP guidelines [4] are available regarding precise dosimetry in man. An effec-
state that the usual activity administered for ablation is tive dose (ED) of 2.4 mSv/MBq is given by the Interna-
3.7 GBq but that some centres may use a lower activity tional Commission for Radiation Protection (ICRP) in
(1.1 GBq) and, as for thyrotoxicosis, some use a dosimetric ICRP80 [14], with 11 mGy/MBq for both the bone surfaces
assessment of uptake and clearance in order to prescribe and red marrow in ICRP53 [15]. Values of the same order
an activity. By destroying any remaining thyroid tissue, of magnitude may be found in the literature.
the theory is that the only remaining source of thyro-
globulin production is any remaining malignant cells,
thus making the measurements of thyroglobulin level a sen- INTRA-ARTICULAR AND
sitive test of any local recurrence or metastatic disease. Met-
astatic lesions have a lower avidity for iodine than normal
INTRACAVITARY TREATMENTS
thyroid tissue and it is customary to administer higher activ-
ities, for instance 7 GBq or more. Treatments for thyroid Intra-articular treatment of arthritis and other intracavitary
cancer require an in-patient stay, until the level of radioac- treatments are performed using colloids of beta-emitting
tivity has fallen sufficiently for safe discharge as outlined in radioisotopes. Yttrium-90 (90Y) colloids may be adminis-
the Medical and Dental Guidance Notes (MDGN) [10]. tered intrapleurally or intraperitoneally to treat recurring
Gamma camera images, using the 364 keV photons malignant effusions. In such cases, the amount of activity
of 131I, may be obtained after treatment to confirm uptake administered is an order of magnitude higher than for
in residual thyroid, recurrence or metastases. Scanning pro- the treatment of arthritis.
tocols may also be used after surgery and before ablation. It For arthritis, radiation synovectomy (or radiosyno-
may also be used for instance, to determine the complete- viorthesis) means radionuclide therapy of joint synovitis
ness of ablation as part of a patients treatment. Iodine- or synovial processes by the intra-articular injection of a
123 may provide a suitable alternative, with better charac- colloidal radiopharmaceutical. As a general rule, yttrium-
teristics for imaging with a gamma camera. The first report 90 silicate/citrate is used for large joints like the knee,
of the use of 131I in treating metastatic thyroid cancer was in rhenium-186 sulfide for medium-sized joints such as the
1946 [11]. Even 50 years after that first report, much is being hip, shoulder or ankle and erbium-169 citrate for small
discussed and written about optimization of these joints as in the fingers. A major difference between this
treatments. treatment and the others discussed in the current chapter
is the route of administration, which is intra-articular,
rather than oral or IV. The radiopharmaceuticals are colloi-
PHOSPHORUS-32 IN THE TREATMENT dal and the particles must be small enough to be taken up
OF REFRACTORY in the connective tissue lining of the joint cavity called the
synovium. This is achieved through the process of phago-
MYELOPROLIFERATIVE DISEASE cytosis by macrophages in the synovium.
The colloidal particles must also be large enough not to
Phosphorus-32 (32P) is a pure beta emitting radionu- leak from the joint before phagocytosis and the appropriate
clide, with a mean particle range in tissue of 3 mm and a size range is around 210 mm. After treatment, absolute
maximum of 8 mm. It is available as a sterile solution immobilization of the treated joint(s) for 48 hours using
of 32P orthophosphate in aqueous solution (sodium splints or bed rest is recommended as this will reduce trans-
phosphate [32P]) which is administered either orally or port of particles through the lymphatics to the regional
as normally occurs, by intravenous injection. There is no lymph nodes.
115
Walter and Millers Textbook of Radiotherapy
Yttrium-90 (90Y) is a pure beta emitter (see Table 7.1), HEDP) [19] and 32P sodium phosphate [20]. Considering
and the usual activity per knee joint is 185 MBq. Rhe- the two more commonly used radionuclides, it should be
nium-186 (186Re) and erbium-169 (169Er) are mentioned noted that the physical half-lives are very different, 1.9 days
for completeness, as they are used outside the UK and dis- for 153Sm and 50.5 days for 89Sr and there is also a variation
cussed in the literature. The rationale for using each radio- in the beta particle energies and hence the mean range in
nuclide in different sized joints may be seen by looking at tissue, 0.6 mm for 153Sm and 2.4 mm for 89Sr.
the average penetration of the beta particles in tissue; Srontium-89 does not have significant gamma emission
3.6 mm for 90Y in large joints, 1.1 mm for 186Re in medium (see Table 7.1) and it is not possible to image the in vivo
joints and 0.3 mm for 169Er in small joints. The high energy distribution readily. However, studies performed with
beta particles emitted by 90Y result in the production of the surrogate gamma emitter 85Sr have demonstrated
bremsstralung radiation (see Chapter 2), which can be uptake at sites of metastases. In contrast, 153Sm emits
detected externally. gamma photons at 103 keV, suitable for imaging with a
gamma camera and scans may be performed following
treatment to confirm uptake in metastases (Figure 7.1).
PALLIATION OF BONE PAIN
IODINE-131 m-IBG THERAPY IN
Radionuclide therapy gives an additional possibility for
the palliation of bone pain arising from osteoblastic NEUROENDOCRINE DISEASE
metastases, which are seen in some cancers with a high
prevalence, such as breast and prostate carcinoma. This sys- Iodine-131 labelled meta-iodobenzylguanidine (m-IBG)
temic approach may be used for patients with multifocal is used in the treatment of neurectodermal tumours.
osteoblastic metastases, as an alternative to external beam Such tumours derive from the primitive neural crest, which
radiotherapy, or for those whose pain is refractory to con- develops to form the sympathetic nervous system (SNS):
ventional analgesia or antitumour therapy [16, 17]. Before malignant neurectodermal tumours include phaeochro-
administration of the treatment, it is essential to verify mocytoma, neuroblastoma, carcinoid tumours, paragan-
that there is evidence of focal increased uptake on bone glioma and medullary thyroid cancer. M-IBG is
scintigraphy. Such increased uptake is due to an osseous structurally similar to the catecholamine noradrenaline
reaction to the development of metastases and, if it is and has been found to concentrate within secretory gran-
not present on a gamma camera bone scan using a 99Tcm ules of cells which produce catecholamines in, for instance,
imaging agent (e.g. MDP or HDP, see Chapter 6), there the adrenal medulla. The first report that 131I m-IBG loca-
will be no selective uptake of the therapeutic radionuclide lizes in phaeochromocytoma was in 1981 [21] and in neu-
and, therefore, no benefit. roblastoma in 1984 [22].
The most widely used radiopharmaceuticals for this Before treatment, any drugs known to interfere with the
treatment are 89Sr strontium chloride (MetastronW) and uptake and/or retention of 131I m-IBG must be withdrawn
153
Sm lexindonam (ethylene diamine tetramethylene (EANM). A thyroid blocking agent must be prescribed,
phosphonate or EDTMP: QuadrametW) [18]. The charac- starting before and continuing for an extended period after
teristics of 89Sr and 153Sm are given in Table 7.1 with fur- treatment, to protect the gland from taking up any free 131I
ther details in Table 7.2. Two further materials are with the subsequent risk of developing hypothyroidism.
mentioned in the SNM and EANM guidelines [5, 6], The dose limiting toxicity is hematological and monitoring
186
Re etidronate (hydroxyl ethylidine diphosphonate or of blood counts is essential after treatment.
116
Chapter |7| Therapy with unsealed radionuclides
Iodine-123 m-IBG is available for imaging such tumours It seems apparent that any text dealing with RIT will be
using a gamma camera and, as part of the preparation for superseded rapidly. In 2005, just two therapeutic radiola-
treatment, patients should undergo m-IBG scintigraphy belled antibodies were approved by the FDA for use in
(either 123I or 131I) to confirm uptake in all known tumour the USA, 90Y ibritumomab tiuxetan (ZevalinW) and 131I.
sites. Treatment may be prescribed either using a set activ- tositumomab (BexxarW).
ity, using an activity per kilogram or by using the results of In both cases:
pretreatment dosimetric measurements with a tracer dose. the antibody is targeted to CD20, an antigen produced
In this last case, an activity may be prescribed for treatment by both malignant and normal B-cells
using a predetermined criterion. For instance, a limit of the approval is for the treatment of relapsed follicular
2 Gy to the total body has been used in the treatment of NHL which is refractory to chemotherapy
children with neuroblastoma [23]. the dose limiting toxicity is haematological.
Typical administered activities are between 3.5 GBq and
Yttrium-90 ibritumomab tiuxetan also has EU approval
7 G Bq and patients require admission to an isolation unit
and both materials are being used in on-going clinical
for a period of time determined by national regulations.
trials.
Very careful arrangements must be made for the treatment
For 131I tositumomab, pretreatment dosimetry is essen-
and nursing of children, who are often under 3 years of age.
tial, to calculate the therapeutic activity required to deliver
The effective dose to a 70 kg adult is 0.013 mSv/MBq,
a total body dose of 0.75 Gy during treatment. This was
or 46 mSv for 3.5 GBq. The radiation dose to the tumour
established as the maximum tolerated dose in clinical
varies widely.
trials. The dosimetry protocol requires measuring the
effective half-life in the individual patient following
RADIOLABELED MONOCLONAL administration of a tracer activity of 131I (185 MBq). The
range of treatment activities administered ranges from
ANTIBODIES IN NON-HODGKINS around 3 to 5 GBq and an inpatient stay in a dedicated
LYMPHOMA facility is required.
With yttrium-90 ibritumomab tiuxetan, there is less indi-
In contrast to most of the treatments already discussed, vidual variation in effective half-life and the treatment is
radioimmunotherapy (RIT) using radiolabelled monoclo- prescribed as 15 MBq/kg, with a maximum of 1.2 GBq.
nal antibodies [24] is a relatively recent introduction. RIT
has been proven to be effective in follicular non-Hodgkins
lymphoma (NHL) and clinical trials are continuing in this RADIATION PROTECTION, WASTE AND
and other forms of NHL, as well as other haematological
malignancies. It remains a challenge to deliver sufficient REGULATIONS
radiation dose with RIT to treat solid tumours, but there
has been some progress in clinical trials of locally adminis- The regulations and the principles behind the radiation
tered RIT, for instance studies using intra-peritoneal protection for the therapeutic use of radionuclides are
administration to treat malignant ascites [25]. encompassed within the principles and regulations which
117
Walter and Millers Textbook of Radiotherapy
apply to all uses of ionizing radiation. These are described visiting by children and pregnant women is
in Chapter 4 where the reader will find in particular sec- forbidden
tions dealing with ARSAC for the administration of radio- emergency decontamination kit and radiation monitor
active substances, the transport of substances, the statutory readily accessible
instruments governing the general use of radiation and spe- staff must wear at least gowns and gloves to protect
cifically its use for medical applications. In particular, the their skin and clothing from contamination
risk assessment of situations involving the administration overshoes should be worn if there is any chance of the
of radioisotopes on an individual basis can be required fre- floor being contaminated
quently due to particular circumstances. The need for ade- if possible, utensils such as cutlery and crockery should
quate staff monitoring and decontamination provision is be disposable and all waste disposal should be dealt
also essential for the safe provision of radionuclide with by authorized personnel
treatment. nursing procedures should be carried out in the
Consideration of the patients circumstances in relation minimum time compatible with good nursing care
to the radionuclide being used is important. Treatments a clearly documented procedure must be provided to
with pure beta emitters, such as yttrium-90, present very lit- allow artificial resuscitation of a patient but minimize
tle hazard to other people unless the radioactivity is the risk of radioactive contamination.
excreted in urine or other body fluids. However, simple Patients who have received radioiodine therapy may not
hygeine precautions with wound dressings for a short be discharged until the radiation dose which they can
period can also reduce any likely loss of activity and main- potentially give to people they come into contact with is
tain the therapeutic benefit to the patient. By contrast, the significantly reduced. This is achieved by adherence to
administration of 131I with its half-life of 8 days, gamma ray simple precautions within specified levels of activity.
emission at 364 keV as well as the beta particle emission The limit for discharge is generally held to be when the
and avidity for the thyroid gland if ingested in the form residual level of activity in the body has fallen below
of iodide presents a more complex problem. Requirements 800 MBq. This limit has no legal standing however, so
and guidance are drawn from several sources including the a careful risk assessment is required before discharge,
IRMER regulations [26] and the MDGN [10]. Patients at whatever level.
receiving more than 30 MBq 131I must be assessed individ- The 800 MBq limit for iodine-131 was arrived at by care-
ually to ensure that they do not pose a hazard to others. In fully modelling likely patient behaviour and compliance. It
general, patients receiving less than 800 MBq may go home corresponds to approximately 300 MBq.MeV, so this figure
directly after treatment. A journey time of less than one was initially taken as a suitable limit for discharge of
hour is considered reasonable for ambulance and public patients who had received other therapeutic radionuclides,
transport. Advice should be given about seating position such as 153samarium or 90yttrium. Unfortunately, due to
in the vehicle to minimize irradiation of fellow passengers. differences in half-life and radiation emitted, the extrapola-
If conveyed by private car, the driver and patient should be tion is not valid [27].
advised regarding journey time and seating position in the The MDGN [10] contains a table of restrictions which are
car. In addition, certain conditions concerning public suitable when discharging patients who have undergone
transport journey times, places of entertainment, use of cut- radioiodine therapy for thyrotoxicosis. This includes
lery and crockery and contact with young children and restrictions on contact with children and any restrictions
pregnant women will be required for the following few on the mode of transport used. Self-discharge must be
weeks. firmly discouraged on the grounds of the hazards to others.
In circumstances when the activity exceeds 800 MBq, Where risk assessment has shown it necessary, all patients
the patient will have to be admitted and cared for in should be given written instructions on leaving hospital
specialized accommodation as follows: about precautions to be taken to minimize the dose to
confinement to a single room with impervious wall others. This may take the form of a card. Even many weeks
finishes and flooring and with coved skirtings to ease after precautions have elapsed, patients may retain enough
decontamination radioactivity in their bodies to set off radiation alarms at air-
the room be designated as a controlled area ports. It is wise to question patients on their travel plans
exclusive use of a toilet and shower facility connected prior to discharge and warn them of the possibility of delay.
directly to a main drain Following discharge from inpatient accommodation, the
suitable warning signage to drainage for maintenance room may not be re-used until it has been monitored and
workers declared free from contamination.
bed linen, towels and clothing must be monitored for In the case of the death of a patient following the admin-
contamination before patient discharge istration of a therapeutic dose of radioactivity, due regard
visiting by adults should be discouraged for the first must be given to the safety of the relatives, pathologists
24 hours and restricted thereafter and undertakers, etc. The MDGN [10] contains a section
118
Chapter |7| Therapy with unsealed radionuclides
giving advice on this but a local policy should be written for adequate inactive effluent flow from the hospital to dilute
each treatment offered in that centre. the waste to a low concentration level, and when the toilets
Staff who prepare, administer or care for patients who have reserved for radioactive waste are connected directly to the
received therapeutic doses should minimize the risk of receiv- main drainage system. Similar conditions must also be
ing doses by adherence to good radiation protection princi- applied to the disposal of radioactive liquid waste from
ples. They must wear protective clothing when handling the laboratories. The waste pipes between the ward/labora-
the radioisotope, the patient or any articles which may be tory and the main sewer should be labelled as potentially
contaminated. Contaminated goods and clothing must be radioactive.
carefully stored for assay and approved disposal by the medi- Some storage facilities are always required for contami-
cal physics staff. Contamination monitoring should be nated belongings or storing high activity waste storage until
undertaken by experienced staff and all results recorded. In it can be disposed of. An example would be the tubing and
addition to film or thermoluminescent dosimeters (TLD) bags from peritoneal dialysis. Such storage facilities must
badge monitoring, there may be a requirement for periodic be adequately shielded, designed to prevent risk of escape
monitoring of the staff for inhaled or ingested contamina- of material and labelled.
tion, e.g. of the thyroid when nursing iodine therapy patients. Once the activity has decayed to extremely low levels, it
Although waste disposal is permitted in gaseous, solid can be disposed of with the rest of the clinical waste. Larger
and liquid form and gaseous waste may be encountered concentrations of activity in solid waste or long-lived radio-
from fume cabinets, the majority of waste is liquid and nuclides will require special arrangements for disposal
solid. Syringes, swabs, paper tissues and all contaminated through authorized routes but, once again, strict activity
material constitute solid waste. Liquid waste arises from limits are imposed.
radioactive solutions from isotope administration, decon- Detailed records must be kept of all disposals of radioac-
tamination procedures and body fluids from patients. The tive materials irrespective of which route has been used.
disposal of radioactive waste from a hospital must be These records should include the type of radionuclide, its
organized, carefully controlled and documented in compli- activity at disposal, the route of disposal and the date of
ance with the UK regulations to avoid hazard to staff disposal.
patients and the general public. The Environment Agency The limits authorized for disposal as liquid waste under
will have set limits of activity for gaseous, liquid and solid RSA93 [28] may be one of the limiting factors in the ability
waste for each site in its authorization. The site must show of a hospital to offer radionuclide therapy. Some countries
that it disposes of all waste by the best practicable means favour the use of delay tanks to store radioactive excreta
before authorization is granted. before release into the environment, however, the ensuing
In most cases, the disposal of radioactive excreta from difficulty in ensuring that the control mechanisms on the
patients is dealt with by discharging to the sewage system. tanks are functioning correctly without exposing mainte-
In this way, the hazard to staff involved in collection and nance workers to unacceptable risk has precluded its wide-
disposal is avoided. This is permitted where there is an spread use in the UK.
REFERENCES
[1] Otte A, Mueller-Brand J, Dellas S, [4] Royal College of Physicians. Radio- [7] Sagel J, Epstein S, Kalk J, Van
Nitzsche EU, Herrmann R, iodine in the management of benign Mieghem W. Radioactive iodine
Maecke HR. Yttrium-90-labelled thyroid disease. Clinical guidelines: therapy for thyrotoxicosis at Groote
somatostatin-analogue for report of a Working Party. Royal Schur Hospital over a 6 year period.
cancer treatment. Lancet College of Physicians; 2007. Postgrad Med J 1972;48:30813.
1998;351:4178. [5] Society of Nuclear Medicine. [8] Pauwels EK, Smit JW, Slats A,
[2] de Jong M, Bakker WH, Procedure guidelines for therapy of Bourquiqnon M, Overbeek F.
Krenning EP, et al. Yttrium-90 and thyroid disease with iodine-131 Health effects of therapeutic use
indium-111 labelling, receptor (sodium iodide) version 2. Society of 131 I in hyperthyroidism. Q J Nucl
binding and biodistribution of of Nuclear Medicine; 2005. Med 2000;44:3339.
[DOTA0,d-Phe1, Tyr3] octreotide, a [6] Luster M, Clarke SE, Deitler M, et al. [9] Robbins RJ, Schlumberger MJ.
promising somatostatin analogue European Association of Nuclear The evolving role of 131I for the
for radionuclide therapy. Eur J Nucl Medicine (EANM).Guidelines for treatment of differentiated thyroid
Med 1997;24:36871. radio-iodine therapy of carcinoma. Journal of Nuclear
[3] Lewington VJ. Targeted radionuclide differentiated thyroid cancer. Medicine 2005;46:28S37S.
therapy for neuroendocrine European Journal of Nuclear [10] Medical and Dental Guidance
tumours. Endocr Relat Cancer Medicine and Molecular Notes. A good practice guide on all
2003;10:497501. Immunology 2008;35:194159. aspects of ionising radiation
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Walter and Millers Textbook of Radiotherapy
protection in the clinical neoplasms. Dtsch Med Wochenschr [23] Fielding SL, Flower MA, Ackery D,
environment. Institute of 1973;98:234751. Kemshead JT, Lashford LS, Lewis I.
Physics and Engineering in [17] Lewington VJ. Cancer therapy using Dosimetry of iodine-131
Medicine; 2002. bone-seeking isotopes. Phys Med metaiodobenzylguanidine for
[11] Seidlin SM, Marinelli LD, Oshry E. Biol 1996;41:202742. treatment of resistant
Radioactive iodine therapy: effect [18] Baczyk M, Czepczynski R, Milecki P, neuroblastoma: results of a UK
on functioning metastases of Pisarek M, Oleksa R, Sowinski J. study. Eur J Nucl Med
adenocarcinoma of the thyroid. J 89
Sr versus 153Sm-EDTMP : 1991;18:30816.
Am Med Assoc 1946;132:83847. comparison of treatment efficacy of [24] Britton KE, Mather SJ,
[12] Parmentier C. Use and risks of painful bone metastases in prostate Granowska M. Radiolabelled
phosphorous-32 in the and breast carcinoma. Nucl Med monoclonal antibodies in
treatment of polycythaemia vera. Commun 2007;28:24550. oncology. III.
J Nucl Med 2005;46 [19] De klerk JM, Zonnenberg BA, Radioimmunotherapy. Nucl Med
(Suppl.):115S127S. Blijham GH, et al. Treatment of Commun 1991;12:333347.
[13] Lawrence JH. Polycythaemia metastatic bone pain using bone [25] Sharkey RM, Goldenberg DM.
physiology, diagnosis and seeking radiopharmaceutical Re- Perspectives on cancer therapy with
treatment. Grune and Stratton; 186-HEDP. Anticancer Res radiolabeled monoclonal
1955. 1997;17:17737. antibodies. J Nucl Med 2005;46
[14] ICRP Publication 80. Radiation dose [20] Roberts Jr DJ. 32P-Sodium (Suppl. 1), 115S127S.
to patients from phosphate treatment of metastatic [26] Department of Health. The Ionising
radiopharmaceuticals, Addendum malignant disease. Clin Nucl Med Radiation (Medical Exposure)
2 to ICRP 53 and Addendum 1 to 1979;4:923. Regulations 2000. Statutory
ICRP 72. Elsevier; 1999. [21] Sisson JC, Frager MS, Valk TW, et al. Instrument 2000 No 1059. The
[15] ICRP Publication 53. Radiation Scintigraphic localization of Stationary Office; 2000.
dose to patients from pheochromocytoma. N Engl J Med [27] Waller ML. Estimating periods of
radiopharmaceuticals. Elsevier; 1981;305:127. non-close-contact for relatives of
1988. [22] Hattner R, Huberty JP, Engelstad BL, radioactive patients. Br J Radiol
[16] Firusian N, Schmidt CG. et al. Localization of M-iodi (I-131) 2001;74:100102.
Radioactive strontium for treating benzylguanidine in neuroblastoma. [28] Radioactive Substances Act. 1993,
incurable pain in skeletal Am J Roentgenol 1984;43:3734. The Stationary Office.
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Chapter |8|
Radiotherapy beam production
John A. Mills, Hamish Porter and David Gill
produce the megavoltage x-ray beams can also deliver elec- assembly which can be manually manipulated to direct the
tron beams. Today, the most commonly used treatment beam onto the patient. The source to surface distance is typ-
delivery system is the linear accelerator which can produce ically in the range of 20 to 50 cm and the field is defined at
both photon and electron beams. This chapter deals with the surface by a mechanical applicator. An example of such
x-ray and electron beams and their production and also a machine is shown in Figure 8.1.
contains a small section on gamma ray beams.
Tube stand
KILOVOLTAGE X-RAY BEAM The tube is mounted on a mechanism commonly referred
to as the tube stand (Figure 8.2). The design of the tube
MACHINES stand enables manipulation of the beam direction by
the machine operator in order to direct it at the patients
Deep x-ray and superficial units provide x-ray beams in the lesion. There are both floor mounted and ceiling mounted
keV energy range. The term orthovoltage is also used and stands. The design allows translational and rotational
this term reflects the arrangement whereby the x-rays are movement of the beam and there may be scales of distance
produced in a direction at right angles to that of the accel- and angle which enable the set-up position or changes to
erating voltage. The units typically take the form of a tube it to be recorded and monitored. Electrical or mechanical
brakes are fitted to the rotational axes and translational
runners in order that the position can be reliably fixed
Cathode Anode in position prior to treatment and monitored during
treatment.
Filament X-ray
window
High voltage circuits
Filter
On early machines, step up transformers were used to pro-
vide high voltages to excite the x-ray tube. The transformers
operated at mains frequency and were very bulky due to the
Applicator large iron core required.
Modern units employ switched mode power supply tech-
niques, to improve voltage stability and make savings in
size and efficiency. The power supply comprises of an input
Figure 8.1 Example of an orthovoltage machine. rectifier to convert mains AC to a DC voltage. A switching
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Chapter |8| Radiotherapy beam production
inverter converts the DC to a high frequency (25 kHz) system to indicate faults, to link into the interlock system
pulsed waveform that is stepped up to 10 kV via a high fre- to ensure safe treatment and to assist in fault diagnosis.
quency transformer. Finally, the waveform is rectified and The high voltage and filament power supply is connected
passed through a number of cascaded multiplying stages to the x-ray tube by means of a high voltage cable. In order
(Cockcroft-Walton) to produce a DC voltage in the 100 to prevent voltage flash over in the connectors, care must be
to 300 kV range. taken to keep all parts clean and use high voltage insulating
The extra high tension (EHT) voltage is monitored and a grease during assembly and reassembly following mainte-
control signal fed back to alter the pulse width of the wave- nance inspection.
form leaving the inverter stage. In this way, a stable voltage
is maintained across the x-ray tube.
The intensity of the x-ray beam produced at a particular Collimation
kilovoltage depends upon the number of electrons emitted
from the filament, this tube current is a function of the fila- The anode construction provides the initial collimation of
ment temperature and hence the filament current. The the beam as the x-rays come off the target almost omnidir-
filament drive voltage is controlled electronically to ectionally (Figure 8.4). This is referred to as a hooded
respond to changes in the AC supply and stabilize the beam anode and the aperture defines the maximum size of coni-
current. A schematic is shown in Figure 8.3. Typically, for cal x-ray beam that could be provided. The collimation is
voltages in excess of 200 kV, two high voltage power completed by use of an applicator which is fixed directly
supplies are used in series. below the tube aperture and provides the following:
The HT generator is controlled externally so that safe the base of the applicator consists of a collimator which
operating parameters can be set for the particular tube in defines the shape and size of the radiation field at the
use. The generator status can also be fed to the operating end of the applicator
Voltage
Main supply Inverter increase
(50Hz) Step up
Direct current,
d.c. supply High Voltage Transformer
supply Voltage
(25kHz) monitor
Volts
Cockroft Control
Gates portion Walton switches
of energy Voltage
0 +
Multiplier
Filament
Supply
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Walter and Millers Textbook of Radiotherapy
Hood Target size. Depth dose data indicating the penetration of differ-
ent HVL beams can be compared in the British Journal of
Radiology, Supplement 25.
Anode
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Chapter |8| Radiotherapy beam production
To provide effective shielding, the thickness of lead for practice between institutions. It will utilize the absolute
the cut-out has to be chosen taking into account the energy dose calibration of the ionization chamber being used
of the beam. This can be done from tabulated data of atten- for the measurement and this will be traceable to a
uation in lead against field size and HVL (beam energy). It is Standards Laboratory. The calibration can be done in air
always prudent, however, for the Radiotherapy Physicists to with the use of mass absorption coefficient ratios to deter-
undertake measurements and verify the shielding that is mine the dose to water or tissue. Alternatively, the measure-
being obtained with the chosen thickness of lead. ment can be done directly at depth in water. For superficial
When the treatment area impinges onto the eye, it is pos- kV units with HVL values up to 8 mm Al, it is typical
sible to insert eye shields to provide some protection to to determine the surface dose rate as this is where the dose
the lens. There are commercial lead and tungsten shields is to be applied. However, for deep x-ray units with
available. The problem encountered with eye shields is HVL values higher than 8 mm Al, it can be preferable
the contribution from scatter which reaches into the region to quote the dose deeper than the surface and closer to
under the shield from the surrounding field. the target. In the latter case, it is preferable to calibrate at
depth in water.
Calibration of dose output
As described above, there are two types of exposure control MEGAVOLTAGE LINEAR
utilized on orthovoltage equipment. For a great many
years, it has been done utilizing a timer. However, in more ACCELERATOR MACHINES
recent years, exposure is controlled by a full field ionization
monitor chamber mounted in the radiation beam. The workhorse of modern radiotherapy is the linear accel-
For timer control, the machine operator requires to know erator which owes its development to the pioneers who
the dose rate of the machine and, for ionization chamber worked to produce higher energy beams than the kilovol-
control, the response of the chamber must be directly related tage beams upon which teletherapy started. The modern
to an absolute dose. The ionization chamber response is medical linear accelerator was born out of the development
normally quantified in monitor units and calibrated to be of megavoltage treatment machines in the 1950s. At this
dose per monitor unit. Hence, for both systems of control, time, betatrons, auto-transformers and Van de Graff gener-
it is necessary to measure the absolute dose delivered by ator designs were utilized to accelerate electron beams to
the beam under a very specific set-up, often referred to as high energy. However, the elegance of acceleration based
the calibration conditions. The time to be set or the monitor upon radiofrequency electromagnetic waves became uni-
units to be set are then determined using relative factors versally adopted to provide high dose-rate megavoltage
from the calibration set-up. For example, the specific dose treatment beams. The fundamental components remain
rate may be measured for a 5 cm diameter applicator unchanged, although the performance, construction and
at 30 cm source to surface distance (SSD). In order to cal- control systems have been developed considerably to take
culate a time to set, relative factors for other applicators, advantage of modern engineering, technology, electronics
difference in SSD and changes in the irradiated area are used. and computers. Today, such medical linear accelerators
The absolute dose is measured in accordance with a pro- are prolific and provide the vast majority of radiotherapy
tocol or Code of Practice. This ensures uniformity of treatments.
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Walter and Millers Textbook of Radiotherapy
Accelerating waveguide
Electron gun assembly
Focusing coils
Steering coils
Bending coils
Target
Radiation head
Isocentre
Electron gun
Figure 8.6 Typical layout of the major components of a linear accelerator. (A) General; (B) traveling wave guide;
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Chapter |8| Radiotherapy beam production
Electron gun
The source of the radiowaves is either a klystron or Beam production is not an energy efficient process and
a magnetron. The klystron utilizes a low power RF signal there is a lot of energy dissipated within the machine as heat.
from a small cavity oscillator. This is applied to a high The stability of beam production relies on the stability of
power electron stream in the klystron and results in a component dimensions, such as, for example, the RF cavities
high power RF wave. By contrast, the magnetron is a mul- in the waveguide. These can be subject to expansion and
tiple cavity device which produces a high power RF wave contraction with heating. Hence, there is a need for a great
directly. Waveguide sections transport the RF from the mag- deal of water cooling on the machine; the target, all the mag-
netron or klystron to the accelerating waveguide section. netic coils, the accelerating waveguide, the RF source and
Because electrons are charged particles, there is a large electrical devices such as transformers. Adequate and
tendency for an electron beam to disperse as it travels along stable cooling is essential for effective beam production.
the accelerating waveguide. Fortunately, this can be coun- The other essential ancillary aspect of the linear accel-
tered by using the interactive force which is applied to erator is the need for the accelerating waveguide to be
any charged particle as it passes through a magnetic field. under high vacuum. For some machine designs, the wave-
The magnetic fields that are used to counter this dispersion guide is factory sealed while for others vacuum pumps
are produced by focusing coils. These coils are wound work continuously in order to maintain the high vacuum
around the accelerating waveguide and produce a magnetic required.
field flux parallel to the direction of the electron beam. The gantry construction of the standard medical linear
This interactive force between a magnetic field and the accelerator is referred to as being isocentric. In effect, this
traveling electrons is further utilized with magnetic fields means that all the main axes of rotation concerning the
at right angles to the direction of the electron beam. One gantry, the radiation head and the patient couch intersect
of these fields is generated by the bending magnet which approximately though the same point in space referred to
bends the electron beam round into a trajectory appropri- as the isocentre This is illustrated in Figure 8.7. The benefit
ate for the radiation head. This magnet also plays a crucial of this isocentric system is that placement of the patient
role in the selection of the beam energy. By altering the such that the tumour is centred on the machine isocentre
strength of the magnetic field, which can be controlled simplifies treatment with the superposition of multiple
by the electrical current flowing in the bending magnet coil, beams.
the appropriate energy selection can be made.
The other use of magnetic fields at right angles to the
The x-ray beam
electron trajectory is to steer the beam into and out of
the accelerating waveguide. It is important to maximize The x-ray beam is produced through bremmstrahlung or
the number of electrons that are accelerated and therefore braking radiation by bombardment of a tungsten trans-
ensuring the most efficient trajectory of the beam along the mission target by the electron beam. The tungsten target
guide minimizes the losses experienced. These magnetic is placed directly in the path of the electron beam imme-
fields are produced by the steering coils and control of diately after it exits from the accelerating waveguide and
the electric current within them can be used to adjust the the bending section. As shown in Figure 8.8, this raw
trajectory for efficiency and correct beam alignment x-ray beam is collimated into the useful beam by the pri-
through the radiation head. mary collimator. The raw beam has a peak intensity in the
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Walter and Millers Textbook of Radiotherapy
x
z
y x
y
Gantry axes z
Radiation
head axes
Isocentre
z
y x
Couch axes
y x
Room axes
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Chapter |8| Radiotherapy beam production
Normalised intensity
Flattened and shaped
intensity profile
Field shaping
secondary Raw beam
collimator intensity profile
10cm depth
in water
Isocentre
Figure 8.9 Raw beam profile after target and uniform beam under IEC conditions.
Intensity (l)
100%
Region for uniformity
and symmetry assessment
80%
l (x)
Symmetry =
l (x)
l (max)
50% Uniformity =
l (min)
Field size
Edge
margin
20%
Penumbra width
0%
Final beam shaping is done utilizing the substantial have been replaced entirely or replaced in part or sup-
secondary collimation system. In early machines, plemented by multileaf collimation (MLC) with leaf
these consisted of two sets of jaws which could set rectan- widths at the isocentre ranging from 4 mm to 10 mm. This
gular field shapes by movement in orthogonal directions. has provided the opportunity for simplified conformal
In virtually all modern machines now, these jaws shaping of the beam to the target volume as well as the
129
Walter and Millers Textbook of Radiotherapy
Wedge profile
Uniform profile
Intensity
100%
50%
Field size
Figure 8.11 A solid wedge photograph and uniform and wedge beam profile.
varying of the beam intensity by rapidly changing the beam across the field during radiation. For example, at the start
shape within the overall field and, in some cases, by of the radiation, the jaws would be entirely closed with
dynamic control of the MLC while the machine is radiating. both jaws on the same side of the central axis. As radiation
A standard conventional method of varying the inten- continued, one jaw would open and traverse across to
sity of the beam has been the use of metal wedges the opposite side of the central axis. The three methods
placed within the beam to modify the uniformity of the are referred to as fixed wedges, motorized wedges and
beam profile in a controlled manner. This modification dynamic wedges.
of the beam intensity has been found to be extremely
useful in obtaining uniform dose distribution within
The electron beam
the target. Figure 8.11 shows the effect which a typical
metallic wedge has on the uniform profile. While in the As well as the x-ray mode of operation, high energy linear
past these wedges were fitted manually by the operator, accelerators are also used to deliver electron treatment
they can now be provided in two ways. First, by having beams. In this mode of operation, the transmission target
a metallic wedge mounted on a motorized platform in is automatically moved out of the beam so x-rays are delib-
the radiation head. The wedge can then be automatically erately no longer produced. The electron beam has a very
moved into and out of the radiation beam. The other way narrow width compared with the required treatment field
is to have one of the secondary collimator jaws move size and scanning and scattering systems have been
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Chapter |8| Radiotherapy beam production
131
Walter and Millers Textbook of Radiotherapy
Detects asymmetry of
the radiation beam
indicators which locate the isocentre of the machine in of the pointer is set to the isocentre (Figure 8.16). The other
space. In combination, the beam alignment to the patient indicator is referred to as a distance meter and, effectively,
can be achieved and verified. this uses the coincidence between the cross-wire projection
There are three main indicators of the radiation beam and the distance meter projection in order to determine dis-
axis: treatment front pointer, treatment back pointer and tances from the x-ray source to the surface of the patient
light field x-wires. These are illustrated in Figure 8.15 and (Figure 8.17). The last indicator is independent of the
the pointers are attached to the radiation head during machine and consists of room mounted lasers which,
the patient set-up. The light field cross-wire projection is through cylindrical lenses, project sheets through the isocen-
achieved through an optical system in the radiation head. tre providing a set of Cartesian coordinate planes with the
Essentially, this generates a light source which, by using isocentre at the origin (Figure 8.18). With the use of surface
mirrors, is effectively positioned at the x-ray target. Cross- marks from the planning stages of the patients treatment
wires are introduced into the light field using a thin trans- preparation, the laser sheets enable the patient to be set
parent film and with the bulb and the cross-wire centre up with the isocentre at the appropriate place within the
exactly on the radiation head rotation axis, an optical pro- patient.
jection of the axis is obtained. It is possible to mount a laser on the treatment machine
The isocentre is indicated by three optical and mechanical which projects a sheet from the base of the gantry through
systems. The first uses the treatment front pointer and the tip the isocentre and the axis of gantry rotation. It is possible to
132
Target
Light source
Isocentre
Cross-wire
Back pointer
Isocentre projection
Mechanical axis
of radiation head Mechanical axis
of radiation head
Central axis Figure 8.15 X-wires, treatment front and back pointers.
of radiation beam
Target
Light source
Mylar
mirror
Distance
graticule
projector
80
100
Cross-wire
projection
140 Isocentre
Mechanical axis
of radiation head
Figure 8.16 Treatment front pointer for isocentre indication. Figure 8.17 Distance meter for isocentre indication.
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Walter and Millers Textbook of Radiotherapy
Vertical sagital
sheet
Vertical lateral
sheet
Isocentre
Lines created by
intersection of sheets
use this sheet in combination with the room sheets instead made that machine parameters at treatment match the pre-
of a mechanical backpointer (Figure 8.19). scription and a record is built up of the treatment delivered.
The structure of a system is illustrated in Figure 8.20.
For each patient, a treatment parameters file is held
Record and verify systems
and the parameters are downloaded from the RV sys-
The task for the machine operators who deliver the treat- tem to a treatment machine at each occasion of treat-
ment has always involved setting up the patient and the ment. The machine is then set up for treatment of the
machine and, in some way, having this checked and patient by the operators and the RV system compares
recorded as independently as possible prior to treatment. the settings on the machine with the values stored in
The increasing complexity of treatments and the imple- the system file. Any differences must be resolved by the
mentation of quality systems with a requirement to dem- operators before treatment can commence. This will nor-
onstrate traceability of the process have made an mally be done by adjustment of the patient and machine
automatic system essential. With the increasing availability set-up to bring it in line with the treatment parameters
of fast computing systems, record and verify (RV) systems but, in exceptional circumstances, parameters can be
were developed to fulfill this role. Essentially, the RV sys- over-ridden subject to appropriate checking and supervi-
tem consists of three distinct components: storage, check sion. The patients file is also used to record the dose
and record. The patient prescription is stored, a check is delivered to the patient on each treatment in order to
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Chapter |8| Radiotherapy beam production
Vertical
sagital sheet
Vertical
lateral sheet
Isocentre
Back pointer
sheet
maintain an accumulated record of the treatment dose electron (TSE) treatment. For both these types of treatment,
given to the patient. the limitation of the accelerator is its field size. However, by
While these systems provide an invaluable aid to the treating patients at greatly extended distance of up to 4 m,
treatment delivery, it should be borne in mind that such full body coverage has been achieved for megavoltage TBI
systems can also fail. As with any computerized data trans- (Figure 8.21). Likewise, techniques to provide electron
fer process, routine checks are required to check that the fields large enough to cover the entire patient have been
system assigns the correct data to a patients treatment. devised for TSE. Figure 8.22 shows the well acknowledged
Stanford technique, however, there are also techniques
which move the patient couch through the beam and tech-
Special techniques
niques which obtain an enlarged field by rotation of the
Although linear accelerators have been designed to deliver gantry during radiation. For these extended source to
beams which will superimpose on each other within the patient TSE treatment distances, high dose rates are spe-
patient in an effective manner, they have also been adapted cially generated on the accelerator in order to reduce the
to fulfill some other treatment requirements. treatment time.
One of the major adaptations has been to provide total Another adaptation of the linear accelerator has been to
body irradiation (TBI) treatment with x-rays and total skin supplement the standard field sizes which can be defined
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Walter and Millers Textbook of Radiotherapy
Patient Identity
Patient Data
Files
Compare settings
YES NO
Alarm Different? Treat
Perspex sheet to
eliminate build up
Couch
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Chapter |8| Radiotherapy beam production
Overall treatment
profile at patient
15 below
Individual
beam profiles
with the collimators in the radiation head with fixed nar- teletherapy. The isotope is produced by neutron bombard-
row beam collimators or a micro multileaf collimator ment through the following process:
which can define small fields with dimensions of less
59Co n ! 60Co g
than 5 cm. These small fields have been used in either static
or arcing treatment techniques for accurate stereotactic Nuclear reactors provided an ideal production platform
radiosurgery and stereotactic radiotherapy. These stereotac- for the substance. The attraction of cobalt-60 was the
tic techniques are used for cranial tumours, such as brain high energy gamma emission produced in the radioactive
metastases, and non-malignant arteriovenous malforma- decay process (Figure 8.23) and also the relatively long
tions (AVM). An early form of dynamic treatment is half- life of the isotope of just over 5 years. The energy of
achieved by rotation of the gantry during irradiation and the gamma rays are almost four times that of the highest
this can be applied with both megavoltage x-ray and elec- deep x-ray unit.
tron beams. Often it is referred to as arc-therapy. In the case
of electrons, the technique can be used to treat a large Cobalt-60 decay
curved surface, such as the side of the chest wall. 60
Co 5.26 years half life
27 310keV
137
Walter and Millers Textbook of Radiotherapy
120
100
300kV
Cobalt-60
80 6MV
25MV
% Dose
60
40
20
0
0.00 5.00 10.00 15.00 20.00 25.00
Depth /cm
The depth dose characteristics of a nominal 1010 cm Herein lies one of the deficiencies of the cobalt treatment
cobalt-60 beam at 80SSD is compared in Figure 8.24 to that unit as this large source in turn produces a large penumbra
for a 10 cm diameter, 0.4Cu HVL kilovoltage beam. The lat- in its radiation fields. The source is housed within a large
ter would typically be produced from acceleration with shielded safe which has a shutter mechanism to transport
about 300 kV and appropriate filtration. The depth dose the source into an exposed position. Typical mechanisms
characteristics for a 1010 cm field size 6 MV and 25 MV are spring-loaded wheels, jaws and sliding mechanism
beam at 100SSD from a linear accelerator are also shown and there were electrical, mechanical, hydraulic and
for comparison. pneumatically driven systems developed. Periodic testing
The advantages are immediately obvious. First, the dose is required to ensure that there is no leakage of radioac-
at depth, say 7 cm is increased by almost a factor of 1.5. Sec- tive material from the source encapsulation. Swabs are
ondly, however, the forward scattering of the electrons pro- taken of the aperture to the safe in order to detect
duced from the photon interactions produces the skin contamination. Emergency personnel procedures are
sparing effect with a maximum dose at 0.5 cm depth rather also required to be in place to ensure that, in the event
than the surface. Cobalt units provided the clinician with of a failure of the transport mechanism, the patient
an enormous technical advantage for teletherapy. can be safely removed from the room and the source
The cobalt unit represents an extremely simple method returned to the safe by manual means. One noticeable
to generate a megavoltage treatment beam. There is no feature of a cobalt head is that it is continually warm. This
requirement for the highly skilled maintenance and costs arises from the radioactive decay and absorption in
associated with linear accelerators and this enables telether- the shielded housing and, in particular, all the b-decay
apy to be provided at low cost in situations where technical indicated in Figure 8.23. It is testament to the reality of
support is not readily available. This is the enormous the energy release from the cobalt source.
potential for these machines: simplicity and economy.
Beam collimation
Radioisotope source
The collimation of the beam is achieved using a system
The radioactive cobalt-60 source consists of a small con- of primary collimator, secondary collimator and penum-
tainer which encapsulates pellets or disks of cobalt with bra trimmers as shown in Figure 8.25. The primary colli-
an activity of typically 200 TBq. Typical dimensions of mator is adjacent to the source and can form part of
such a source is a 2 cm diameter by 2 cm long cylinder. the drum assembly within which the source is stored.
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Chapter |8| Radiotherapy beam production
Radiation source
Source
Primary collimator
Collimators
Field shaping
collimator
Isocentre
Penumbra Penumbra
trimmers Beam profile
Isocentre
Figure 8.25 Collimation system for cobalt machine. Figure 8.26 Penumbra diagram.
It forms the initial beam which will set the maximum so that the axes of the radiation head rotation and the gan-
size possible for the final treatment field. The penumbra try rotation intersected. This enabled isocentric treatment
of a radiation field is dependent upon three aspects: of the patient with multiple beams intersecting within
the size of the source, the distance of the secondary colli- the target and enhancing the dose there simply by rotation
mator jaw from the source and electron scatter at the of the gantry. Due to the massive shielding for the radioac-
edge of the beam (Figure 8.26). Scatter really only becomes tive source, the radiation head presented a considerably
a problem at very high energies above 15 MV photon heavy load for the gantry assembly to accommodate. This
beams. However, the radiation source at 2 cm is very large. led to relatively large displacements between beams at
If then the secondary collimator jaws were placed one the isocentre and could well be of the order of 10 mm with
above the other, the penumbra across the inner jaws gantry rotation.
would be larger than across the outer jaws. So, in order One additional set of movements which was available
to provide a more equitable size in both directions, the on several machines was pitch and roll (see Figure 8.27).
jaws are interlaced as shown in Figure 8.25. The distance The advantage of these two movements was that, for some
from the source is extended even further by the use of poorly non-ambulant patients, the beam could be directed
penumbra trimmers which can be fitted to the ends of the for treatment with them upright in a chair or even remain-
main secondary collimators. Although this technique is ing in their bed. Such treatments would be single field and
effective, it is not always practical because of patient often single shot treatments for palliation. Nevertheless, it
positioning. provided a valuable treatment technique for the clinician
and operator.
In compact rooms, the radiation head was balanced
Design of gamma-ray teletherapy on the gantry by a shield in order to reduce the radiation
protection requirements in the room. Wedges were
machines
also available for these machines and consisted of metal fil-
Initially, there were fixed head cobalt treatment machines ters placed on trays directly below the secondary collima-
followed by rotating gantry mounted machines tors. No dosimetry monitoring was installed to control
(Figure 8.27). The rotating gantry machines were arranged the radiation delivery. The delivery was controlled by a
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Walter and Millers Textbook of Radiotherapy
Head Head
rotation rotation
Isocentre Vertical
timer which controlled the period during which the source have been three approaches involving linear accelerators
was exposed to the patient from its safe. Because there was a and other more compact electron accelerators. The first
finite time during which the source would be transported approach was to provide a standard gantry mounted linear
to the fully exposed position, this was accommodated by accelerator in a surgical theater with suitable modifications
modifying the exposure time with a transit time. The dose to eliminate any explosion hazards. This assigns one partic-
rate of the source was checked periodically by absolute ular theater for intraoperative treatment. Another approach
measurement under reference calibration conditions. This has been to use a very compact linear accelerator mounted
would typically be monthly and, in addition, a comparison on a mobile assembly which can self propel between thea-
would be made against the known physical decay predic- ters. Both approaches, however, utilize the techniques to
tion in order to insure the purity of the isotope. produce an electron beam from a linear accelerator. Other
approaches have utilized compact accelerators, such as a
betatron, which are mounted within a chosen theater or
on a mobile assembly.
CUSTOM TELETHERAPY MACHINES One aspect of note is the alignment of the electron appli-
cator to the target area. Attempts have been made to ensure
Although the gantry mounted medical linear accelerator that there is no direct contact between machine and patient
has found extensive use, there have been treatment tech- and sophisticated arrangements have been devised for this.
niques which have required the adaptation of the linear
accelerator and also development of highly specialized
treatment machines. Robotic machines
The isocentric gantry mounting of teletherapy machines pro-
vides an efficient method to direct multiple beams at the tar-
Intraoperative electron get with relatively simple movements of the gantry and
patient couch. Modern robotic control systems coupled with
beam machines
stereotactic radiographic localization of the patients posi-
A treatment technique that has found limited acceptance is tion has offered the prospect of delivering multiple beams
to irradiate the tumour bed following resection of the from virtually any direction in space. Such a highly accurate
tumour surgically. It is known as intraoperative radiother- system has been developed with a compact linear accelerator
apy (IORT). This treatment is done with a single dose dur- mounted upon a robotic arm. The location of the patient is
ing the surgical procedure and with the target exposed to determined from two kilovoltage images which, with use of
the machine. Because of the localization of the target and image processing, uses bony anatomy or implanted markers
relatively shallow depth, electron beams are ideal. There in order to track the position of the patient during treatment
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Chapter |8| Radiotherapy beam production
and align the machine to ensure the required delivery trajec- designed to deliver narrow intensity modulated beams
tory of the beam is correctly obtained. This flexibility in the which alter in profile as they are rotated around the
multiplicity of beam delivery directions coupled with high patient and, in effect, combine to produce a required dose
accuracy has enabled complex tumour volumes in close distribution within that slice of the patient. The patient
proximity to critical organs to be irradiated. In some cases, moves through the machine and adjacent slices are
the radiation delivery can be achieved when conventional stacked together producing a continuous dose distribution
surgery would have so high a risk of complication that it throughout the patient tailored to the requirements of
is rendered impossible. the clinician. In fact, the Tomotherapy machine is based
upon the gantry design of a CT scanner and it is also able
Stereotactic machines to generate megavoltage CT images for patient realign-
ment prior to treatment. What is notable about this
Stereotactic radiotherapy and radiosurgery deliver a high machine is that the original basis of its design was the
radiation dose to small volumes localized using stereotactic production of intensity modulated beams for full confor-
frames in order to ensure a high positional accuracy of the mal treatment.
treatment. Although, as mentioned above, a standard lin- Manufacturers of standard linear accelerators have pro-
ear accelerator can be utilized to deliver such a treatment, duced systems which can deliver intensity modulated
machines have also been developed which are dedicated beams as the machine rotates around the patient. However,
to this purpose. One well known machine is the Leksell while this provides very effective conformal dose distri-
gammaknife which consists of a treatment cavity for the butions efficiently, some of the benefits of a dedicated sys-
head within which there is housed a large array of cobalt tem like Tomotherapy of simultaneously treatment of
sources. The sources array focuses all the beams into a small multiple targets and also treating the entire length of the
volume, the dimensions of which are determined by colli- patient are lost.
mators. The positioning of the patients skull within the
treatment cavity is located using a stereotactic frame bolted
to the skull and ensures that extremely accurate localization IMAGE GUIDANCE
of the compact treatment volume is achieved.
Besides this specialized machine, a standard linear
accelerator has been adapted by one stereotactic facility sup- Megavoltage imaging to verify patient set-up and the loca-
plier. The machine has been fitted with a high resolution tion of critical tissue in relation to the radiation field has
multileaf collimator which is only applicable for very small been carried out for many years with slow film. Because
stereotactic volumes. It is installed within a dedicated room of the poor contrast between soft tissue and bony anatomy
designed with stereotactic kilovoltage imaging facilities to at megavoltage energies, attempts were often made to add
ensure highly accurate tracking of the patient and the target. filtration to the film cassettes to enhance the image contrast.
Adjustment of the patient set-up and movement of the Custom film holders, which could be treated as an acces-
machine is executed to provide accurate dose delivery. sory, were also made available to facilitate such imaging
at any angle of the gantry. Over the past 20 years, electronic
systems for both planar and CT imaging of the patient have
Dedicated intensity modulated become available. This development, along with the move
machines to reduce treatment margins on fields, to reduce the dose to
critical tissue and increase the dose to the tumour, has,
Intensity modulation to produce conformal radiation dose
in the interest of accuracy, expanded the role of imaging
distributions based upon inverse treatment planning
in radiotherapy. Indeed, it has become such an essential
was promoted by Brahme in the late 1980s. Intensity mod-
part of the treatment process that linear accelerators are
ulation was not novel having been implemented with
now always supplied with an on-board imaging device.
mechanical devices including the use of compensators to
account for inhomogeneity such as lung within the body.
The Scanditronix microtron and racetrack microtron
designs attempted to address all aspects of beam modula-
Planar x-ray imaging
tion, covering energy, beam intensity and beam shaping Planar imaging of the field being delivered represents the
with multileaf collimation. This machine design provided simplest verification of the location of the field in relation
complete modulation of the beam. However, the basis to bony landmarks. Such systems are a logical extension of
of the machine was a standard linear accelerator gantry the slow film used in the past but, with electronic planar
and, in a default condition, the machine reverted to deliver devices, there exists an opportunity for image enhancement
a standard beam identical to that of a standard linear and automatic comparison between images to quantify
accelerator. patient movement. There are basically two planar imaging
In contrast, the Tomotherapy machine is completely systems: a camera viewed fluorescent screen system and a
dedicated to intensity modulation delivery. It has been solid state amorphous silicon system. Both types of system
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Walter and Millers Textbook of Radiotherapy
can produce high resolution, high contrast images. Therapy However, besides these aspects, there is a need for protec-
imaging techniques involve using the treatment field alone tion of the staff and patients by the provision of machine
as well as using the treatment field superimposed on a interlocks and shielding. The radiation head itself is con-
larger field in order to assess better the treatment fields structed with shielding to minimize the radiation leakage
relationship to patient anatomy. Imaging protocols are outside the treatment beam. For electron treatment, this
now widely used to monitor and correct patient position is also addressed within the applicator design and the dia-
during treatment. These imaging devices are being utilized phragm settings.
to make significant decisions about patient position and, as Room door and maze barrier interlocks are installed to
such, their accuracy is of great importance. The devices are try to ensure that no accidental irradiation of staff can
mounted on retractable arms attached to the gantry drum occur. Besides these, the treatment machines have many
and positional corrections for gantry displacement can be interlocked circuits. These interlocks are of two types. The
required routinely as well as routine image correction first type is to ensure that the beam is operating within cho-
parameter determination to account for the deterioration sen performance limits. An example of such would be the
in the imaging devices. monitor on a linear accelerator which ensures that the
beam is uniform and symmetric about the central axis.
Another would be the monitor of the bending current
Cone-beam imaging which ensures that the energy of the beam remains stable
A logical extension to planar imaging has been to utilize and would detect any fault in the circuit which could affect
the sequence of images from a complete gantry rotation it and the energy of the beam. The second type ensures that
to generate CT image slices. This has been done for both fitments on the machine are correctly set. An example of
megavoltage images and kilovoltage images. Of course, this on a kilovoltage machine would be that the filter that
for the kilovoltage images, there needs to be a separate had been fitted agreed with that selected at the treatment
kilovoltage radiation source fitted onto the treatment console. This would typically also be applied to the appli-
machine. The great benefit from CT imaging is to provide cator. On a linear accelerator, a typical example would be to
positional information about soft tissue within the patient indicate that the target was in position.
as opposed to relying on bony anatomy. As opposed to One well-established safety system on linear accelera-
standard diagnostic CT scanners which pass the patient tors is the provision of the two monitoring ionization
through a slice of radiation, it is more efficient to utilize chambers which are completely independent and moni-
the entire cone of the radiation beam from the machine tor the entire field. The primary chamber, often referred
or from the kilovoltage source. In effect, the reconstruction to as Channel 1 is calibrated to deliver a known dose to
process which produces the CT image slices uses the over- a reference point from which doses can be calculated
lap of the divergent beam as the machine rotates around and predicted. The other chamber, referred to as Channel
the patient. This gives rise to the term cone-beam CT 2, the backup channel is set so that in the event of a
imaging and the reconstruction is calculated on the entire Channel 1 failure the difference between the two channels
common volume as opposed to a slice-by-slice basis. The will be detected and the irradiation terminated. Should
megavoltage CT images can also be used for dose predic- Channel 1 fail completely, Channel 2 is set so that it
tion. The imaging devices are again fitted to the gantry will terminate the treatment having delivered a very
using retractable mechanisms which suffer mechanical dis- small additional dose than that intended by the clinician.
tortion during gantry rotation. Two aspects are critical On linear accelerators there is also a tertiary termination
here for accurate cone-beam imaging. The first is that system provided by a timer which should be set so that
suitable corrections are determined in order to reduce it would terminate the treatment in the event of both
imaging artifacts and the second is that the positional reg- Channel 1 and 2 failures with only a small additional dose
istration between the kilovoltage image centre and the being given to the patient.
megavoltage treatment centre accurately agree.
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Chapter |8| Radiotherapy beam production
addition, it provides the baseline set of performance data water, cabling for the machine and ventilation should
against which subsequent check or quality control mea- also be placed to avoid primary beam irradiation. Away
surements will be made. Besides measuring standard data, from the primary shielding, the room walls should be
such as output factors, depth dose and tissue phantom adequate for scattered radiation. While for megavoltage
ratios for example, specific data for beam dose algorithms there will be cost savings associated with differentiation
in computer treatment planning systems along with verifi- between primary shielding and scattered radiation shield-
cation data for the dose predictions are gathered and used ing, for kilovoltage the entire room can be shielded for
for validation. In the case of imaging and any other ancil- the primary beam.
lary equipment relevant commissioning measurements The next feature concerns room access which may be
should also be devised. direct or using a maze. Here, there are considerations
such as staff access and also patient considerations about
apprehension of being left alone in a room. Direct access
Quality control requires a substantial shielding door to be fitted in the
Quality control of the equipment is required to ensure case of megavoltage and, at kilovoltage energies, the door
satisfactory operation. It is required routinely and on a peri- shielding can also be substantial enough to require a
odic basis in order to demonstrate the continued satisfac- motorized door. For a maze entrance, three aspects are of
tory operation of the machine. It is required following significance: cross-sectional area, distance along the maze
machine breakdown and repairs to ensure that the opera- and bends. The area concerns the cross-section of the
tion has been returned to a satisfactory level and, lastly, maze at the room exit and the smaller this can be made
it is required following adjustments to the running of the consistent with patient access including a bed, the less radi-
machine to ensure again that the satisfactory operation ation will enter the maze. Reduction of the cross-section of
of the machine has been maintained. the maze at the treatment room end by fitting a lintel can
As with the commissioning of equipment, the good prac- make a worthwhile contribution to protection. Secondly,
tice of quality control has grown over the years and is now the length of the maze will increase the distance between
established in statutory legislation, such as IRMER 2000. the entrance and exit and provide a dose reduction. Lastly
and significantly, the scatter from a right-angled bend
within a maze can make a very significant contribution
to reducing the dose.
TREATMENT ROOM DESIGN In Figure 8.28, a typical megavoltage treatment room lay-
out is shown with the features described above indicated
The details of the treatment room design are very depen- for clarity.
dent upon the treatment machine, be it megavoltage or For high energy megavoltage beams, one particular
kilovoltage. There are two main aspects of room design aspect of concern is neutron production due to a photon
to consider. The first concerns radiation safety and the pro- neutron interaction in the nucleus. This interaction occurs
tection of personnel while the second relates to the ergo- at megavoltage energies and is nominally considered a
nomics of the room. The layout of the room is important problem for photon beam energies above 10 MV. Here
to ensure efficient treatment, patient access, as well as the aspects described above are not readily applicable and
machine maintenance. expert advice needs to be sought. Nevertheless, despite
For radiation protection, many of the features employed the problems which neutrons bring, there are readily
and the materials used can also be related to the actual available solutions which enable safe room design with
location of the room, either its adjacencies to public areas direct and maze access, even up to 25 MV. Several aspects
or whether it is a new room or a re-used and modified concerning neutrons are worthwhile mentioning. The first
room. Although there can be many aspects to detailed is that sharp corners in the rooms aid the reduction of
room design, there are general features which all room the neutron flux. Secondly, care should be taken to avoid
designs utilize to exploit very fundamental characteristics metal content in the construction materials including
of radiation. the concrete aggregate as gamma activation can occur trad-
The purpose of the shielding is the protection of mem- ing a neutron problem for a photon problem. This is
bers of the public and workers associated with the treat- also the case for wood lining which was considered
ment centre, particularly those who will spend a appropriate in the past. Lastly, specialized lining, includ-
considerable portion of their working day in the vicinity ing commercial lining substances for the maze and other
of the room and involved with patient treatment. penetrations can be used to reduce significantly the prob-
These general features concern first, the direction of lem to well below protection limits.
the primary beam and providing sufficient shielding to For more details on protection requirements, legislation
attenuate the direct beam. Also with regard to beam direc- and the choice of materials see Chapter 4.
tion, the position of room access and the access of penetra- Besides safety, the layout within a room for equipment
tions into the room for services such as electrical supply, and storage should be given consideration. Adequate
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Walter and Millers Textbook of Radiotherapy
FURTHER READING
[1] Thwaites DI, Tuohy JB. Back to the [2] Karzmark CJ, Morton RJ. A primer [3] Stedeford B, Morgan HM,
future: the history and development on theory and operation of linear Mayles WPM. The design of
of the clinical linear accelerator. Phys accelerators in radiation therapy. 2nd radiotherapy treatment room
Med Biol 2006;51:R34362. ed. Medical Physics Publishing; 1997. facilities. IPEM; 1997.
144
Chapter |9|
Radiation treatment planning: immobilization,
localization and verification techniques
John Conway, Janet Johnson
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Chapter |9| Radiation treatment planning: immobilization, localization and verification techniques
8. the excess plastic is trimmed from each shell to provide baseplate for daily set-up. Etched lines on the plate aid in
a flange that enables the two halves to be held together visualizing the laser lines projected on the plates. This loca-
with plastic press-studs. Side supports are molded and lizer box is removed prior to treatment.
attached to the shell to enable it to be fixed to the This type of non-shell fixation can be as accurate as
treatment head support. head shell methods provided that no displacement of the
mouth bite occurs that could compromise the rigidity of
the system. Patients that may be unsuitable for shell type
Thermoplastic shells immobilization, such as children and phobic patients, will
Commercial systems are now widely available that do often prefer this technique; however, because of limitations
not require vacuum forming techniques; these perforated imposed by the system design, it is unsuitable for use with
thermoplastic materials may be softened in a hot-water tumours of the lower oral cavity and neck.
bath or warm oven and shaped directly onto the patient,
Figure 9.1B. This system utilizes a U-frame in which the
Stereotactic frames
attached thermoplastic, when heated and softened,
stretches from the tip of the nose to the baseplate, where Stereotactic frames were originally designed for stereotactic
the U-frame is indexed and locked down. While this system intracranial surgery, biopsy and electrode placement but
is very easy to use and provides a snug fit for excellent fixa- have since been extensively adopted for radiosurgery head
tion, it also can, in some cases, exhibit shrinkage, leading to immobilization, Figure 9.1C. The high level of precision
patient discomfort due to the stretching of the thermoplas- required for radiosurgery, such as Gamma Knife and
tic required with this type of system. Stretching resulting X-knife systems, necessitates a means of relating three-
from prolonged use during the course of treatment can lead dimensional patient image coordinates to 3D locations
to inaccuracies in set-up and, although here is a cost benefit in frame coordinates to submillimeter accuracy. The most
from repeated use, sterilization requirements can limit this. common system in use is the Leksell Stereotactic System
A reinforced thermoplastic is also available that improves Frame which is rigidly attached to the patients head using
rigidity, comfort, and immobilization. Solid thermoplas- four small screws placed with local anesthetic. The frame
tic reinforcement strips, melted into the perforated sheet, is shown in figure 9.1C. The frame provides the basis for tar-
provide rigid fixation and rotational stability necessary for get coordinate determination and is used to immobilize and
treatments requiring more precise immobilization such as position the patients head within the radiosurgery collima-
intensity modulated radiotherapy (IMRT) and conformal tor helmet. The centre coordinates of the target volume are
radiotherapy treatments. positioned at the intersection of the beams (from 200 cobalt
These thermoplastic shells are a particularly attractive sources for the Gamma Knife) so that target-centering is
alternative to the vacuum formed shells to those sites which always achieved within this geometrically rigid system. Relo-
do not have extensive pretreatment preparation facilities. catable versions of the stereotactic frame are also available
The material is easily molded, transparent and the perfora- that are closer in design to the head-arc fixation method.
tions allow visual assessment of the final fit.
Body immobilization
Non-shell fixation systems
Numerous techniques are available for immobilization of
These systems of head restraint are based on a custom areas other than the head and neck. The major devices used
impression of the patients maxillary teeth and hard palate are best discussed in relation to their site-specific needs:
fixed to a plastic dental bite block (tray). Some designs Breast. Treatment of the breast commonly requires the
incorporate a vacuum applied through the bite block that use of three fields two coplanar glancing beams to the
secures it to the maxillary structures; a vacuum pump is breast and a supraclavicular field. All fields will often make
placed on the treatment couch and attaches to the mouth use of the asymmetric collimators to bring one edge of each
tray via a suction tube. Any decrease in pressure indicated field to the beam central axis, thereby removing the effect of
by the vacuum gauge is indicative of a misplacement of the beam divergence from that one edge. This does not remove
bite block. The mouthpiece is attached to two hollow the penumbra, and the alignment of the superior edges of
carbon-fiber composite columns mounted on a baseplate the breast fields with the inferior edges of the supraclavicu-
by a patient-specific fixation set consisting of a transverse lar fields is critical. To achieve accuracy in this set-up
plate and an angle plate. Moving the plates against each requires careful positioning of the patient so that all fields
other gives enough degrees of freedom to provide exact can be treated without moving the patient. The use of a spe-
positioning. Once adjusted, the fixation set stays assembled cially designed breast board is preferred. The device may
throughout the entire treatment ensuring precise reposi- consist of a support which inclines the patients upper body
tioning for the next fraction. A laser localizer box, consist- and provides an elbow support and/or a hand-grip for the
ing of side Perspex plates and top plate, are attached to the patient to grasp while holding the arm/s above the head;
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Walter and Millers Textbook of Radiotherapy
A B
Figure 9.1 (A) Vacuum formed perspex shell, (B) Thermoplastic shell (Orfit), (C) Stereotactic frame (Leksell).
(With kind permission from Elekta).
all these positions can be varied to meet the individual of shapes and sizes of bag are available to immobilize any
requirements of the patients treatment and locked into part of the anatomy or the whole of the patient, for total
position, linear and angular measurement scales allow body irradiation (TBI), for example. The attenuation in
the set-up to be recorded and reproduced at each fraction. the polystyrene is minimal, but being opaque, consideration
Pelvic region. This is one of the most difficult areas of the must be given to the beam entry ports during the initial evac-
body to provide effective immobilization. Some systems uation. Radiation damage to the plastic will eventually cause
utilize a single sheet of thermoplastic over the entire abdo- vacuum failure and necessitate the replacement of the bag.
men or pelvis that fixes to a baseplate, this is a larger version Other devices, such as ankle stocks and foot rests, can min-
of that described for the head. An alternative to this is to use imize movement by impeding body rotation or slippage
a large sealed plastic bag loosely filled with small expanded on the treatment couch. The use of a belly-board for
polystyrene spheres, Vac-Fix. The bag is manually formed prone patients, providing a cut-out in the patient support
round the patient while the air pressure in the bag is grad- which allows the abdomen to fall anteriorly, ensures that
ually reduced using a vacuum pump. At approximately much of the radiosensitive small intestine falls out of the
half atmospheric pressure, the bag becomes rigid and fits high dose region.
firmly round the patient, preventing any significant move- Thorax. For modern radiotherapy, the problems imposed
ment. The rigidity can be maintained throughout a course by respiratory movement can be considerable. Normal
of treatment and until the vacuum is released, when the bag breathing causes movement of the chest wall and introduces
and contents may be re-used for another patient. A variety uncertainties with regard to target volume position during
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Chapter |9| Radiation treatment planning: immobilization, localization and verification techniques
VOLUME DEFINITIONS
Accurate treatment depends on voluming. The parameters Figure 9.2 Prostate showing GTV, CTV, PTV, Bladder and
used in defining treatment volumes are described in detail Rectum.
in two documents published by the International Commis-
sion on Radiation Units and Measurements (ICRU),
Reports 50 and 62 Prescribing, Recording and Reporting to allow for a physiological process, the SM is required
Photon Beam Therapy [1, 2]. to allow for the technical factors that cause uncertainties.
The following are a transcript of the definitions: The SM may be reduced by improved immobilization of
Gross tumour volume (GTV) is the gross palpable or visible/ the patient and improved set-up accuracy. The IM can only
demonstrable extent and location of the malignant growth. be reduced through techniques such as respiratory gating
Clinical target volume (CTV) is a tissue volume that or image guided radiotherapy. The organs at risk (OAR)
contains a GTV and/or subclinical microscopic malignant volumes will also exhibit the same uncertainties in posi-
disease, which has to be eliminated. This volume thus has tion and these will also require a margin to be added
to be treated adequately in order to achieve the aim of the concept of Planning Organs at Risk Volume (PRV) is
therapy: cure or palliation. analogous to the PTV (See figure 9.2).
Planning target volume (PTV) is a geometrical concept, and
it is defined to select appropriate beam size and beam
arrangement, taking into consideration the net effect of all NON-CT CONTOURING DEVICES
the possible geometrical variations and inaccuracies in
order to ensure that the prescribed dose is actually Contours are all important in producing dose distribu-
absorbed in the CTV. tions. The value of radiation treatment planning depends
Treatment volume is the volume enclosed by an isodose on the reproducibility of the shape of the patient on a
surface, selected and specified by the radiation oncologist day-to-day basis throughout the course of treatment. The
as being appropriate to achieve the purpose of treatment. couch where the patient contour will be taken therefore
Organs at risk (OAR) are normal tissues whose radiation should be identical in every respect to the couch on which
sensitivity may significantly influence treatment planning that patient will be treated. It is imperative that the patient
and/or prescribed dose. is correctly positioned before the contour is taken for
ICRU62 is the supplementary report to ICRU 50 and dis- planning purposes. Since the advent of radiotherapy treat-
cusses in more detail the complex factors that account for ment planning, a variety of physical devices has been avail-
delineation of the PTV. An Internal Margin (IM) is defined able for taking patient contours. The simplest of these
to accommodate for the variations in size, shape and consists of a material (lead strip, flex curve) that can be bent
position of the CTV as a result of anatomical variations around the patient and retains the shape while being trans-
caused by organ movement. An additional Set-up Margin ferred to paper in order to trace the contour.
(SM) must be then added to allow for the uncertainties Adjustable templates have been used that allow for more
of patientbeam position. Whereas the IM is required complex shapes to be transposed. A large number of
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Walter and Millers Textbook of Radiotherapy
INF CAMERA
SAGGITAL LASER
LATERAL LASER
INF CAMERA
DIGITISER
adjustable pins or rods (3 mm diameter) held in a frame TPS and are generally compatible with the planning soft-
can accurately reproduce the surface shape in an axial ware. The ability of these systems to provide 3D skin con-
plane. The frame is transferred to a drawing board and tours are particularly useful in breast planning where CT
the contour traced onto paper. planning may be less practical because of limitations of
Another simple method of obtaining a contour(s) from the CT scanner to accommodate patients in the position
an immobilization shell is by fixing the shell within a frame required for treatment to the breast (see figure 9.3).
so that a movable pin that can rotate around the plane to be
contoured provides radial distance measurements; this sys-
tem relies on radial coordinate measurements to transpose
the contour shape of the required plane to paper. Many of PHYSICAL SIMULATION
these physical devices involving the use of contact techni-
ques have been superseded by non-contact devices such The treatment simulator is essentially a diagnostic x-ray
as laser imaging/optical devices or through the use of com- unit that emulates an isocentric linear accelerators geomet-
puterized axial tomography; the latter will be described in rical movement. The simulator has been an aid to radio-
detail in the following sections. therapy for nearly half a century, and enables highly
Recently, the use of optical systems, which have the benefit accurate localization of the target volume, the verification
of no direct patient contact, have been introduced to provide of the proposed treatment plan and, in some cases, even
both single and multiple contours of the patient in the treat- precise visualization of the organs at risk.
ment position. These systems are commonly installed within The unit allows real-time imaging of the beam portal and
the simulator room and utilize the in-room alignment lasers a facility to produce x-ray films of each treatment field.
(two laterals and one sagittal) that project both an axial and a The movements of a radiotherapy simulator are defined
vertical line on the patients skin. Multiple views of these laser in the publication IEC 1217- Radiotherapy Equipment
projections can be imaged by using four CCD cameras, coordinates, movement and scales [3]. A physical simula-
mounted at ceiling height in each corner of the room, focused tor should have at least as good, or better, accuracy in posi-
on the laser lines. Software manipulation of these four images tioning as the treatment unit and its mechanical tolerance
enables a reconstruction of an axial contour and a sagittal must be excellent (e.g. an isocentre accuracy of 1 mm diam-
contour. Multiple contours of the patient can be acquired eter sphere should be possible). The simulator geometry
by moving the couch either longitudinally (axials) or laterally should permit all the required beam directions and field
(sagittals) and capturing images at each position. definitions that are achievable on a linear accelerator.
This remote method of contour acquisition has many Modern physical simulators (e.g. Varian Acuity) do
advantages over the physical methods described above; not have the limitations of the image intensifier systems
the key benefits are its inherent non-contact with the patient that have been used for decades. The availability of an
and the technique requires no manual handling of a device. amorphous silicon panel to provide a digital imaging
Optical systems provide digital images of the patients exter- device has resulted in simulators that are almost identical
nal contour that can quickly and easily be transferred to the to the therapy unit and have few movement constraints.
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Chapter |9| Radiation treatment planning: immobilization, localization and verification techniques
The simulator couch again needs to be identical to that target volume using surface anatomical landmarks. This
used on the therapy unit and should have the same range can then be adjusted using fluoroscopy. Two orthogonal
of lateral, longitudinal, vertical and rotational movements. films/images should be taken (typically an AP and a lateral
Coordinate scales between the simulator and linear acceler- view, although any orthogonal arrangement may be used).
ator must be identical. The ability to accommodate all treat- It is usually prudent to record positioning details at this
ment accessories and ensure precise emulation of the stage along with the film exposure factors.
patients position is essential. Prior to moving the couch, a contour is taken using an
The size of image that can be obtained during physical sim- appropriate contouring method which ensures that the film
ulation is limited by a number of factors: the physical size of data and the contour data are coincident. This may be taken
the image detector, the focusaxis distance, the focusdetector while the patient is on the couch or, alternatively, the lasers
distance and the ability to stitch images together using a merge may be used to mark the plane on the shell surface so that a
function. Dual and Quad merge techniques allow the acqui- contour can be taken from the shell at a later time.
sition of an image larger than the size of the imager (which The size and position of the volume is marked on each
is typically 30 40 cm2). The enlarged image is created by film and the data transferred to the TPS for calculation
moving the detector plate and acquiring multiple images all and plan optimization. The plan should be accepted by
of which contain the beam central axis. Software enables these the oncologist prior to verification.
images to be referenced to this common central axis point and
aligned accurately to provide extended images in both the Verification
horizontal and vertical directions. This facility is particularly
Once the optimal treatment plan has been produced
useful for large pelvic fields or extended spine fields. Auto-
based upon the contour and geometric data from the
matic merging of multiple images is less successful when there
images, the plan must be verified prior to commencement
are significant differences in absorption within the images,
of treatment.
e.g. a pelvis where large air gaps cause high contrast gradients.
The patient re-attends the simulator and adopts the treat-
During the localization procedure, the simulator is used
ment position using the immobilization shell and posi-
much like a diagnostic x-ray unit where the patient is posi-
tioning details recorded from the localization procedure.
tioned on the couch in the treatment position and moved
Using the parameters from the treatment plan, each field
while imaging the anatomy. The desired location for field
is set up in turn, applying the correct size, shape and direc-
placement requires x-ray visualization in real-time until
tion of the beam. Using fluoroscopy, a comparison can be
the required position is reached. In order to minimize radi-
made between the volume marked at localization and that
ation exposure to the patient during this procedure, a utility
achieved during verification. Local protocols will specify
called motion control is available. This function allows the
tolerances for positional accuracy.
control of field placement, e.g. x/y blades, collimator or
Using the light projected field display, the entry points
field centre by adjusting these parameters on the captured
and field borders can be transferred to the shell to ease
(frozen/stored) image. Subsequent live activation of the
treatment set-up on the linear accelerator. A verification
imaging system initiated an automatic change to the
film/image may be taken as confirmation of the final field
parameter values and patient position on the physical sim-
portal to be delivered and gantry couch and field data may
ulator. The advantage of this function is that clinical deci-
be transferred via a network to the linear accelerator.
sion and minor adjustments can be made on the captured
If the beam arrangement is particularly oblique, it may
image with a final check made with an x-ray exposure.
be difficult to interpret the anatomy seen during fluoros-
A typical head and neck physical simulation procedure
copy and it may be necessary to supplement the beam por-
is described below (although where a CT based facility
tal information with an AP and lateral view as a means of
is available, this offers a superior method of anatomical
accurately confirming the position of the isocentre.
localization and contouring).
It is difficult to verify intricate beam shaping and multi-
leaf collimator (MLC) configuration using conventional
Localization simulation, but this may be achieved either by using a phys-
ical device, attached to the accessory mount, which has
The patient is required to adopt the position on the simula-
radiopaque markers to define the leaf positions or by using
tor that is optimal for treatment delivery. The immobiliza-
a digital shape projection device (Figure 9.4).
tion shell is then applied and final checks should be made
to ensure that the patient is comfortable, that the head posi-
tion is appropriate for the treatment being planned and that
the contour of the shell fits accurately to the patient. Magni- CT SIMULATION
fication markers of a known size may be applied to the shell
for use during the planning stages. The term CT Virtual Simulation was first introduced in a
The couch position is then moved so that the isocentre is publication by George Sherouse in 1987 [4] who recognized
approximately incident upon the centre of the proposed that a suitable software package in conjunction with a
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Chapter |9| Radiation treatment planning: immobilization, localization and verification techniques
Figure 9.5 (A) Beams Eye View (BEV) on a Treatment Planning System with Digitally Reconstructed Radiograph (DRR) on Virtual
Simulator; (B) Screen shot of Virtual Simulator with surface rendering and transverse slice.
treatment volume, visualization of the treatment field and are also incorporated into 3D planning systems but do
verification of the plan design. Successful implementation not include the ability to provide coordinate information
of the virtual form of this simulator depends on software that relates to the patient position on the scanner couch
manipulation of the CT data. and the provision to mark the isocentre and reference
The CT simulator equivalence to the physical simulator points.
includes software capabilities to contour target volumes The treatment planning portion of the CT simulation
and critical structures, placement of treatment isocentre, process starts with the definition of a treatment reference
beam design and generation of digital reconstructed point that can either coincide exactly with the position of
radiographs (DRR). Many of the software control features the isocentre or alternatively can be an estimate of its
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Walter and Millers Textbook of Radiotherapy
Figure 9.6 Large Bore CT Simulator. Figure 9.7 BEV/DRR with shift information.
position. The former method will require the definition of approach is to mark the patient before scanning and to
the target volume to define precisely the treatment isocen- set this position as the patient reference origin.
tre and will require the oncologist to be present; whereas Virtual simulation requires marking of the GTV, CTV, PTV
the latter method does not require the target volume to and OARs; the isocentre and field parameters can then be
be defined and the final isocentre position can be found defined using the TPS. The plan is sent for calculation and
using shift coordinates. These shift distances, Figure 9.7 optimization to the TPS and exported back to the virtual sim-
are relative to the reference point and can be applied at ulator workstation for verification. The DRRs for all beams are
the first treatment in order to align precisely the isocentre printed (laser imager) and approved by the oncologist.
to the target. The shift coordinate method is commonly Shift coordinates are printed from the relationship between
used in a busy department where there is limited time to the isocentre to patient reference origin coordinates. These
wait until targets are contoured or where the oncologist are transferred to the treatment machine with the plan details.
is not available during the scanning session. Worksheets and DRRs are printed (see figure 9.7).
The advantages of CT virtual simulation can be summar-
ized as follows:
A TYPICAL HEAD AND NECK CT full 3D simulation allowing unique verification of
SIMULATION PROCEDURE beam coverage and avoidance in 3D
beams can be simulated and verified that are not
Localization requires the immobilization shell to be attached possible with conventional simulation, e.g. vertex fields
to the flat CT couch in order to emulate exactly the patient the verification image the DRR can contain more
positioning on the treatment machine. Careful consider- information than conventional simulation and can be
ation should be given to the design of the head fixation manipulated to enhance tumour visualization
device to enable compatibility between the CT and acceler- there is a much closer connection to diagnostic
ator table supports. information with CT simulation allowing integration
The scanning parameters are usually a trade-off between of multimodality images.
maximizing DRR resolution and keeping the number of During the early use of CT simulation, it was evident that
slices to a manageable size (typically 3 mm slice thickness the inability to image organ movement (e.g. lung) was a
and 1.5 spiral pitch). The scanning extent is determined significant disadvantage over physical simulations fluo-
from the pilot (scout) view and the external contours are roscopy. However, the improvement in image acquisition
often produced at a remote virtual simulation workstation and reconstruction speeds has provided the ability to fol-
while previewing the scanned slices. low respiratory movement. The technique is often called
A reference slice plane is selected and the patient refer- respiratory gated acquisition and 4D viewing, this method
ence origin coordinates created and transferred to the CT enables images to be acquired at a rate of more than 16
couch and/or lasers. The CT longitudinal couch, vertical frames per second that enables the full movement of
couch and sagittal laser positions are set to define the the patients diaphragm to be visualized within a movie
patient reference origin and the patient is marked. loop. The definition of lung tumour margins can now
The patient session is now finished. An alternative be assessed in 3D.
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Once the two image data sets are matched then volume
MULTIMODALITY IMAGES FOR contouring on the MRI images is automatically translated
PLANNING to the CT study. This technique provides the advantages
of the MRI images for tumour delineation while maintain-
ing the CT study for accurate calculation of the treatment
CT imaging plays a crucial role in radiotherapy planning as dose distribution.
it provides the electron density information that is required Automatic registration methods such as mutual informa-
to correct the absorbed dose for the different tissues through tion use rigid and non-rigid matrix transformations that are
which the beams will pass. able to compensate for rotational as well as translational
CT imaging also provides excellent definition between differences between the two image sets.
tissues having marked differences in x-ray attenuation New imaging modalities that provide functional or
values (e.g. air/bone/soft tissue), however, the contrast of tumour kinetic information for radiotherapy treatment
these images is poor for structures with similar electron planning are becoming widely accepted. Positron emission
densities (e.g. tumour/soft tissue). tomography (PET) and single photon emission CT (SPECT)
Magnetic resonance imaging (MRI) is based on the produce nuclear medicine images that enable improved
measurement of radiofrequency radiation resulting staging of malignant disease and improved treatment
from transitions induced between nuclear spin states planning by ensuring that gross tumour volumes are more
of hydrogen atoms (protons) in the presence of strong accurately defined. Information from these functional imag-
external magnetic fields. Unlike CT, where the signal ing modalities can be used to design more conformal radia-
intensity is dependent on x-ray attenuation and its con- tion dose distributions and to prescribe additional dose to
trast on the electron density of tissues, MRI depends on specific tumour microregions.
the intrinsic tissue properties associated with proton The specific activity of the radiopharmaceutical fluoro-
densities and spin relaxation times. Therefore, MRI 2-deoxyglucose (18F-FDG) produces uptake in malignant
has the ability to differentiate between tissue of similar tissue that enables highly accurate determination of the
density thus providing better delineation, not only of extent of solid tumour spread. FDG is taken up by glucose
tumour extent, but also of the adjacent critical soft tis- transporters and its concentration can be measured (images)
sue organs. by the retained activity within various tissues. FDG uptake
MRI also provides unrestricted multiplanar, volumetric, correlates strongly with the presence of cancer.
vascular and functional information. The introduction of combined PET/CT scanners has
Some of the problems associated with using MRI for improved the availability of this new modality. The PET
treatment planning are: images are superimposed upon the CT images, both of
1. inherent image distortion, particularly at the periphery which are simultaneously acquired during a single scan
of the image (typically 3 mm for heads and up to session. Planning can be performed either in treatment
15 mm for pelvic images) position, requiring modifications to the scanning proto-
2. pixel intensities are not related to electron density cols, or in diagnostic position with image registration
values and therefore cannot be used for heterogeneity being used to accommodate the change in patient posi-
correction (i.e. density/dose) when calculating tion between functional image and treatment planning
treatment plan dose distributions patient position.
3. the physical restrictions of the MRI scanner mean that a Specialized software can register the PET/CT study with
patient cannot be easily positioned in the treatment the therapy planning CT study to enable contours on the
position. A quantitative method called image PET images to be transposed to the planning images.
registration is used that provides fusion of CT and MRI There is increasing evidence that, in many clinical
image studies. situations, radiotherapy treatment may be planned more
accurately if supplementary functional images of the patient
MRI data are transferred to a TPS where the therapy CT are available. In practice though, the lack of access to PET
images and the MRI images are registered. Manual and and the problem of image registration have restricted the
automatic methods of registration are now available as part use of combined anatomical and functional information:
of sophisticated software systems provided with CT simula-
tors. The manual methods involve matching fiducials that PET is prohibitively expensive, which has limited its
are visualized on both CT and MRI; these fiducials are routine clinical use to only larger oncology facilities
opaque markers or bony structures so that image transla- multimodality image registration is a difficult problem,
tion in the three coordinates directions achieve a match which is further complicated by the significant
between the two studies. The accuracy of image registration anatomical changes that may occur between the
can be assessed by the accuracy to which the fiducial mar- different imaging sessions due to surgery, chemotherapy,
kers match. patient weight change or fluid collection.
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Chapter |9| Radiation treatment planning: immobilization, localization and verification techniques
diagnostic x-ray systems mounted on the linear treatment-room CT scanners that are adjacent to the
accelerator that can provide orthogonal images or CT linear accelerator and can provide pretreatment or
(cone beam reconstructed) images post-treatment CT images.
REFERENCES
[1] ICRU Report 50. Prescribing, Commission on Radiation Computers in Radiation Therapy.
recording and reporting photon Units and Measurements; 1999. Bruinvis et al, editors. Elsevier,
beam therapy. International [3] IEC 1217. Radiotherapy equipment North-Holland; 1987.
Commission on Radiation coordinates, movement and scales. [5] Goitein M, Abrams M. Multi-
Units and Measurements; 1993. IEC; 1996. dimensional Treatment Planning:
[2] ICRU Report 62. Prescribing, [4] Sherouse GW, Mosher CE, Beams Eye View, Back Projection,
recording and reporting photon Rosenman J, Chaney EL. Virtial and projection through CT sections.
beam therapy (supplement to ICRU Simulation: Concept and Int J Radiat Oncol Biol Phys
Report 50). International Implementation. The Use of 1983;9:789797.
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Chapter | 10 |
Principles and practice of radiation
treatment planning
Peter J. Childs, Margaret Bidmead
Special electron techniques 180 lead to increased waiting times for other patients. Complex
Arcing electron treatment 180 and non-standard plans can also increase the risk of errors.
Where the treatment intent is palliation, for example
Total skin electron irradiation (TSEI) or TSET (total
relief from pain arising from metastatic disease, then a sin-
skin electron therapy) 181
gle treatment beam will usually fulfill the purpose. This can
Differences between kilovoltage and
electron therapy 181 be justified as the most important consideration is to give
the treatment as soon as possible, with minimal distress to
Special techniques 182 the patient, and the consequences arising from irradiating
Total body irradiation 182 excess normal tissue do not apply to a patient with a short
Stereotactic radiotherapy and radiosurgery 182 life expectancy.
Gamma units 182 Where the treatment intent is curative radical treatment,
consideration must be given to short- and long-term side
Linacs 182
effects arising from the irradiation of healthy tissue. The
Stereotactic treatment planning 183 complexity of a treatment plan is likely to increase, espe-
Treatment plan checking 183 cially when an organ at risk (OAR), also referred to as a crit-
Independent dose check 184 ical structure, lies adjacent to the planning target volume
Plan checking at treatment 184 (PTV), and the prescribed dose greatly exceeds the tolerance
dose of the OARs.
References 184
It is important that the planner appreciates the radiosen-
Further reading 184 sitivity of normal tissue. OARs can be considered as serial
(e.g. spinal cord), parallel (e.g. lungs), or a combination
of serial and parallel (e.g. the heart). In a serial organ, if
INTRODUCTION any part of the organ receives a dose above its threshold
then there will be total loss of function, e.g. paralysis in
The goal of treatment planning of external beam radiother- the case of the spinal cord. In a parallel organ, part of the
apy is to produce a dose distribution within the patient that organ may be severely damaged but the rest continues to
will destroy the tumour while sparing as much healthy tis- function. Therefore, it is important to consider the volume
sue as possible. The planning role is usually carried out by of the parallel organ that is receiving the damaging dose.
radiographers, physicists, or technologists with expertise in For example, the severity of lung pneumonitis significantly
producing either an optimum plan, or a selection of com- increases if the dose exceeds 20 Gy so the plan would be
promise plans for the clinician to approve. The planner evaluated by considering the volume of lung exceeding this
must have sufficient clinical knowledge to understand dose V20. For a patient with two healthy lungs, it would
where compromises may have to be made, either in sparing be normal practice to consider both lungs as a single organ.
some of the target volume dose or in accepting higher than Table 10.1 gives typical tolerance doses for organs. How-
desirable doses to radiosensitive healthy tissue. ever, these values should not be taken as absolute, as frac-
Most treatment sites will have locally agreed standard tionation affects the ability of normal tissue to repair
treatment protocols and the planner will normally have a damage. The quoted dose may represent an increased risk
limited range of variables with which to optimize the plan. rather than a stochastic threshold above which all patients
The planner must take the clinical requirements stated in will be affected. The patients clinical condition and drugs
a prescription and planning request and translate them into may affect radiosensitivity of some organs. The complete
the best plan for the individual patient. This must then be clinical picture is also important, for example in the abdo-
presented to the clinician in a clear format so that what in men region, the planner must know whether one of the
many cases is a complex three-dimensional plan can be kidneys is already non-functioning as this will enable them
readily appraised. Over the years, tools and techniques have to design a plan that may reduce the dose to the healthy
evolved to enhance this critical communication between kidney at the expense of dose to the already damaged one.
staff groups. The ICRU reports 50 and 62 [1, 2] referred Treatment planning computers offer a variety of tools
to in Chapter 9 provide an effective methodology of pre- used to localize treatment volumes, virtually simulate
scribing the volume to be treated and the means of display- the field arrangement, and to calculate the dose distribu-
ing the dose distribution produced by the treatment plan. tion. This chapter covers the production of desired dose dis-
The intention of the treatment can drive the complexity tributions to treat a specified PTV and the tools relevant to
of the plan, given that most radiotherapy centres now pos- this process. The majority of radiotherapy treatments are
sess therapy machines capable of delivering highly sophis- delivered using megavoltage x-rays or electrons from linear
ticated treatments. The cost (i.e. complexity) of the accelerators. However, there are some specialized treatment
treatment must be balanced against the benefit and, in techniques appropriate to a limited range of diseases. These
many instances, the simplest plan is the best plan. The cost techniques may be delivered with a conventional linear
may be measured in increased treatment time, which could accelerator, or may require specialized equipment such as
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Chapter | 10 | Principles and practice of radiation treatment planning
Table 10.1 Typical normal tissue tolerance doses for generally accepted risks. Note that these may vary for individual situations
due to clinical condition and other therapies increasing radiosensitivity and that correction must be made for different
fractionation
Spinal cord 45 Gy Although a serial organ, the length of the cord receiving
the dose may be taken into account
Lung V20 (e.g. <32%) mean lung dose <18 Gy Normally consider total volume of both lungs (if the
GTV or PTV lies within the lung then its volume should
be subtracted from the total lung volume and higher
V20 volumes may need to be accepted)
Heart <40 Gy to entire heart Normally the heart volume outlined will include blood
No more than 1/3 of heart volume to receive 60 Gy
the Tomotherapy device or Gamma knife. The use of a plan based on the effectiveness of the dose delivered
modern treatment delivery equipment with dynamic con- rather than the physical dose alone. Inverse planning
trol of multiple simultaneous movements, such as couch, may be performed by optimizing the dose distribution
gantry, and multileaf collimators, may be restricted by through the use of normal tissue complication probability
the treatment planning process as complex software is (NTCP) and tumour control probability (TCP).
required to simulate and calculate dose distributions. Spe- Modern treatment planning is a complex process. As well
cialist software is required to plan treatments for devices as striving to meet the optimum clinical objectives, it is also
such as Tomotherapy and Gamma knife. important to comply with local practice for the patient set-
The reasoning behind the prescribed dose required to kill up instructions, and local protocols established for reliable
a specific tumour type is discussed in Chapter 17. The treat- and safe treatment delivery. For the beginner, this can
ment planner is given this in the plan request and is solely be frustrating as, even for basic plans, to some extent the
concerned with delivering this dose at the specified fraction- process can only be learnt from ones own mistakes.
ation. However, it is important to have the dose and dose per
fraction available at the time of planning as the dose limits
to critical structures will depend on the dose rate.
Much of radiotherapy dose and fractionation is based PATIENT DATA
largely on clinical results evaluated over decades. However,
better knowledge of how specific tumours and normal tis- The patient contours may be acquired in the form of mul-
sues respond to radiation, in individuals, or groups of tiple computed tomography (CT) slices or, in some cases,
patients, could lead to more effective treatments. If reliable derived from external contours alone, possibly with some
radiobiological data relating to both the tumour and nor- estimation of the dimensions and density of significant
mal tissues are available then it may be possible to prepare internal heterogeneities, such as the lung. The detailed
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anatomy derived from CT images is the optimum means of correction tools on CT scanners, there are usually signifi-
obtaining accurate dose distributions as the CT numbers cant artifacts present surrounding metal objects especially
can be converted to electron density maps, which the treat- for bilateral hip implants, and a manual overlay of the den-
ment planning computer (TPS) will use to calculate sity may be required (Figure evolve 10.2 ). The use of MR
how the beams are attenuated and scattered. However, imaging in the presence of non-ferrous implants may pro-
CT- density tables can also be manipulated to obtain vide useful information that may be transferred to the dis-
enhanced digitally reconstructed radiographs (DRRs), so torted CT dataset.
it is important to use a table that is specifically intended Cardiac pacemakers present a problem, not only in per-
for dosimetry rather than imaging (see Chapter 9). turbing the treatment beam, but also in their sensitivity to
CT is the best imaging modality for radiotherapy in terms radiation and electromagnetic interference from linear
of dosimetry and spatial accuracy, but does not always accelerators. Ideally, pacemakers should not lie in the path
provide the best images for tumour or critical structure of a treatment field and should only receive scattered radi-
localization. Normal practice is to register the diagnosti- ation dose of less than 2 Gy. The cardiologist should be
cally superior magnetic resonance (MR) or positron emis- consulted to ascertain the required level of monitoring dur-
sion tomography (PET) images onto the CT images (see ing and after the treatment.
Chapter 9). However, it is possible to use the MR images Contrast may be present in a CT scan, for example,
directly for some sites, by applying distortion correction to visualize nodes in head and neck images (Figure
to the MR images and assigning bulk heterogeneity correc- evolve 10.3 ), or may be present in the bladder as a result
tions to visible structures such as bone. of contrast used elsewhere.
When using a TPS with 3D scatter correction, it is impor- This contrast will not usually be present during the actual
tant that the CT scan extends beyond the PTV, ideally by at treatment, but its presence during planning does not
least 2 cm, so that the adjacent anatomy is accounted for in usually have a significant impact on the dosimetric accu-
the calculation and not assumed to be air by the TPS. racy. However, this should be verified whenever a new
The contours used for planning must represent the contrast-based localization technique is introduced.
patient contour during treatment delivery bearing in Care should be taken to ensure that the CT image repre-
mind that treatment will take several minutes, whereas sents the treatment set-up. Sometimes, the patient cannot
CT scans are acquired in seconds. Most contouring techni- be scanned in the same position as for treatment due to
ques, whether CT or external outlines only, are very rapid restrictions of the CT scanner aperture, particularly when
snapshots compared to treatment delivery times. There- immobilization devices are employed. For some sites, the
fore, either the planning procedure, or the treatment scan may be performed feet first into the scanner while
delivery, must account for patient movement. For the the patient may be treated in the head first orientation.
vast majority of treatments, the treatment plan must be In this case, the TPS or scanner software may be utilized
designed to account for this patient movement by the addi- to mirror and restack the scans into the treatment position.
tion of margins around the clinical target volume. However, When such techniques are employed, there must be clearly
modern technology now offers practical methods of gated visible quality assurance (QA) tools to verify that the soft-
treatments that only deliver the dose to the patient while ware has processed the images correctly, such as couch mar-
they are in the same position as during the therapy CT scan, kers identifying the couch superior-inferior and lateral
or tracking treatments, that can follow the PTV movement. orientations.
These are discussed in the final section of this chapter. The CT couch, immobilization supports, bolus, or non-
Figure evolve 10.1 shows the effect of patient breathing treatment-related devices may be present in the CT scan.
on a thoracic CT image acquired in spiral mode. The The user should be aware of how the TPS will handle, or
appearance of the liver clearly indicates the breathing ignore, structures that lie outside the patients external con-
motion that otherwise might not be apparent. tour and how to compensate for TPS calculations that do
Radiotherapy patients may have prostheses, dental fill- not account for beams passing through these structures.
ings, breast implants, and other artifacts present externally High density couch bars on the treatment unit couch
or internally. Sometimes these will be present during imag- may need to be accounted for in plans with beams passing
ing but may be removed by the time treatment commences through the couch and, ideally, the positions of these bars
(for example, drainage tubes). Where the artifact is made of should be overlaid on the CT image so that the plan is
material similar to tissue density such as breast implants designed to avoid them.
(although some breast implants contain high-density mag- The planner should also be aware of any anatomical
nets), the CT-density table will correctly allocate the density abnormalities in the CT scan that may affect the treatment
required. However, for metal implants, the CT scan must be plan. It may be preferable to avoid regions where surgery
acquired with an extended CT scale and the TPS CT-density has taken place, or to avoid abnormalities unrelated to
table must be extended typically to give Hounsfield num- the disease being treated, such as a hernia.
bers of up to 32 000 if metal implants are to be identified It is important to appreciate the shortcomings of the TPS
and the correct density assigned. Even with artifact algorithms, especially in the presence of heterogeneities.
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6 95 1.3 1.9 1
Beam energy 10 95 2.2 3.2 1
The first parameter the planner selects is the beam energy,
by considering the depth of dmax and the penetration 15 95 2.6 4.9 3
properties of the beam (Table 10.2 shows typical values 20 95 2.6 6.7 10
for commonly used energies). Low energy beams, e.g.
46 MV are suited to more superficial volumes, e.g. head
and neck PTVs, while deep pelvic PTVs will require
1020 MV. Beam energies above 15 MV do not give a great enable a treatment plan isocentre to be located on a conve-
benefit to the planner, but their frequent use on a Linac can nient anatomical set-up point rather than being restricted
introduce radiation protection problems from neutrons. to the centre of the PTV. Secondly, they enable the beam
The build-up region is a significant feature of the MV divergence of adjacent fields to be matched to one another
beam in that it gives skin sparing, allowing doses that (see below).
would severely damage the skin to be delivered deep into Although un-wedged treatment fields can be considered
the patient, even from a single beam. However, a PTV that as delivering a uniform dose across their area, this is not
extends from near the surface to a depth requiring MV strictly true, especially at points several centimetres away
photons may require bolus to be added to the skin of the from the central axis. Due to the varying beam energy
patient. By placing this tissue equivalent material on the across the field, this non-uniform dose will also vary with
skin, the build-up region is shifted into the bolus and the depth. Therefore, manual calculations for asymmetric
maximum dose of the beam is delivered to on or near fields will require the addition of an asymmetric factor to
the skin. Unless the PTV is superficial, the planner should account for the beam profile.
consider the impact of patient immobilization devices on
the build-up region. Isocentric plans
For a single field treatment, the machine isocentre may be
Asymmetric fields set to the surface beam entry point (fixed source-to-surface
A standard field set on a treatment machine will be sym- distance (SSD) beam), or at depth. Although the beam
metric, i.e. the centre of the field defined by the collimators characteristics will be slightly different in these two set-
will be centred on the machine isocentre. Asymmetric fields ups, there is no significant dosimetric advantage either
(i.e. where one or both of the X and Y collimator settings way, and the treatment method is determined by consistent
are not equal) have two benefits to the planner. First, they local practice.
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For efficient treatment delivery of multiple beam plans, it moving in one of the collimators across the field during
is preferable to produce isocentric plans. In this arrange- the beam on time. The machine is programmed to deliver
ment, the machine isocentre is positioned inside the either a continuously variable wedge angle or a set of dis-
patient, and typically inside the PTV. Thus, once the patient crete wedge angle values typically 15 , 30 , 45 , 60 and
has been positioned for the first beam, it is only necessary described by the isodose wedge angle that is generated.
to rotate the gantry and/or couch and collimator angles, to For the planner, there are a number of consequences
deliver the subsequent beams. arising from these different technologies.
Dynamic wedges tend to produce more penetrating iso-
doses at the thin end of the wedge with higher doses in the
Extended focus skin distance (FSD) plans superficial region of the thin end than physical wedges.
Most treatment machines have a maximum field size of 40 Physical wedges (fixed or motorized) tend to have more
40 cm so to treat longer volumes with a single field an rounded, blunt, profiles.
extended FSD beam is required. Here, the isocentre is posi- The wedge direction may be limited, i.e. not both sets of
tioned outside the patient to take advantage of the beam jaws can generate dynamic wedges, or physical wedges can-
divergence. Although the daily set up of these plans will not be rotated into both collimator planes. When planning
be more complex, they have the distinct advantage of avoid- with multileaf collimators, this may limit the effectiveness
ing beam matching for PTV dimensions up to 5055 cm. of the multileaf collimator (MLC) shielding if the wedge
orientation restricts the planner to a suboptimal collimator
rotation (Figure evolve 10.5 ).
Wedges Physical wedges (fixed or motorized) significantly atten-
Megavoltage treatment machines have integral beam mod- uate the beam at the central axis and a 60 wedge may
ifying techniques which are referred to as wedges (see typically transmit 25% of the open field dose. Therefore,
Chapter 8). They alter the uniform dose distribution of the treatment time is increased 34 fold and this factor
the radiation beam in a simple and controlled manner to can often justify the use of segmented treatments which,
produce a dose gradient across the field. although more time consuming to plan, do offer improved
Wedges are essential for most multifield plans to produce PTV dose homogeneity at no additional cost during the
a uniform PTV dose and serve two purposes. treatment delivery.
First, they allow one field to compensate for the depth dose
fall off of another field in the plan (Figure evolve 10.4A ).
Secondly, they compensate for a density gradient in the Compensators
path of the beam (Figure evolve 10.4B, C ). The simplest Prior to the advent of asymmetric collimators and modern
application of this is missing tissue when a beam enters an treatment planning computers, physical compensators
oblique patient contour, but heterogeneities within the offered the only means of varying the dose intensity across
patient may also require correction especially the lungs and the beam area. Although their use is now restricted to a
large pelvic bones. limited range of applications, the concepts of physical
There are several techniques used in treatment machines compensator design are useful in producing treatment
for generating wedge-shaped isodoses (see Chapter 8) and plans.
the technology used can influence the plan. Fixed wedges Compensators can be designed to correct for missing
may be positioned in the beam for the entire delivery of tissue in the beam path so that a uniform dose is deliv-
the beam. This is less commonly used as it requires each ered at a specified depth plane or a varying depth PTV
field to be manually set up inside the treatment room (e.g. spinal cord). They may be placed on the patients sur-
but, in some machines, may be the only method of permit- face and designed simply to replace the missing tissue
ting a wedge to be orientated in all four directions in the with a tissue equivalent material. This is not good practice
field. These are described in terms of wedge angle of the iso- as there is a complete loss of the build-up effect and rarely
dose distribution that they produce (not the physical shape has clinical value in megavoltage treatments. A compensa-
of the wedge itself). tor located in the accessory tray of the treatment machine
A motorized wedge is a physical wedge-shaped filter will reduce the loss of build-up and will normally be
positioned inside the treatment head and is designed to constructed from high density material such as alumin-
be in the beam for part of the treatment time. This gives ium or lead sheets, or steel granulate in a moulded poly-
the planner a continuous range of wedge angles from zero styrene mold.
(wedge out of the field) to typically 55 (when the wedge is Compensators may be used to produce a uniform dose
in the beam for the entire delivery of that field). These will to the spinal cord from an open posterior field or as an
typically be described by the TPS as the open/wedge seg- approximate missing tissue compensation in TBI treat-
ments of the beam. ments, but their widespread use is limited by the labour
A dynamic wedge uses no physical wedge in the path of intensive construction and the need to set them up manu-
the beam, but generates the wedged isodose effect by ally for each field in multiple field plans.
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Walter and Millers Textbook of Radiotherapy
symmetry should be assessed for small MU increments number of beam measurements to be taken in order to
before such fields are used. build up a library of radiation beams of different open
In contrast, while dynamic collimation is potentially and wedged field sizes. The Milan-Bentley algorithm was
more efficient, this advantage may be outweighed by the one of the first models of this type and is still in use today
complexity of the delivery method and beam dosimetry, in some planning systems.
reproducibility of delivery, maximum leaf speed, the lack This algorithm is also frequently used as the method of
of conventional image verification and the need for addi- point dose checking on an independent system. Measure-
tional QA dose and fluence measurements. ments required are percentage depth doses (PDDs) along
the Central Axis (CAX) of the beam and off-axis ratios
(OARs) in the form profiles across the beam (as shown
Dynamic treatment techniques
in Figure 10.7A and B), output factors as a function of field
The IMRT delivery can be more efficient if the segmented size, wedge factors for each wedge, cGy/MU for reference
treatment is replaced by a continuous exposure with the situation with a 10 10 cm field and a knowledge of dmax
MLC leaves moving while the beam is on. In this sliding depth. The planning computer can then interpolate these
window method each leaf pair sweeps across the beam basic data and apply corrections to produce isodose curves
with the leading and trailing leaf travelling at varying in a tissue equivalent phantom. In order to calculate the
speeds so that the beam aperture varies with time and thus dose to a patient, a heterogeneity correction is often
the dose deposited is modulated. applied. This can be done by various different methods,
such as bulk density equivalent path length, pixel-by-pixel
Arc therapy equivalent path length, power law method (Batho) or the
ETAR method. Irregular fields are calculated using scatter
Most treatment units are capable of continuously irradiating integration techniques, such as the Clarkson method.
as the gantry is rotated and this was once a popular technique
for avoiding high doses to healthy tissues. However, with
the introduction of MLC-based conformal treatments, the Pencil beam models
benefits of static fixed fields became far more advantageous
Pencil beam models have been introduced to provide a
for all but small volume spherical radiosurgical treatments.
more accurate method of calculating irregular fields and
Improved control of linac motion and dose delivery has made
are therefore more suitable for use in dosimetry of confor-
a further refinement of IMRT possible, intensity modulated
mal radiotherapy and IMRT inverse planning algorithms.
arc therapy (IMAT). Here, the set of fixed beams is replaced
They are, however, still prone to some inaccuracy in very
by arcing beams, in which the MLC leaves move as the gantry
inhomogeneous situations. Figure 10.8 illustrates an exam-
is arced. This technique has the potential to deliver the best
ple of a pencil beam kernel generated by a Monte Carlo cal-
conformality to the PTV in short treatment times.
culation to represent the elemental dose distribution from
a single infinitesimal beam element at a specific energy.
PLANNING TOOLS, CALCULATION Multiple elements are then summed to represent the total
fluence across the radiation field as shown in Figure 10.9.
AND DISPLAY There are several limitations of this method in a clinical
situation, such as in the calculation of dose to lung, as the
Algorithms for dose calculation in side-scatter produced in a real situation is not correctly
modelled as illustrated in Figure 10.10.
treatment planning systems
There are several algorithms in use in different treatment
Three-dimensional techniques
planning systems in order to calculate dose to a patient. They
have varying degrees of accuracy and, in some treatment Three-dimensional techniques aim to model fully, radiation
planning systems, present a choice between a fast calculation transport in three dimensions to provide accurate calculations,
and a more accurate dose calculation. For example, a simple taking full account of perturbations to dose-distributions
fan-line model may be selected to determine field size, gan- from inhomogeneities of arbitrary shape, position and
try angle, wedge etc. and then a more accurate calculation density. These calculations can give accurate results for
can be used for the final patient treatment plan. beams of irregular cross-section, under and near the edges of
Algorithms can be represented as follows. beam modifiers and at density interfaces. Convolution
techniques are best at this, and the collapsed cone method
is the most frequently used of these techniques. These con-
Stored beam data models volve the 3D distribution of primary energy with a point-
Stored beam data models are based on the use of measured spread function which describes the transport of energy
data which, typically, are stored as fan-line matrices diver- away from a primary photon interaction site. These con-
gent from the source. Generally, this requires a large volution algorithms provide very high accuracy with the
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Chapter | 10 | Principles and practice of radiation treatment planning
Source
Central axis
A
dmax
Depth dose
(17 points)
Dose calculation
point
5 profiles
(47 points) Dose = PDD OAR
2D fluence
B
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Walter and Millers Textbook of Radiotherapy
Actual situation they give absolute dose, if the dose prescription has been
included in the treatment plan. It is a matter of local proto-
col as to which method is used, although prescriptions spe-
Lung cifying different doses to different volumes within the same
plan are best displayed in absolute dose.
In order to calculate dose to a surface or volume, a matrix
of reference points spread over the volume of interest is
required. The number of points and their spatial resolution
is always a trade-off between speed and accuracy.
The x and y coordinates of these points are in the trans-
verse plane and the z coordinate is in the superior-inferior
plane. The z coordinate is frequently interpolated as the
slice thickness of the planning CT scan can vary. The iso-
Calc point dose contours are produced by linear interpolation
between points, therefore, the separation of these points
needs to be small enough to allow sufficient dose detail
at organ and PTV boundaries.
Generally, isodose curves are normalized to give 100% to
a reference point (such as the ICRU 62 reference point).
This makes both the assessment of PTV coverage and the
Pencil beam model dose uniformity across the volume easier. The aim is usu-
ally to cover the PTV with the 95% isodose curve while
ensuring the maximum dose within the volume does not
Lung exceed 107% [1, 2].
The dose distribution can be displayed on multiple views
of reconstructed sections (e.g. transverse, sagittal and coro-
nal sections on a single screen), and also on a 3D recon-
struction of anatomy with isodose surfaces displayed.
Useful features are:
opaque and translucent colour wash displays give a good
overall impression of the dose distribution, but can
obscure target volumes, so should be interchangeable
with conventional isodose lines (Figure evolve 10.11 )
Calc point
zoom and pan facilities
isodose surfaces displayed as wire frames superimposed
Figure 10.10 Limitation of the pencil beam model to account on rendered surfaces, with real time manipulation
for changes to lateral scatter affecting a calculation point. a volume of regret is a dose reduction technique
applied to the dose distribution. A window of
acceptability of dose level is chosen and portions of
Treatment plan evaluation tools organs outside this window can be highlighted. For
critical organs, this is a one-sided test, where regions
The ideal radiotherapy treatment plan produces a uniform where the dose is above the acceptable level are
coverage of the target volume without giving significant displayed. For target volumes, regions of either too
dose to surrounding normal tissue. 3D planning is a realis- high or too low dose can be shown. This display feature
tic option for many cases, due to the increased availability is particularly useful when checking the coverage of
of radiotherapy CT scans, virtual simulation, MR, fast com- arcing beams, e.g. for stereotactic radiotherapy.
puter hardware and improved algorithms. Treatment plans
are therefore more difficult to compare and evaluate, hence
the need for plan evaluation tools.
Beams eye view
Several such tools are in use as discussed. A useful 3D tool for field placement is the beams eye view
(BEV) which shows the patients anatomy from the source
position of the therapy machine, looking out along the axis
Isodose distributions of the radiation beam. The BEV approach is useful for iden-
Isodose information is presented as lines or surfaces of tifying the optimal beam angles at which to irradiate the
equal dose. They show either relative or normalized dose, target and avoid irradiating adjacent normal structures,
if the dose is expressed as a percentage of a reference dose or by interactively moving the patient and the treatment
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Chapter | 10 | Principles and practice of radiation treatment planning
Volume (%)
with physical
colour and be able to highlight, include, exclude, shade 20 compensator
them interactively while adjusting beam parameters. or IMRT
A visual and quantitative representation of machine
and treatment couch parameters is also necessary, 10
together with customizable limits and restrictions of
beam, collimator and couch angles for specific 0
treatment machines. 85 90 95 100 105 110 115
The limitation of BEVs is that it is a one-field Dose (%)
presentation, so that field overlap is not immediately
Figure 10.12 Differential DVH comparing a standard and a
observed until the dose calculation is done.
compensated breast plan.
Another view available on some planning systems is
the physicians eye view (PEV) or observers eye view
(OEV) which enables the viewer to look at the patient measure of homogeneity over the treatment volume for
from all angles to obtain an overview, while multiple two differently compensated plans.
fields are being displayed. The standard plan gives a wider spread of dose over the
volume of interest compared with the compensated plan
An extension of the concept of a BEV is to use a DRR, a digi-
which shows a large volume receiving much less variation
tally reconstructed radiograph. The DRR is reconstructed by
in dose.
various methods from the CT scan data set which has been
More often used are cumulative dose volume frequency
used for patient voluming and planning. This has the
distributions, which are plots of the volume receiving a
advantage of being the same data set, so that any possible
dose greater than, or equal to, a given dose, against dose.
transfer errors which may occur between simulator and CT
The volume accumulates starting at the highest dose
scanner are eliminated. The accuracy of the reconstruction
bin continuing towards zero dose, eventually reaching
of the DRR depends on the slice thickness of CT data and
100% of the total volume. In most cases, the volume
the computing tools available to reconstruct the radio-
is specified as the percentage of the total volume of a
graphs. CT information can be enhanced to extract more
particular structure receiving dose within each interval,
bony structure from the CT data and suppress the soft tissue
however, it may be expressed as absolute volume in
to obtain an image with well-differentiated bony land-
some cases.
marks. Using such tools, one can also produce an image
DVHs can be used during the planning process to check
which is closer in appearance to either a megavoltage portal
whether the dose is adequate and uniform throughout the
image or a diagnostic image.
target volume. They show that hot and cold spots exist, but
do not indicate where they occur, nor whether there are sev-
Dose volume histograms
eral of them. However, as they do not display spatial infor-
Volume calculations on a 3D treatment planning system mation, they should not be the only method of plan
provide a large amount of data which can be difficult to evaluation used.
interpret and evaluate when displayed as isodose curves The main use of DVHs is as a plan evaluation tool. They
on several transverse, sagittal and coronal planes. It is much can be used as a graphical way of comparing different treat-
easier to condense the 3D dose distribution data to a graph ment plans on a single graph, for specifically identified
which displays the radiation distribution within a specifi- organs at risk and PTVs. DVH PTV comparisons should
cally defined volume of interest, so that summarizing show a uniformly high dose throughout the volume, the
and analyzing the data are possible. Such a graphical repre- shape approximates to a step function and a steep slope
sentation is called a dose volume histogram (DVH). shows that a large percentage of the volume has a similar
The DVH can be expressed as: dose (Figure 10.13A).
For OARs, the DVH should have a concave appearance
The summed volume of elements receiving dose in a (Figure 10.13B) but, for different critical organs, it may
specified dose interval, against a set of equally spaced be acceptable either to deliver a relatively high dose to a
dose intervals. This is a differential dose volume small volume or a small dose to a large volume.
histogram and shows the absolute or relative volume in An example of plan comparison for three different dose
each dose interval (bin) directly. distributions is shown in Figure 10.14A and B.
DVHs for OARs have a concave appearance. Figure
An example is shown in Figure 10.12 of the evaluation of 10.14B shows comparative DVHs for a rectal volume
a breast dose distribution using selected dose bins as the where 50% of the volume is receiving 60, 63 or 66.5 Gy
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Walter and Millers Textbook of Radiotherapy
100
100% Ideal
PTV GTV
80
Volume %
Plan 1
Volume
60
Plan 2
Plan 3
40
20
Actual
74Gy
PTV
0
100%
Dose 0 10 20 30 40 50 60 70 80
Prescription dose
A A Dose (Gy)
e.g. 65Gy
Percentage prescribed dose (%)
Ideal OAR 0.0 13.5 27.0 40.5 54.0 67.5 81.1 94.6
100%
100 55.5
74Gy
80 44.4
Volume (cm3)
Rectum
Volume %
Volume
60 33.3
Plan 1
40 Plan 2 22.2
Plan 3
20 11.1
Actual OAR
0
0 10 20 30 40 50 60 70 80
B Dose (Gy)
100%
Dose
Prescription dose Figure 10.14 (A) DVH comparison of three dose distributions
B e.g. 65Gy for the target. (B) DVH comparison of three dose distributions for
the rectum.
Figure 10.13 (A) Ideal and typical DVHs for a PTV. (B) Ideal and
typical DVH for an organ at risk.
Structures with irregular boundaries can give calculation
errors when calculating with a regular rectangular grid.
depending on the different treatment plan. It is also useful Also, structures that are long and thin require a finer reso-
to display both absolute dose and absolute volume, lution in one direction than the other. The ideal solution is
together with normalized values, on the same graph. to be able to adjust the voxel size dynamically to the dimen-
sions of the structure in x, y and z independently.
The dose for each voxel can be determined at the same
DVH calculation requirements and methods time for the outlined volume of interest, by linearly interpo-
The 3D image is made up of a sequence of CT scans. This lating the dose to the centre of the voxel from the dose
can be represented as a 3D grid with cubic volume ele- matrix. All contributing voxels are collected into the appro-
ments, equally spaced in the x and y directions, but not priate dose bins of the histogram, for each structure. The user
necessarily in the z direction. The volume of the voxel can specify the number and dose interval of the bins to cus-
can then be defined by the product of the x and y grid tomize the resolution of the DVH plots. These bin values can
spacing and the slice thickness. A reasonable resolution then be expressed in graphical form. It is important that the
for sampling the volume of typical anatomical structures dose and volume calculation windows are large enough to
is about 23 mm. include totally all the voxels in any specific structure.
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Chapter | 10 | Principles and practice of radiation treatment planning
Grid spacing for dose calculation is a compromise. The be used to compare different treatment modalities such
finer the grid, the greater the calculation accuracy in regions as protons and photons when performing treatment
of steep dose gradients, for example close to the beam planning studies, before doing clinical trials.
edges. The disadvantages of a fine grid are the increased
computation time and the creation of large data files. In Dose surface histograms and dose wall
general, two criteria are specified:
histograms
1. the desired dose accuracy
There are some clinical organs where it could be more
2. the maximum acceptable distance between the
relevant to consider the wall of the organ rather than the
estimated and actual isodose contours.
whole volume, such as the rectum. Dose to rectal wall is
For example, 2% dose accuracy or 2 mm isodose positional more likely to represent patterns of morbidity than dose
accuracy will be achieved with a grid spacing of 5 mm. to volume and rectal dose maps can be extracted from
The range of expected dose values is divided into equal dose surface histograms to give an estimate of areas of high
intervals when constructing a histogram. For each inter- dose which may relate to patterns of morbidity. An exam-
val, the volumes of the voxels receiving dose within that ple of such a map is shown in Figure 10.15.
interval are accumulated in the appropriated element of
an array, or bin. Cumulative DVHs are obtained by adding
volumes accumulated in each bin with the volumes in Dose statistics
all bins corresponding to higher dose intervals. For cumu- Dose statistics as outlined in Table 10.3 give a simplified
lative DVHs, the appropriate dose interval for the view of the dose in a specified structure for evaluation
bins depends on the doseresponse curve for the structure purposes.
of interest. A dose of 0.5 Gy has been shown to be
reasonable, whereas 2 Gy is too wide an interval. Differ-
ential DVHs treat the volume in each bin as a separate
Other tools
quantity, and a bin interval of between 2 and 5 Gy is A publication by Willoughby et al [3] describes a system of
reasonable. evaluating and scoring radiotherapy treatment plans using
an artificial neural network. Treatment plans were assigned
a figure of merit by a radiation oncologist using a five-point
Clinical use and limitations of DVHs rating scale. DVH data extracted from a large training set
were correlated to the physician-generated figure of merit
It is not strictly correct to compare plans with different dose
using an artificial neural network, and the net was tested
computational parameters because different dose calcula-
on another set of plans. The accuracy of the neural net in
tion algorithms may not handle heterogeneities, or penum-
scoring plans compared well with the reproducibility of
bra etc. in the same way. The dose matrix resolution can
the clinical scoring and the system is promising for the reli-
affect the results of the DVH, especially in regions of steep
able generation of a clinically relevant figure of merit.
dose gradient.
Also useful are:
Interpretation of the DVH plot is fairly subjective and
implications of small differences between DVHs are not side-by-side transverse/sagittal/coronal plans
well understood. This indicates the usefulness of an objec- video loop stepping through two plans displayed side by
tive numeric score, such as TCP or NTCP to provide a rank- side, particularly with colour wash displaying isodoses
ing when comparing plans. (Small changes in DVH often zoom facility over the relevant area to be compared can
result in significant differences in the computed TCP and be useful
NTCP values.) dose at a point interactively integrated and displayed
DVHs do not indicate the complexity of the field arrange- simultaneously on both plans
ments and will not show any use of illegal couch, collima- dose difference displays
tor angles etc. surface dose display, e.g. on the surface of the spinal cord.
In summary, the DVH is a very useful tool for 3D plan The other aspect of plan evaluation which has not been
comparisons and as an input parameter for TCP and NTCP addressed is the accuracy of the actual dose delivery, which
calculations. TCP and NTCP are quantitative methods of is dependent on complexity of plan, size of margins, repro-
predicting the likelihood of local control. DVHs and the ducibility of set-up etc. Some sort of uncertainty analysis
predicted behaviour of the cell population in question should be developed to include these other aspects of treat-
are used as input data. There is, however, large uncertainty ment plan evaluation.
in the clinical data, so absolute probabilities are not attain-
able, but relative probabilities can be used to assess differ-
Forward and inverse planning
ent treatment plans. DVHs should, however, be used in
conjunction with other plan evaluation tools, especially The individual treatment beams for IMRT can be deliv-
those which will give spatial information. They can also ered using MLCs in either dynamic or multiple-segment
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Length: Inf-Sup
Width: Rt-Lt
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Chapter | 10 | Principles and practice of radiation treatment planning
Forward planning can also be used to generate more Optimal fluences converted to deliverable leaf motion
complex plans, such as the generation of concave dose dis- sequences must take into account the MLC limitations of
tributions in the pelvis [4] or head and neck [5]. While the the machine. This should be considered when choosing
dose distribution of such plans may not be quite as confor- beam orientations, selecting gantry and collimator angles
mal as those produced by inverse planning, they may be an to ensure, for example, that the width of the target volumes
improvement on a standard treatment plan. in BEV is not larger than the maximum beam width that
These planning methods use optimization, so it is nece- can be delivered at one time.
ssary to define dose-volume constraints, as for inverse Each planning system has its own characteristics,
planning. However, unlike inverse planning, the resultant therefore, practice with the system when developing
plan is directly deliverable, to include user-defined restric- class solutions to achieve local planning techniques is
tions, such as number of segments and minimum segment important, as is the establishment and participation in
size, and also incorporates any MLC limitations. clinical trials.
The calculation process is in two stages. First, the TPS cal-
culates the optimum dose fluence for each beam. Then this
Inverse-planned IMRT ideal dose is converted to a deliverable set of segments that
Inverse planning means devising a set of dose constraints the treatment unit is physically capable of. There may be
which are entered into an optimization routine to generate significant differences between the ideal and achievable
a solution with usually five or more beams. Essential to this fluences, so the planning process will be more efficient
is a fully outlined set of 3-dimensional volumes of interest with access to the final distribution being available during
and defined values as to the acceptable dose levels to be the planning stage. The planner must still ensure that the
delivered to or avoided by those volumes. calculated plan is sensible and deliverable and skilled
Typical dose constraints for all IMRT plans on the PTV manual intervention to an inverse plan is usually required.
are 99% of the volume needs to receive at least 90% of For example, removing very small segments, or those with
the prescribed dose, and 95% of the volume should receive low MUs. The planner must also be aware of the limita-
at least 95% of the prescribed dose. Simultaneously, there is tions of the TPS algorithm as there may be significant
a constraint that only 5% of the volume receives no more errors in calculations of small or elongated fields, or fields
than 105% of the prescribed dose, and 2% of the volume with small MLC apertures compared with the secondary
receives no more than 107% of prescribed dose. In addi- collimator settings.
tion, there are dose constraints on the organs at risk similar
to the dose constraints that would be used for conformal
radiotherapy. There may also be the need for constraints
to avoid high dose regions throughout the irradiated vol- BEAM ARRANGEMENTS
ume by adding false structures with appropriate dose con-
straints to force the calculation. This section does not attempt to provide a comprehensive
There is a lot of published work on finding class solutions atlas of treatment plans or an in depth planning guidance
for IMRT plans, in order to define numbers, angles and ener- for each site, but uses a few clinical examples to demon-
gies of beams. A number of authors have found that, for strate planning techniques.
some sites, a small number of appropriately selected beam The first step in preparing a plan is to decide on
orientations can provide dose distributions as satisfactory the position of the isocentre. Although the centre of the
as those produced by a large number of unselected equis- PTV might appear to be the best location, in practice, it
paced orientations [6, 7]. The general increase in numbers may be preferable to set the isocentre to predefined skin
of incident gantry angles means that lower energies are suit- marks which have been set at the time of CT scanning.
able for deep-seated tumours [8], although some groups [9] The skin marks will have been chosen to lie on a stable
have preferred to continue using higher energies. skin location, perhaps at a standard anatomical point
During the inverse planning process, the optimization or height above the couch, and avoiding steep body con-
algorithm will only attempt to cover or spare those volumes tour gradients. This results in a simpler and safer set-up
that have been completely outlined. It may therefore be nec- and the fields will then be aligned to the PTV by asymmet-
essary to outline volumes where strict dose sparing is not ric collimator settings.
required, however, the planner would prefer to avoid hot Another strategy is to select the isocentre position based
spots and ideally reduce the dose within these volumes. A vol- on the internal anatomy of either the PTV or adjacent critical
ume that does not strictly relate to anatomy may be drawn in structures. This can minimize the dose to critical structures
order to apply a dose constraint with a relative low priority by eliminating beam divergence without complicating the
that will help to avoid dose overspill in this area. Expanded field arrangement. Examples are breast treatments without
volumes (i.e. extra margins) can be used to ensure coverage of the beams diverging into the lung or abutting nodal fields,
targets. Depending on the leaf widths and motions this may or brain treatments avoiding beam edges diverging into crit-
require differing margins in different directions. ical structures, such as the lens. Another aspect regarding
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Walter and Millers Textbook of Radiotherapy
choice of internal anatomy relates to the dose computation dimensions, but with the collimator rotated 90 . For multi-
algorithm and placement of the isocentre in solid material beam plans, it may be possible to achieve uniform dose
and not in an air cavity in order to improve the dose predic- with a single turned wedge on one field only.
tion accuracy at that point for checking.
The beam energy is chosen by considering the depth
Parallel-opposed fields
of dmax and the penetration properties of the beam
(Table 10.2 shows typical values for commonly used ener- The typical isodose distribution arising from a parallel-
gies). Low energy beams, e.g. 46 MV are suited to more opposed field is shown in Figure evolve 10.18 . If the sep-
superficial volumes, e.g. head and neck PTVs, while deep aration is not too great for the available beam energy, then
pelvic PTVs will require 1020 MV. Beam energies above a dose range of 7 to 5% is perhaps just achievable. The
15 MV do not give a great benefit to the planner, but their high dose regions may present a problem at wide separa-
frequent use on a linac can introduce radiation protection tions and also the hour-glass shaped contour at about
problems due to neutron production. the 9095% level may result in unacceptably low doses
The build-up region is a significant feature of the MV at the midplane of the volume. Wedges may be employed
beam in that it gives skin sparing allowing doses that where the contour slopes or internal heterogeneities are
would severely damage the skin to be delivered deep into present and the use of shielding can produce irregular dose
the patient. However, a PTV which extends from near the distributions conforming to complex PTV shapes. Clinical
surface to a depth requiring MV photons may require applications include large pelvis volumes and whole brain
bolus to be added to the skin. By placing this tissue equiv- treatments.
alent material on the skin, the build-up region is shifted
into the bolus and the maximum dose of the beam is
delivered to on or near the skin. Unless the PTV is super-
Beams weighted in 2:1 ratio
ficial, the planner should consider the impact of patient The standard parallel-opposed distribution can be modi-
immobilization devices acting as build up and increasing fied to deliver a higher dose to one side of the PTV without
the surface dose. resorting to a more complex plan. It must be clear what the
Standard field arrangements may be modified for spe- plan request means by 2:1 weighting. For simple manually
cific patient situations such as metal hip implants. Here, calculated plans, it would usually mean that the ratio of
it is preferable to avoid beams entering through the implant MU set is 2:1. However, with computerized plans, a dose
so a three-field arrangement must be modified such as reference point may be positioned somewhere other than
shown in Figure evolve 10.17 . at the midplane depth so it must be clear to which point
the 2:1 ratio applies. The presence of heterogeneities fur-
ther complicates the issue as the TPS may adjust the set
Single fields
MUs to deliver equal dose from each field to a point by
Most plans are based on the intersecting of multiple field compensating for the different densities each beam has tra-
paths to create a high dose region, but single fields may versed. This demonstrates the potential hazards arising
sometimes be the ideal choice especially for superficial from changing from basic manual calculations to CT-based
PTVs. The spine can be treated with a single posterior field, dosimetry where a seemingly simple request for 2:1 weight-
although this will usually be done as part of a multifield ings can take on several different interpretations (see Figure
arrangement to treat the whole central nervous system. evolve 10.18 ).
To cover a PTV length of greater than 40 cm, the field
may need to be treated at extended SSD, i.e. the isocentre
will be positioned off the skin surface (see Figure Breast treatments
evolve 10.20 ). To produce a uniform dose to the cord The breast can be treated with a parallel-opposed pair, but
lying at varying depths, a compensator may be employed, the technique is generally refined to minimize lung dose by
but the most efficient technique is to use top up fields all creating a non-diverging edge, either by fully asymmetric
centred on a single isocentre, delivering a few MU to other- fields with the central axis along the field edge, or by
wise underdosed sections of the PTV. slightly angling the fields so that the central axes are not
parallel to one another but the back edges are (Figure
evolve 10.19 ).
Turned wedges Wedges will usually be required to produce a uniform
Wedges are usually most beneficial with the wedge in the PTV dose by compensating for the missing tissue and
plane of the plan (usually the transverse patient plane). the presence of lung. Due to time constraints, the PTV is
However, if the patient contour varies out of this plane, a not outlined if treating the entire breast and the PTV is nor-
turned, or longitudinal wedge may be required to produce mally defined during simulation or virtual simulation and
an even dose in the superior-inferior direction. This may will not be specifically contoured and the gantry angles
be accomplished by overlying two fields with identical determined by the accepted amount of lung in the field.
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Chapter | 10 | Principles and practice of radiation treatment planning
175
Walter and Millers Textbook of Radiotherapy
Oesophagus
Field matching
Traditionally, the oesophagus has been treated with two
Matching two fields may be essential in order to treat large
phases with the intention of minimizing the cord and lung
volumes as described in the section above, with feathering
critical structure doses. Phase one is an anterior-posterior
used to spread the uncertainty of the set-up, especially
parallel-opposed pair which also irradiates the cord usually
when a single isocentre technique cannot be utilized.
to a dose slightly higher than the dose the PTV receives dur-
Figure 10.28A and B shows how asymmetric fields can
ing this phase. As cord tolerance is approached, a phase two
simplify field matching and are commonly used, especially
plan is introduced, usually an anterior and two posterior
in head and neck treatments to match two distinct but
oblique fields. The oblique fields avoid the cord completely
abutting PTV shapes into a single treatment.
but it continues to receive an exit dose from the anterior
However, matching may also be necessary when a previ-
field. Therefore, it is essential to plan the phase two before
ous treatment is adjacent to a PTV currently being treated.
much of the phase one treatment has been delivered as if
Matching diverging fields can be complex and a compro-
the phase two is not started in time, the total cord dose
mise is usually a pragmatic approach, especially in pallia-
may exceed the tolerance over both phases. This arrange-
tive, low-dose treatments. If the planner has confidence
ment is intended to minimize lung dose by using the A-P
in the location of the previous set-up then an attempt to
beam arrangement up to cord tolerance. More recently, car-
match the beam divergence may be practical. Alternatively
diac toxicity has become a concern, especially where che-
the match may be made at a critical structure such as the
motherapy is also administered, and the heart is outlined
spinal cord, and the overdose and underdose regions adja-
as a critical structure. The treatment is delivered using a sin-
cent to the cord is accepted (Figure 10.29).
gle four-field plan and the lateral fields are angled and con-
formally shaped to cover the PTV while shielding the heart
from as much high dose as possible. Thus, the cord maxi-
KILOVOLTAGE PHOTON THERAPY
mum dose, and the lung and heart volume doses are all
optimized in a single plan.
Kilovoltage beams have very limited penetration so are
generally used as a single field to treat very superficial
Non-coplanar planning lesions, although opposed fields may be suitable if the
The majority of plans have the central axes of all the fields separation is small. Depth doses are highly dependent
in one plane usually the axial patient plane, although on the filtration as well as the accelerated electron energy
a sagittal, coronal, or oblique plane may be preferable and, although the beam energy is commonly described by
in some circumstances, e.g. a wedged pair to treat the orbit the accelerating potential in kilovolts (kV), a more accu-
(Figure evolve 10.25 ). rate description of the beam penetration is the half value
176
Chapter | 10 | Principles and practice of radiation treatment planning
177
Walter and Millers Textbook of Radiotherapy
110 110
4 MeV 4 MeV
100 6 MeV 100 6 MeV
90 8 MeV 90 8 MeV
80 10 MeV 80 10 MeV
70 12 MeV 70 12 MeV
% Depth dose
% Depth dose
15 MeV 15 MeV
1 cm bolus
60 60
18 MeV 18 MeV
50 50
20 MeV 20 MeV
40 40
30 30
20 20
10 10
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11
Depth in water (cm) Depth in patient (cm)
Figure 10.30 Typical central axis percentage depth doses in water for 10 10 cm electron fields. On the left, no build-up and, on the
right, with build-up.
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Chapter | 10 | Principles and practice of radiation treatment planning
If the 90% isodose is selected to cover the PTV and the correction tables should be used, or an inverse square cal-
dose prescribed to this isodose, then this will result in a culation made, based on the virtual source distance. Where
111% maximum dose at dmax. However, this will always the patient contour varies within the field, it is a matter for
be within the PTV. The 90% or 95% isodose is selected clinical judgment as to where the prescribed dose is deliv-
as they provide a useful range to cover the PTV, while the ered and where an over- or underdose is acceptable.
100% peak would, at most beam energies, be of insufficient
range to deliver the prescribed dose to more than a few
Patient contour effects
millimeters in depth.
If an electron beam is incident on a steep gradient in the
patient contour, then the uniform scattering that produces
Penumbra
the standard isodose and depth dose characteristics no lon-
The penumbral region of any treatment beam determines ger exists, and the light field projected onto the skin gives a
the field margin that must be applied around the PTV. In misleading indication of good coverage. Electrons are cas-
electron fields, this is not so easy to define as in photon caded along the edge of the gradient to greater depths
fields, as the penumbra varies significantly with depth before depositing their dose. For shallow gradients, this
(Figure 10.31). The clinician must appreciate the dose pro- effect may only result in a small modification to the depth
file and whether adequate coverage at the field edges will be dose but, for steep gradients, the cascaded electrons deposit
achieved. If coverage of the 95% isodose at the dmax depth a significant dose, often beyond the targeted volume. All
is the only point of interest then the margin can be taken as these effects are highly energy dependent and therefore
A in Figure 10.31A. However, for small fields in particular, require a reliable planning algorithm or careful experiment
the rounded profile of the 95% contour becomes signifi- to confirm the actual dose distribution. Whenever practica-
cant and the field could be described as being entirely ble, this situation should be avoided. The beam angle of
formed of penumbra as shown in Figure 10.31B. incidence should be carefully set up by gantry, collimator,
and couch rotations to minimize non-orthogonal inci-
dence. If the electron beam is incident on a cavity such
Standoff and stand in
as the ear, then the ear should be filled with a wax plug
It may be impossible to position the applicator at the stan- or wet gauze. Bolus should always extend beyond the field
dard treatment position. For example, neck treatments may edge so as to avoid a sharp gradient and variations in bolus
be obstructed by the shoulders, or the patient surface may thickness should be gradual. It may be necessary to employ
present a variable SSD across the field area. The inverse bolus to block up some target volumes, e.g. around the ear
square law cannot usually be applied in the same way pinna or nose, to provide lateral scatter into the PTV and to
as for photon beams produced by the same treatment generate the uniform dose distribution predicted by the
machine as each electron energy has a virtual source dis- standard isodose distributions. Note that field defining col-
tance due to the multiple sources of electrons ranging from limation will not produce a significant scatter contribution
the scattering foils through to the photon collimators and due to self-absorption. However, shielding within the field
the electron applicator. Therefore, either standard standoff must be coated with wax or similar materials to prevent
backscattered electrons from enhancing the dose to adja-
cent tissue. Examples of internal shielding are nasal and
mouth shields to prevent the beam from penetrating
50% isodose
beyond the PTV.
(field size definition)
Heterogeneities
95%
A 90% Bone will attenuate an electron beam due to its higher
85% density and this can be advantageous where the PTV lies
dmax 80% above bone as this reduces the dose to underlying tissue.
70% Lung and other air cavities can be a significant hazard in
60%
electron beams as their transmission is minimal com-
50%
pared to water and the electron beam entering lung will
not be significantly attenuated until it reaches the lung tis-
sue interface. Therefore, great care should be taken when
using higher energy beams (greater than 12 MeV) to
ensure that the dose limits of critical structures underlying
the air cavity are not exceeded. The commonest example
Figure 10.31 Electron isodose distributions for fields (A) 8 of this is in electron breast boosts where the heart may
8 cm and (B) 3 3 cm. receive a significant dose.
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Walter and Millers Textbook of Radiotherapy
The use of CT planning can demonstrate the effects of Arcing electron treatment
heterogeneities, but unless the calculation algorithm has
Initially, many treatment sites appear good candidates for
been verified under all conditions, the isodose distribu-
arcing electron therapy where multiple fixed fields are
tions should be considered for indication only. CT
replaced by a single beam arcing over the patient and thus
planning can be useful for identifying the depth of critical
eliminating problems of matching junctions. However, in
structures, e.g. the spinal cord in neck node treatments even
practice, arcing therapy is of no practical value in all but
if the TPS dose calculation is not used.
a small number of cases. Figure 10.32 shows the cross-
sectional view of an arc with a narrow slit beam (typically
25 cm wide), centred on a deep isocentre, sweeping over
Field matching
the patient. The arc commences and terminates with the slit
A perfect match between electronelectron or electron irradiating shielding so that each part of the patient receives
photon fields is not possible and a compromise is always the same exposure to the slit beam.
needed either to underdose at the junction and risk Figure 10.32 shows why this treatment is rarely applica-
recurrence or overdose and accept potential tissue damage. ble to widespread surface lesions. The dose to each point
The underdose or overdose regions are not in the same depends on the dose rate of the treatment machine, the
location and are dependent on the electron beam energy. slit width, and the time that each point of the patient is
Typically, a gap at the skin surface between the 50% in the beam. This in turn depends on the arcing speed
isodose edges of an electron and photon beam of 2 mm but, more crucially, it also depends on the distance from
will give an acceptable compromise. No gap will produce the isocentre. If Points A and B in the diagram are at the
doses of typically 120% or more, while a 5 mm gap will same depth and the SSD at Point B is 3 cm greater than
result in a significant low dose region of 70%. Angling at Point A then the dose at Point B will be approximately
the photon beam a few degrees away from the electron 6% less than that at Point A due to the inverse square law.
beam will give a very small reduction in the overdose However, Point B is closer to the isocentre so the sweeping
region. The use of spoilers, e.g. Perspex build-up in the beam will spend much longer irradiating this point than
electron beam can broaden its penumbra and make Point A resulting in a much higher dose at this point.
the set-up less critical [10]. Therefore, contours with any significant variation in cur-
Matching two electron beams is similarly very difficult vature will introduce large dose ranges across the arc.
and will often be complicated by the fact that the beams There are few sites where this can be achieved for
are not parallel to one another as the reason for matching more than 30 of arc and the back is probably the best
is to cover a large or highly curved contour (e.g. the skull). location for this treatment. The head is unlikely to be a
The match border on a curved surface may be created by a site where arcing therapy offers any advantage over fixed
lead strip which shields the surface from one field and is fields even when matching of abutting fixed fields is the
then positioned on the other side of the junction to shield alternative.
the surface from the abutting field. Even with careful In principle, varying the slit width during the arc could
immobilization, such junctions are prone to significant adjust the output, but this requires specialized technology
over- or underdosing, especially with oblique fields and to perform and is not available as a standard treatment
where the lead cannot be perfectly positioned in direct skin option. A specialized treatment planning computer is also
contact. Therefore, junctions should generally be feath-
ered by moving the junction two or three times during
the treatment course to reduce severe over- and underdos-
ing.However, many electron treatments are boost fields so
a high-dose region of 120% of the boost dose may only be
present for say 25% of the overall treatment and thus repre-
sents a total dose of 105%. Skin
Verification measurements should be performed with collimation Ideal
thermoluminescent dosimetry or film to estimate the dose A contour
distribution in unusual electron treatment set-ups.
B
Skin
Special electron techniques collimation
The majority of electron treatments are undertaken with
direct single fields using the standard beams on the linear
accelerator. However, there are two established special
Isocentre
techniques which, although not used widely, are worthy
of description. Figure 10.32 Electron arc treatment.
180
Chapter | 10 | Principles and practice of radiation treatment planning
required to design this complex treatment as the contour patient and potentially leading to small adjustments in
will vary along the slit as well as around the arc. As arcing treatment position in subsequent fractions.
beams have entirely different characteristics to fixed fields
of the same energy, and the inevitable variation of contour
through the arc, many hours of pretreatment phantom DIFFERENCES BETWEEN
measurements and in vivo verification during the treat- KILOVOLTAGE AND ELECTRON
ment are required to design the treatment.
THERAPY
Total skin electron irradiation (TSEI) or
While both modalities are suited for superficial treatments,
(TSET, total skin electron therapy) the mechanism of dose deposition is different, resulting in
The treatment of mycosis fungoides and similar malignan- clinically significant differences in the features of the dose
cies requires irradiation of the entire skin surface and, distribution.
given the rarity of the disease, this complex treatment Depth dose characteristics will usually favour electron
delivery is performed at only a few specialized centres. beams due to the sharp fall off in dose beyond the PTV,
An even dose distribution is required to a depth of only although if the prescribed dose is to be delivered to the patient,
typically 6 mm for the 90% isodose level, but often surface bolus material may be required for lower energy (typi-
encompassing the entire skin surface of the body. It is cally <10 MeV) electron beams. This is due to the build-up
extremely difficult to come close to achieving 95 to effect present in electron beams, but which is negligible in
107% uniformity however complex the treatment tech- kV x-ray beams where the maximum dose is at the surface.
nique may be. The predominant interaction of a low energy kV photon
A wide variety of techniques has been developed to beam is photoelectric absorption with a probability of
attempt to achieve this dose coverage. A small single field interaction in tissue approximately depending on Z4
at an SSD of 12 m which scans, or arcs, over the patient (Z being the atomic number). Therefore, there is an
is one option, but the commonest technique is to use an enhanced dose absorption in bone, which can be signifi-
extended SSD of between 3 and 7 m so that the patient is cant if high doses are prescribed to superficial regions with
covered in one or two beams. The dose rate of a standard underlying bone, such as the scalp. At 100 kV (3 mm Al
linac is increased to reduce treatment times and the dose HVL), the dose absorption in bone will be 4.5 times greater
delivered in daily fractions over several weeks, for example than in water. By 300 kV (3 mm Cu HVL), this is reduced to
36 Gy in 1 Gy daily fractions, as not all treatment positions 1.05 times the water dose as Compton interactions pre-
are delivered in each fraction. The x-ray component of the dominate and the atomic number of the absorbing mate-
electron beam is in the range of 14% of the maximum rial is no longer significant.
electron dose for these techniques, so the whole body dose The relatively high energy of electrons in an electron
is not normally of concern. beam compared with those generated in a kV beam results
Beam energies of between 4 and 10 MeV are usually in a large range and they can therefore penetrate into tissue
employed, although the energy at the patient is reduced well beyond the field edge. The consequence of this is a
by scattering in air, and energy degraders and scattering much broader penumbral region than is present in a kV
screens placed in the beam to improve dose uniformity x-ray beam, and this penumbra varies with depth. There-
and appropriate beam penetration. The standard depth fore, the use of electron beams to treat PTVs very close to
doses will not be applicable under these conditions and critical structures, such as the lens, should be avoided if
extensive commissioning work is required to determine possible. The sharp penumbra of a kV beam makes it the
depth dose and dose rates under these unique treatment ideal modality where critical structures are adjacent.
conditions. The patient is usually standing and will adopt The SSD of a kV machine will typically be far shorter than
a different pose at each fraction to be treated effectively at a linear accelerator usually ranging from 25 to 50 cm.
different beam angles to deliver an even dose and to mini- Therefore, the inverse square law dependence of dose will
mize self-shielding. Additional static fields may be required be far more significant in kilovoltage than electron treat-
to boost regions that have not received sufficient dose due ments, e.g. a 2 cm air gap results in a dose reduction of
to self-shielding or extreme obliquity of the incident beam, approximately 12% at 30 cm SSD compared with a reduc-
e.g. the soles of the feet and top of the head. tion of approximately 4% for an electron beam at a stan-
Evaluation of the dose delivered is difficult as the dose dard linear accelerator SSD.
from different beams with a wide range of angle of inci- There is usually less demand on a kV treatment machine
dence must be measured at very shallow depths. Thermo- than on a linear accelerator, so where the physical differ-
luminescent dosimetry is ideal in this area. There is ences in the beam are of no clinical significance, then the
limited scope for precise treatment planning for individual use of kV may reduce departmental waiting times and facil-
patients prior to treatment delivery and in vivo dosimetry is itate a treatment starting sooner than on a linear accelera-
important in verifying the delivered dose to the individual tor. For a few patients, the increased treatment time arising
181
Walter and Millers Textbook of Radiotherapy
from the lower dose rates of a kilovoltage unit compared to These surface dose measurements must be carefully related
those from a linear accelerator may be a disadvantage. to the dose at depth usually the midplane dose at the
abdomen, or dose to lung, and may be significantly influ-
enced by electron contamination and the unpredictable
SPECIAL TECHNIQUES scattered radiation doses in this set-up.
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Chapter | 10 | Principles and practice of radiation treatment planning
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Walter and Millers Textbook of Radiotherapy
isocentre position set up instructions are correct and Plan checking at treatment
unambiguous
imaging data such as orthogonal DRRs, are correct. Although record and verify systems make set-up errors less
likely than when daily manual input of field parameters are
used, the plan data should include enough information,
Independent dose check such as a scaled patient outline or SSDs for each beam,
The TPS dose calculation must be independently checked, to confirm that the plan is being delivered correctly. Portal
either manually, or most likely, using a separate dose calcu- imaging is highly effective in checking beam positions but
lating computer, which should use a different beam data set it is critical that the image data sent to the treatment unit are
and perform a different calculation to that of the main correct and clearly represent the isocentre positioning.
planning system. Usually, the dose check will use a simpler In vivo beam entrance and/or exit dose measurements
calculation method, so differences between the plan and may be performed and these require appropriate data from
the check calculation will be expected in certain patient the planning computer for example applying the correct
situations, such as the presence of heterogeneities, small, build up depth for the measurement device.
and/or highly wedged or asymmetric fields, but these dif- Even with a perfect set-up, the patient anatomy (both
ferences should be predictable. Once the limitations of external or internal) may change from when the planning
the checking algorithm are established, a dose check toler- data were acquired, and the plan may need to be adapted,
ance can be set with 2% tolerance and an action level of either with a simple adjustment of monitor units or, in
3% being typical values. some cases, a complete replan is required.
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extracranial tumors using an Adaptation and verification of the Onkol 2001;177:437.
accelerator; clinical experience of the relocatable Gill-Thomas-Cosman Tepper JE, editor. Stereotactic radiosurgery.
first thirty-one patients. Acta Oncol frame in stereotactic radiotherapy. Int Semin Radiat Oncol 1995;5.
1995;34:86170. J Radiat Oncol Biol Phys Tepper JE, Webb S, Evans P, editors.
Cosgrove VP, Jahn U, Pfaender M, 1994;30:68591. Innovative technologies in radiation
Bauer S, Budach V, Wurm RE. Laing RW, et al. Stereotactic radiotherapy therapy. Semin Radiat Oncol 2006;16.
Commissioning of a micro of irregular targets: a comparison Thomson ES, Gill SS, Doughty D.
multi-leaf collimator and between static conformal beams and Stereotactic multiple arc radiotherapy.
planning system for stereotactic non-coplanar arcs. Radiother Oncol Br J Radiol 1990;63:74551.
radiosurgery. Radiother Oncol 1993;28:2416.
Tsai J, Buck BA, Svensson GK, et al.
1999;50:32536. Leksell LT. The stereotactic method and Quality assurance in stereotactic
Gill SS, Thomas GT, Warrington AP, radiosurgery of the brain. Acta Chir radiosurgery using a standard linear
Brada M. Relocatable frame for Scand 1951;102:316. accelerator. Int J Radiat Oncol Biol
stereotactic external beam Lutz W, Winston KR, Maleki N. A system Phys 1991;21:737.
radiotherapy. Int J Radiat Oncol Biol for stereotactic radiosurgery with a Verhaegen F, Seuntjens J. Monte Carlo
Phys 1991;20:599603. linear accelerator. Int J Radiat Oncol modelling of external radiotherapy
Graham JD, et al. A comparison of Biol 1988;14:37381. photon beams. Phys Med Biol
techniques for stereotactic McKerracher C, Thwaites DI. Assessment 2003;48:R10764.
radiotherapy by linear accelerator of new small-field detectors against Walton L, et al. The Sheffield stereotactic
based on 3-dimensional dose standard field detectors for practical radiosurgery unit: physical
distributions. Radiother Oncol stereotactic beam data acquisition. characteristics and principles of
1991;22:2935. Phys Med Biol 1999;44:214360. operation. Br J Radiol
Gross MW, Engenhart-Cabillic R. Normal Serago CF, Houdek PV, Hartmann GH, 1987;60:897906.
tissue reactions after linac-based Saini DS, Serago ME, Kaydee A. Tissue Warrington AP, Laing RW,
radiosurgery and stereotactic maximum ratios (and other Brada M. Quality assurance in
radiotherapy. Front Radiat Ther Oncol parameters) of small circular 4, 6, 10, fractionated stereotactic radiotherapy.
2002;37:14050. 15 and 24 MV x-ray beams for Radiother Oncol 1994;30:23946.
Figure evolve 10.1 An example of an Figure evolve 10.4 (A) A single field would increase the wedge angle
artefact arising from the patient produces a dose gradient in excess of required
breathing normally during a thoracic 30% across the PTV. (B) A three-field Figure evolve 10.5 The wedge
CT scan beam arrangement will result in a orientation normally takes priority in
Figure evolve 10.2 Substantial distortion uniform dose across the PTV. The producing the optimum dose
will be produced in CT scans with metal lateral fields are highly wedged to distribution. For some treatment
implants and especially in bilateral metal compensate for the dose gradient machines this results in suboptimal
hips (A). Here it is usually necessary to shown in (A) and also the missing MLC shielding as shown in (A) as
override the CT numbers with a density of tissue shown in (C). compared with (B) where the MLC
1 g/cm3 (gray shaded area) (B) (C) Missing tissue M allows more orientation is optimum for this
Figure evolve 10.3 Transverse CT slices. transmission through air than tissue so concave PTV shape
Left image without contrast and right more dose is deposited at A than at B. Figure evolve 10.6 The left image shows
image showing the uptake of contrast The presence of internal MLC blocking with a non-uniform
agent into neck nodes heterogeneities such as bone C margin at the X1 and X2
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Chapter | 10 | Principles and practice of radiation treatment planning
collimators. Also, the Y1 collimator has Figure evolve 10.18 Isodose Figure evolve 10.21 Left image shows
not been brought in optimally to cover distributions produced by parallel- transverse view of wedged pair with low
the MLCs to minimize interleaf leakage. opposed beams. Left image beams are weighted segment field used to boost
In the right image, the isocentre has equally weighted, central image the dose to part of the PTV(shown in
been shifted in the X leaf direction by weighting is 2:1 at mid-plane and right blue). On the right, the BEV of boost field
half the width of the MLC leaves, thus image weighting is 2:1 at point A showing partial shielding of the cord
optimizing the margin around the PTV Figure evolve 10.19 (A) Varying the Figure evolve 10.22 Three-field rectum
Figure evolve 10.11 Tumour and nodal wedge angle and relative beam treatment
volume in the left image with the right weightings may not produce a Figure evolve 10.23 (AD) Bronchus
image showing an IMRT plan satisfactory dose distribution especially treatment. (E) Segments used in the left
delivering different doses to the when considering all the slices in a CT anterior oblique field in (C) instead of
tumour and nodal volumes contour set. (B) By adding a segmented a wedge
Figure evolve 10.16 The use of field, the high-dose regions (shown in Figure evolve 10.24 CNS junction
additional segmented fields within the green) can be shielded and the lower Figure evolve 10.25 Planning in the
two wedged fields which alone dose regions thus boosted. A sagittal plane to avoid adjacent critical
produced the dose distribution on longitudinal wedge may also assist in structures, in this case the
the left (A) improves the dose this process. (C) The result of using a contralateral eye
uniformity to that shown in the segment field on the plan in (A) Figure evolve 10.26 Breast junction
right image (B) Figure evolve 10.20 Sarcoma with Figure evolve 10.27 Non-coplanar skull
Figure evolve 10.17 Modified three-field parallel-opposed fields, isocentres Figure evolve 10.33 Fiducial marker
beam arrangement to avoid prosthesis outside target system with isocentres shown
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Intentionally left as blank
Chapter | 11 |
Brachytherapy
Paul Symonds, Charles Deehan
In brachytherapy, most radionuclides are photons emitters, inadvertently to low doses of radiation from the patient.
however, beta or even neutron-emitting sources are used Staff exposure can be minimized by afterloading techni-
for some applications. The present chapter describes the ques or the use of low energy radionuclides (see below).
physical aspects of sealed sources and how they are used Large tumours are usually unsuitable for brachytherapy.
in brachytherapy. However, brachytherapy may be employed as a boost treat-
ment following reduction in size by external beam radio-
therapy and/or chemotherapy.
INDICATIONS FOR BRACHYTHERAPY The radiation dose falls off rapidly from the sources,
therefore, in order to treat the required tissue volume
The extent of the neoplasm must be known precisely as adequately, accurate geometric positioning is critically
treatment is often given to a relatively small volume and important. The spatial arrangement of sources used varies
geographic miss is otherwise likely. depending on the type of source applicator, the anatomical
The site should be accessible for both inserting and, position of the tumour and the surrounding dose limiting
where appropriate, removing sources and allowing satisfac- normal tissue. Accurate positioning of sources or applica-
tory geometric positioning of those sources. tors requires special skill and training and this is not uni-
versally available.
Surrounding structures, such as lymph nodes that may
ADVANTAGES OF BRACHYTHERAPY contain overt or microscopic cancer, will not be irradiated
by the implant or intracavitary treatment.
The probability of local tumour control increases with
increasing radiation dose, however, so does the probability
of normal tissue damage. Brachytherapy allows the delivery RADIONUCLIDES IN BRACHYTHERAPY
of a highly localized radiation dose to a small tumour vol-
ume, increasing the chance of local control. There is a sharp
fall off of radiation dose in the surrounding normal tissue, Gamma emitters
therefore, the risks of complication are reduced. Radium, which has a half-life of 1600 years, and its alpha
The overall duration of brachytherapy is relatively short,
emitting gaseous daughter product radon, were used for
and can vary from a minute or two to several days depend- many years as the major source of gamma rays for brachy-
ing on dose rate, prescribed dose and treatment distance
therapy. The major source of gamma rays is the gaseous
from the radiation source. Constant low dose rate irradia- daughter product radon. When they were used, radium
tion (below 1.0 Gy/hr) takes advantage of the different
tubes and needles had to be gas tight and frequently
rates of repair and repopulation of normal and malignant checked for leaks (for radium the mean photon energy is
tissue to produce differential cell killing. Hypoxic cells are 0.78 MeV). The gamma rays used are highly penetrating
relatively resistant to radiation treatment. Reoxygenation and very thick lead shields are required to provide adequate
may occur during low dose rate radiotherapy with initially radiation protection. Other radionuclides with more suit-
resistant hypoxic cells becoming well aerated and sensitive. able properties are now available and as a result this mate-
Often in brachytherapy treatments, the dose distribution rial is no longer in use.
within tumour volume is not homogeneous. Treatment is The ideal radionuclide should have the following
often prescribed to the minimum dose received around properties:
the periphery of the treated volume. Areas close to the radi-
ation sources in the centre of the tumour volume often
Radioactivity
receive up to twice this dose. Hypoxic cells are situated in
avascular, sometimes necrotic, areas in the centre of At low gamma ray energies photoelectric effect can cause
tumours and the higher doses received here help to com- the absorbed dose in bone to be higher than that of soft tis-
pensate for the relative radioresistance of these hypoxic sue. Emission energy should therefore be high enough to
cells. Irregular shaped tumours can be treated by judicious minimize this but be low enough to reduce the level of scat-
positioning of radiation sources and critical surrounding tered radiation and satisfy radiation safety requirements
normal tissues can be avoided. At higher dose rate (above and sheilding cost constraints. A useful working range
12.0 Gy/hr) the radiobiological issues considerations are lies between 0.2 and 0.4 MeV. Where present unwanted
similar to those of external beam treatments. charged particle emissions should be easily screened, radio-
nuclides should also have no gaseous disintegration pro-
ducts and have a high specific activity.
DISADVANTAGES OF
BRACHYTHERAPY Half-life
For temporary implants the half-life should be long enough
Many of the sources used in brachytherapy emit gamma so that radioactive decay does not need to be taken into
rays and nursing and medical staff may be exposed account when calculating treatment times. Although most
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Chapter | 11 | Brachytherapy
centres do not now keep a permanent stock of radionu- volume dm. The factor g (<1) is the fraction of the energy
clides, where these are kept a very long half-life is desirable lost in the bremsstrahlung process and the production of
to avoid frequent replacement of stock. delta rays.
191
Walter and Millers Textbook of Radiotherapy
Active wire
Skin or mucosa
Insert hollow
needle and secure
with suture
Tumour
Figure 11.1 Iridium-192 wire implants. (A) Wire is supplied in 500 mm length, coiled. (B) Wire is inserted using needle guides.
(i)- Hollow needle is inserted and sutured in place. (ii)- Active sheathed wire is inserted down the needle. (iii)- Non-active part of
sheath is cut and crimped. (iv)- Wire is secured by a screw-on end cap.
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Chapter | 11 | Brachytherapy
Hairpin
Figure 11.1, Contd (C) Thicker wires in the form of Single and Double Hairpins may be used. (D) Gutter guides are inserted into the
treatment volume and hairpins are pushed into the guides, sutured in place and the guides removed.
into tumours through suitable introducers. In the USA, As iridium produces gamma rays of mean energy
iridium is available in the form of seeds sealed in thin 0.370 MeV, lead shields of only 2 cm in thickness provide
nylon coated ribbon. Although iridium in the form men- very good protection. The only major disadvantage of irid-
tioned here is generally used for low dose rate treatments, ium is the relatively short half-life, therefore, fresh material
it can also be used as a high activity source for HDR sys- should be used for each implant, at low dose rate and HDR
tems (see Figure 11.2A and B). sources are normally renewed every 3 months.
Source - Iridium-192
Indexer
0.9 mm
Figure 11.2 (A) Two Nucletron HDR afterloaders and an enlarged view of the indexer into which the source transit tubes connect.
(B) 192Iridium HDR source and dose distributions.
(By kind permission of Nucletron UK Ltd).
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Walter and Millers Textbook of Radiotherapy
Iodine-125
Iodine125 with a half-life of 60 days is used for permanent
implants of the prostate. It has been used clinically since 0.9mm shielding
the early 1960s and is the daughter product of xenon- 0.1mm surface
125 which is produced by an (n-gamma) reaction. filtration
The low photon energy of iodine-125 means that
the half-value layer (HVL) thickness of lead required
for protection is only 0.02 mm and, in tissue, this HVL is 18mm
in the region of 1.7 cm. As well as having a relatively short
half-life, the gamma rays produced by this radionuclide 23mm
(2735 KeV) are of very low energy and very little radiation
is emitted from the patient following the implant.
Cobalt-60 Radius of
curvature 15mm
Treatments of retinoblastoma have been effected using
cobalt-60 ophthalmic applicators of similar construction Figure 11.3 The strontium eye plaque is fabricated so that low
to the ruthenium applicator (see beta emitters below). energy beta radiation is filtered out allowing therapy to be given
Their longer half-life was an advantage, but the high-energy with higher energy beta radiation.
gamma radiation gave higher doses to other vital structures,
e.g. the lens, macula and optic nerve, than with the ruthe- of silver and a thicker protective layer of 0.9 mm of silver
nium beta particle radiations. The cobalt-60 applicators on the back. The spherical radius of the window is
had a useful dose rate of typically 0.06 Gy min1 at the sur- 12 mm. The applicator is designed for suturing to the sclera
face, reducing to 50% at 2 mm. for 710 days. The useful dose rate is typically 0.1 Gy min1
at the surface reducing to 50% at 2.7 mm. A 15 mm
Beta emitters acrylic visor is recommended to protect the eyes of the
operator when using the ruthenium applicators.
The major use of plaques emitting beta ray radiation is in
the treatment of eye tumours. Plaques can be made of
strontium-90 or ruthenium-106/rhodium-106. Neutron emitters
Californium-252 has been used in the past to treat
Strontium-90 gynaecological tumours in particular. It is made by bom-
The strontium-90 (T 28.7 years) compound is incor- barding plutonium-239 with neutrons in a high flux reac-
porated in a rolled silver foil bonded into the silver tor. Californium decays by alpha emission with a half-life
applicator and formed so that it presents an active concave of 2.64 years a process which effectively determines the
surface of 15 mm radius to the cornea, with a surface filtra- overall practical half life of this source. However the most
tion of 0.1 mm silver. Strontium-90 is only useful when desirable property of this radionuclide is that it emits neu-
in radioactive equilibrium with its daughter product, trons as a result of a process known as spontaneous fission
yttrium-90 (T 2.7 days). The silver filter is designed to with a half life of 85 years. Neutrons produced have an
absorb low-energy beta particles from the strontium decay average energy in the range 2.12.3 MeV, also produced
(0.546 MeV max, range in water 1.2 mm) while transmitting x-rays with an energy in the range 0.5 to 1 MeV. In theory,
the higher-energy beta particles from the yttrium-90 these sources should be more effective against hypoxic
(2.27 MeV max., range in water 11 mm). The back of tumours. However, these theoretical advantages have never
the applicator is finished with a much thicker (0.9 mm) layer been convincingly demonstrated clinically and the radia-
of silver to reduce the transmitted dose rate to a relatively tion hazards involved have markedly restricted the use of
safe level. A variety of plaques is available, each designed these substances. The specific activity of 252Ca is high
to give a useful dose rate of approximately 1 Gy min1 at and therefore can be made up into small sources which
the surface reducing to 50% at 2 mm (Figure 11.3). are suitable for brachytherapy applications.
Ruthenium-106
Ruthenium-106 (T 369 days) is a fission product of RADIOBIOLOGY OF BRACHYTHERAPY
uranium and decays with a low-energy beta emission to
rhodium-106 (T 30s) which has a higher-energy beta As with any radiation treatment, brachytherapy exploits dif-
emission, namely 3.54 MeV max. The ruthenium applica- ferences between intrinsic radiosensitivity, repair and
tor is made of silver with a window thickness of 0.1 mm repopulation of normal and malignant cells. The major
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Chapter | 11 | Brachytherapy
195
Walter and Millers Textbook of Radiotherapy
Ar Al
GYNAECOLOGICAL CANCER
2cm
Manual loading and afterloading
From when brachytherapy was first introduced up until the
mid-1970s, brachytherapy sources were loaded into rubber
applicators and positioned by hand. Sources remained
Active source in place during the treatment and then were manually
retrieved. This, of course, had the consequence that staff
involved in the process from beginning to end were
Non active exposed to ionizing radiation.
spacer In the late 1970s, sources with a high specific activity
were readily available, for example cesium-137. In addition,
developments in computer controlled delivery (micropro-
Ovoids
cessors) and new flexible carriers made it possible to produce
Figure 11.5 MDR source positions and the Manchester devices that could automatically deliver and retrieve treat-
A points. ment sources.
Manually inserted low dose rate (LDR) cesium with
An alternative method of prescribing is to treat to toler- or without supplementary x-ray treatment can produced
ance the surrounding normal tissues. The maximum rectal excellent tumour control rates unsurpassed by more mod-
dose can be either measured directly or more commonly ern methods of brachytherapy. The serious complication
calculated using orthogonal radiographs. This dose is often rate was also low, at 5% or less. Such results remain the
expressed as percentage of the A point dose and, in most gold standard against which modern techniques must be
centres, is between 60 and 70% of the A point dose given judged. The most widely used technique was the Manche-
by brachytherapy. ster system in which preloaded sources were placed in the
A growing number of centres are prescribing by making uterus and against the cervix (see Figure 11.5).
use of CT and MR imaging. This image guided brachyther- The dose rate at point A was approximately 0.5 Gy/h,
apy makes use of many of the planning tools and features which proved to be biologically very advantageous.
developed for external beam treatment planning. Data sets A typical regimen used to treat an early stage 1b carcinoma
acquired using different imaging modalities can be co- of cervix was two insertions of approximately 72 hours
registered to allow accurate delineation of tumour and given 1 week apart to give a total dose of 75 Gy to point A.
organs at risk and different treatment options can be com- The International Commission of Radiation Units
pared using dose volume histograms. and Measurement (ICRU) Report 38 [4] has proposed
that volume (defined as height, thickness and width)
enclosed by the 60 Gy isodose line from combined
Types of implants
brachytherapy and external beam treatment should be
Implants can be classified as manually (see below) inserted, used for reporting (but not prescribing) absorbed dose
afterloaded or remote afterloaded. Manual insertion of following gynaecological treatments. This concept has
radiation sources should be avoided if possible owing to been accepted in parts of Europe but not in the USA or
the radiation hazards to operating staff and nurses. After- the UK [5].
loading is when radioactive material is loaded into hollow Although most centres have discarded manually inserted
needles, catheters or applicators which have been inserted sources, a few centres still treat carefully selected patients,
into the tumour area previously. Manipulation of these such as those who are frail and elderly or are bleeding
cold applicators carries no radiation hazard for medical heavily from a cervical tumour. Frail patients tolerate man-
and nursing staff so that time can safely be taken to ensure ually inserted sources better than the more rigid (and
optimal source geometry. uncomfortable) afterloading applicators. Manually inserted
Most implants are of the removable type. The radiation sources along with appropriate gauze packing are an excel-
sources are removed after delivery of the prescribed lent haemostat.
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Chapter | 11 | Brachytherapy
197
Walter and Millers Textbook of Radiotherapy
0.8 mm 0.5 mm
3.0 mm
4.5 mm
Emission: 30 ke V photons
Half-life: 60 days
Half value layer: 0.02 mm lead or 1.7 mm tissue
A B
Figure 11.6 Prostate Brachytherapy. (A) Radiograph of seed implant (B) Iodine-125 Seed.
(By kind permission of Oncura Ltd).
198
Chapter | 11 | Brachytherapy
Figure 11.7 HDR afterloader for breast treatment using Iridium-192 stepping source. The source travels along flexible polythene
tubes which have been inserted in theater.
(By kind permission of VARIAN UK Ltd).
administered followed by an interstitial boost treatment. hairpins are inserted. A typical dose for a low dose rate
Depending on the size of the residual breast tumour this implant is 65 Gy given over 67 days.
can be given using either a single or double plane of iridium
sources. Sometimes to ensure precise geometry, rigid nee-
dles are used secured in a template rather than flexible plas- ANAL CANCER
tic tubes.
Implantation is rarely used as the sole treatment of anal
cancer. Patients are initially treated with external beam
TONGUE AND FLOOR OF MOUTH radiotherapy to doses of 4045 Gy over 45 weeks. Patients
with tumours greater than 5 cm also should receive chemo-
A T1 or T2 tumour on the lateral edge of the anterior two therapy, either mitomycin-C and 5-fluorouracil or
thirds of tongue can be very satisfactorily treated by iridium cisplatin-based combinations.
hairpins. Larger tumours are usually treated first by external After 12 months to allow the tumour to regress and the
beam radiotherapy (with or without chemotherapy) and reaction to settle, the patient undergoes an implant which
the implant is used merely as a boost treatment. In French is carried out under general anaesthesia. A horseshoe-
centres, sometimes brachytherapy of the tongue is accom- shaped jig is placed against the anal skin and up to eight
panied by a functional neck dissection to treat the lymph hollow needles are inserted 1 cm apart through the jig to
nodes in the suprahyoid region of the upper neck. cover the area of the tumour plus a safety margin. The nee-
Under general anaesthetic the tongue is both inspected dles extend beyond the tumour for two reasons. The first is
and palpated to find out the full extent of the tumour. Gut- to include occult disease and a margin of 1 cm is usual.
ter guides (see Figure 11.1B) are inserted to the tumour- The second is to compensate for gradual reduction of radi-
bearing structure at 12 mm intervals under fluoroscopic ation dose at the end of the implant. Fifteen percent is
control. The most posterior gutter guide is inserted first added to length of the iridium at each end to ensure the
and attempts are made to keep all subsequent gutter guides clinical volume receives the full dose. A hollow syringe
parallel with this. Three gutter guides (occasionally four) barrel is inserted into the anus to allow the escape of flatus
are inserted to treat the tumour with a 1 cm margin of nor- or faeces. The jig is stitched against the patients skin
mal tissue. Once the operator is satisfied about the geome- and the needles are secured by a locking bar. The iridium
try of the implant, iridium hairpins are then inserted into is later inserted to give a dose of 1525 Gy in 22 days to
the gutter guides. The hairpin is pressed down using a sur- the reference isodose line using the Paris system. This
gical hook and then the gutter guides are removed. The irid- technique has yielded an impressive 93% three-year sur-
ium is secured to the dorsum of the tongue by a stitch vival in a series of 48 patients with tumours under 5 cm.
around the crossbar of the hairpin. The length of hairpins Six out of a total of 79 patients (7.6%) developed severe
depends on the size of the tumour but usually 4 cm long late complications.
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Walter and Millers Textbook of Radiotherapy
[1] Dale RG, Jones B. The clinical reporting intracavitary brachytherapy cancer. Surgical Oncology
radiobiology of brachytherapy. Brit J in gyneacology. ICRU report 38. 2009;18:25567.
Radiol 1998;71:46583. Maryland: Bethesda; 1985. [8] Acher P, et al. Prostate brachytherapy:
[2] Sundar S, Symonds P, Deehan C. [5] Aird EGA, Jones CH, Joslin CAF, et al. dosimetric results and analysis of a
Tolerance of pelvic organs to Recommendations for brachytherapy learning curve with a dynamic
treatment for carcinoma of cervix. dosimetry. British Institute of dose-feedback technique. Int J
Clin Oncol 2003;15:2407. Radiology; 1993. Radiat Oncol Biol Phys
[3] Denton AS, Bond J, Mathews S, et al. [6] Orton CG, Seyedsadr M, Somnay A. 2006;65:6948.
National audit of the management Comparison of high and low dose- [9] Vale CL, Tierney JF, Davidson SE,
and outcome of carcinoma of the rate remote afterloading for cervix Drinkwater KJ, Symonds P.
cervix treated by radiotherapy in and the inportance of fractionation. Substantial improvement in UK
1993. Clin Oncol 2000;12:34753. Int J Radiat Oncol Biol Phys cervical cancer survival with
[4] International Commission on 1991;21:142534. chemoradiotherapy: results of a
Radiation Units and Measurement. [7] Moule RN, Hoskins PJ. Non-surgical Royal College of Radiologists Audit.
Dose and volume specification for treatment of localised prostate Clin Oncol 2010;22:590601.
200
Chapter | 12 |
Networking, data and image handling and
computing in radiotherapy
John Sage
RT image 208
CHAPTER CONTENTS
RT treatment summary 208
Introduction 201 Data burden 208
History 202 Data security 208
Benefits and hazards of computerization 202 Backup 208
Networking 202 Archive 209
Link layer: physical infrastructure 202 Software development 209
Network layer: addressing 203 Concluding remarks 210
Transport layer: send and receive 204 References 210
Application layer: the program 204
Network security 204 INTRODUCTION
Dicom 204
Dicom services 205
Technology is so much fun but we can drown in our
Dicom communication 205 technology. The fog of information can drive out
Dicom data objects 205 knowledge. Daniel Boorstin
Dicom conformance 206
Radiotherapy data 206 Computers permeate every aspect of modern radiotherapy.
Data storage 206 With their application, we can deliver ever more intricate
treatments. However, every technological innovation comes
Image quality 207 at a cost in equipment, maintenance and added complex-
Dimensions and scale 207 ity. With care, these costs can be kept in balance and benefits
Bit depth 207 to the patient achieved.
Compression 207 Computing in radiotherapy has developed as computers
have grown more powerful. In 1965, Gordon Moore,
Colour 207
co-founder of the computing giant Intel, predicted that
Radiotherapy data types 207 microchip complexity would increase exponentially for at
Tomographic images 207 least 10 years [1]. In fact, Moores law still holds today, with
Planar images 208 processors doubling in complexity approximately every
2 years. Moores law typifies the growth in all aspects of
Curves, annotations and overlays 208
computing. Hard disk drive capacity nearly doubles each
RT structure set 208 year while the cost per gigabyte nearly halves [2].
RT plan 208 This growth has consequences for radiotherapy. The use-
RT dose 208 ful lifetime of any item of computer software or hardware is
going to be fairly short. In the NHS, a lifetime of 5 years is Intensity modulated radiotherapy would be totally unfeasi-
used for IT equipment, compared to 10 years for a linear ble without computers or data communication. Even sim-
accelerator [3]. This growth also needs to be considered ple techniques are enhanced by the use of computers.
when planning for long-term needs. It will be more costly If data are transferred directly between computers there is
to purchase 5 years data storage immediately than it will less chance of human error. The use of record and verify sys-
be to buy half now and half in 2 years time, at a quarter of tems has certainly reduced the number of random human
the cost. errors at the point of treatment delivery [4].
Ultimately, the hazards of computerization relate to our
History increased dependence on computer systems and the faulty
assumption that they are reliable. Computers and networks
For many decades, radiotherapy was developed without do fail. A radiotherapy department that is reliant on a sys-
computers. Isodose planning and linear accelerators tem can be crippled if that system is the victim of compo-
both pre-date the use of computers. In the 1960s, the first nent failure, a virus, or even theft.
investigations were made into using computers for radiother- As systems become more complicated, they are harder
apy. Such use required access to one of the small number of to check for errors. It should never be assumed that
large mainframe computers, probably at a university, since the computer is correct. Furthermore, computers do not
personal computers were not invented until the 1970s. The remove the risk of human error altogether. Proper use
first widespread use of computers was for calculating isodose of a system relies on operators performing tasks correctly.
distributions, replacing laborious manual calculations. In If they do not then incorrect information can be passed
the late 1970s, the first use was made of computed tomogra- down the line and used at a later stage. Where errors do
phy (CT) data for radiotherapy planning. This required a occur in computerized systems they may affect a series
magnetic tape reader connected to the planning system to of patients or a single patient for every fraction of their
read the CT scanner tapes. treatment [5].
As networking technology became available, it was pos- In order to reduce these risks, we need to reverse the
sible to connect computers directly together. However, CT assumption that the computer is reliable. Key checks should
scanners still used different file formats. In 1985, the Amer- be made, during system testing and for individual treat-
ican College of Radiology and the National Electrical Man- ments. Is the isocentre correct? Is the patient reference posi-
ufacturers Association created a standard for medical tion correct? Where there are multiple data sets, has the
images called ACR-NEMA. In the third version, in 1991, correct one been used for the treatment? When every plan
the standard was developed to specify how systems should had to be calculated and delivered manually, each person
communicate directly. To mark this change a new name for involved had to understand fully the technique and the
the standard was used: Digital Imaging and Communica- treatment. Now that the treatment can be delivered at
tion in Medicine, or DICOM 3.0. the touch of a button, that level of understanding is critical
In the 1980s, the first record and verify systems appeared. to detect errors.
Later, it became possible to transmit plans from the
planning computer to the record and verify system, driven
by the use of multileaf collimators in the 1990s. It was also
in the 1990s that electronic portal imaging devices were
NETWORKING
developed. Accompanying them was a need to obtain ref-
erence images in electronic form, whether digital simulator Networks are commonly described as having a number of
images or digitally reconstructed radiographs. layers. In one of the simpler descriptions, the TCP/IP
At the turn of the millennium, radiotherapy centres were model, four layers are described [6]. In order to understand
filled with computer systems transferring data. Managing these layers, we draw a comparison with the postal system
these could be difficult and expectations frequently exceeded (Table 12.1).
the realities of what could be achieved. These frustrations led Because the network is layered in this way, any changes
to the recent development of radiotherapy, or oncology, that occur in one layer do not affect the others, so you do
information systems. These act as a central hub of the net- not need to write a new application because you have
work: receiving and organizing data from various sources. bought a new modem.
This coordination of data is going to be vital for the era of
image guided radiotherapy.
Link layer: physical infrastructure
Benefits and hazards of Two computers can be connected by a single cable. But
what if four computers need to be connected? It is possible
computerization
to connect them via a network loop so that a packet of data
The more advanced techniques that we practise would not sent by A is visible to B, C and D, but will only be picked up
be possible at all without the assistance of computers. by the computer it is intended for. The problem with this is
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Link The infrastructure of cables, switches, modems and so on which The infrastructure of vehicles and sorting
allow information to be moved from one place to another offices which allow post to be moved around
Network The addressing system which allows a single computer to be The addressing system which allows post to
identified and for data to be routed to it be directed to the correct destination
Transport The process of packing the data and sending it into the network. Taking letters to the post office to send and
Also the process of receiving data from the network picking up received letters
Application Defining the data to be sent and interpreting any data received Writing and reading your post
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Walter and Millers Textbook of Radiotherapy
Gateway
Subnet A Subnet B
gateway know that this single data packet came from a ping
Windows IP Configuration
request and that it should send a return message? Also, how
Ethernet adapter Local Area Connection:
can a computer make multiple connections of different
Connection-specific DNS suffix . : hospital.nhs.uk
IP Address . . . . . . . . : 192.168.123.45
types without them getting confused? Each computer has
Subnet mask. . . . . . . . : 255.255.255.0 a whole series of network ports. When a computer receives
Default Gateway . . . . . . : 192.168.123.1 a data packet addressed to port number 7, it knows that
this is a ping request and responds accordingly, whereas
Figure 12.3 Sample output of ipconfig. requests for web pages are normally addressed to port 80.
Imagine having a whole series of slots outside your house
and the postman sorting them out for you into bills, junk
mail and so on.
Pinging 192.168.123.1 with 32 bytes of data:
Reply
Reply
from
from
192.168.123.1:
192.168.123.1:
bytes=32
bytes=32
time<1ms
time<1ms
TTL=255
TTL=255
Application layer: the program
Reply from 192.168.123.1: bytes=32 time<1ms TTL=255
Reply from 192.168.123.1: bytes=32 time<1ms TTL=255
The final layer is the program itself, which is often the hard-
est part. Just because you can send a letter to anywhere
Ping statistics for 192.168.123.1:
Packets: sent = 4, Recieved = 4, Lost = 0 (0% loss) in the world, it does not mean that they will be able to
Approximate round trip times in milli-seconds: understand what you have written.
Minimum = 0ms, Maximum = 0ms, Average = 0ms
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Chapter | 12 | Networking, data and image handling and computing in radiotherapy
MEASURES
Virus Attack
Figure 12.5 Potential impact of network hazards and measures to mitigate them.
images between systems. Dicom aims to be a complete are able to establish communication with the dicom server,
specification for such transfer and specifies requirements but this does not necessarily mean that the connection will
over all the network layers. be successful.
The second common misconception about dicom is that The security of dicom servers varies widely. Some will
two dicom compliant devices will communicate correctly. communicate with any system that has the correct address
This mistake is the root cause of a great deal of anxiety. Given and port. This makes setting the system up easy but security
the huge variety of medical imaging equipment, dicom is not will be poor. Others will make further checks. Each dicom
prescriptive. There is a great deal of variation possible within program has a name, called an application entity title (AET).
the standard. Where there is variation, dicom provides us Most servers will refuse a connection to a system that does
with a common language to describe the functionality of a not call it by the correct name. Furthermore, many servers
system and check whether two systems are compatible. will check the AET of the requesting system against a list of
known AETs.
Upon connection, the two systems perform what is
Dicom services known as a handshake. They swap credentials. They deter-
Dicom connections are not always about the transfer of mine whether the action that is being requested is sup-
images from one computer to another. A connection ported and whether to continue with the action. Then
may be in order to print an image, send a worklist to a scan- information is exchanged and the association is closed.
ner, or find patient images. Each of these possibilities is
called a service class. Furthermore, in any transaction there
Dicom data objects
will be a service class provider (SCP), and a service class user
(SCU). So, a server may offer the storage class as SCP One key problem in sending data between imaging systems
and a number of systems may send images to it as SCU. is defining the exact meaning of the information sent.
Dicom solves this through the use of a data dictionary. Each
possible piece of information about the image, called a data
Dicom communication element, is catalogued and given a code. The exact definition
To establish a dicom connection we need two critical pieces of the information for each code is contained in the
of information. First, we need to know the IP address of the standard.
computer we wish to connect to. Secondly, we need to Any data object, such as a radiotherapy plan or a CT
know which network port the dicom program is monitor- image, will consist of a collection of data elements rele-
ing. Port 104 is reserved for use by dicom programs and is vant to that object. The dicom standard details which data
normally the correct port. However, this is not always the elements are mandatory for a given object and which
case, a single computer may even run several dicom servers are optional. Another new term, the service-object pair
on different ports. With these two pieces of information, we (SOP), is used to describe the application of a particular
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Walter and Millers Textbook of Radiotherapy
service class to a data object. We may talk about a general Dicom conformance
SOP class, such as CT image storage, or even a particular
Whereas the CT object in the example above is a valid CT
SOP instance, one specific stored CT image.
object according to the standard, it contains very little
Figure 12.6 shows an example minimal CT object. Each
information and would probably be rejected by many
row of the diagram shows the entry for each of the separate
dicom servers. This is the problem. By allowing manufac-
data elements. For each data element there is a two number
turers to choose which data elements are contained in
code which relates that element to the dicom data dictionary.
the data object, the standard creates room for incompatibil-
The data elements are grouped by the first number. In this
ity. It becomes very important for manufacturers to
example, group 0008 is the identity group and contains all
describe exactly how their system behaves, which data ele-
the elements which help uniquely identify this object. Group
ments are important and which are ignored.
0010 is the patient demographics group, group 0018 the CT
The dicom standard specifies a common format for such
parameters group, and so on. The last of all of the data ele-
descriptions, the dicom conformance statement. It should be
ments contains the actual image data itself.
possible to determine whether two systems will be able to
One special class of data element, the unique identifier
communicate successfully by comparing their dicom confor-
(UID), consists of a long numeric code. This code must
mance statements. In practice, these documents are quite
be truly unique and may not be reused. In the sample
long and an incompatibility might be difficult to spot.
below, there are three kinds of UID. The values for the
SOP class UID are defined in the standard and each code
describes the object. In this case, this is the code for a stored
CT image. The SOP instance UID is the unique code for this RADIOTHERAPY DATA
object. No other dicom object in the world may have the
same UID. In this way, a dicom server can tell if it is sent
Data storage
the same image twice and can disregard one of them.
The study instance UID is the unique code for this study Data storage essentially comprises a number of switches,
for this patient. All images in this study will contain the which are on or off. The smallest size of data storage is
same study instance UID and a dicom server can use this one switch, called a bit, which can store a one or a zero.
correctly to group images together. More bits are used to store larger numbers. If eight bits
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Chapter | 12 | Networking, data and image handling and computing in radiotherapy
Image quality
A B
There is a trade-off between the quality of the image and the
space it takes up. For reference, a standard CT slice uses Figure 12.8 (A) 4 bit image showing significant degradation for
512 kB. To illustrate this section, a test image is used which only 50% space saving (B) Compressed image taking up just 2%
also requires approximately 512 kB, Figure 12.7A. of the original space, but differences are visible.
A B
Figure 12.9 Three 8 bit images combine to form a 24 bit colour
Figure 12.7 (A) Test image (B) at reduced resolution. image.
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Walter and Millers Textbook of Radiotherapy
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Chapter | 12 | Networking, data and image handling and computing in radiotherapy
SOFTWARE DEVELOPMENT
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Walter and Millers Textbook of Radiotherapy
A B
CONCLUDING REMARKS
Figure 12.11 Division of effort in software development
projects. (A) What is often perceived as required. (B) A much
more realistic and safe approach. This simple introduction to the use of computers in radio-
therapy will, regrettably, by the very nature of the subject
be out of date almost instantly. It is important to obtain
up-to-date guidance on specific aspects. One guide worthy
requirements. Important decisions, such as the program- of specific mention is IPEM report 93, Guidance for Com-
ming language to be used, should not be left solely to missioning and QA of a Networked Radiotherapy Depart-
the programmer as this will affect the ability of a centre ment [12]. The field of radiotherapy computing overlaps
to support the software in the future. This phase should traditional work boundaries and there are frequently pro-
also include a risk assessment of the impact of software fail- blems with IT professionals who do not fully understand
ure and consequently any safety requirements. the requirements of radiotherapy as much as radiotherapy
Documentation is vital to maintaining a safe software sys- professionals who do not fully understand the technical-
tem. Not just user manuals but clear technical documenta- ities of IT. Out of this situation a new breed is rising, the
tion and description of the operation of the computer radiotherapy IT specialist. Such people will be extremely
code itself. It is not sufficient for all documentation to be important to ensure that we continue to reap the benefits
written retrospectively as important details can be forgotten. of computerized radiotherapy.
REFERENCES
210
Chapter | 13 |
Quality control
John A. Mills
IPEM81. An example of a locally set tolerance may be that an adverse affect in some of these accidents. Many accidents
the field size on a megavoltage treatment machine can be highlighted the need for standards to be established in both
made to lie within 1.5 mm when another type of safety and performance.
machine can achieve 1 mm for the same amount of work. The acceptable variation in dose delivery has been iden-
Effective quality control needs to fulfill two roles. One is tified from clinical experience and radiobiological studies
to demonstrate the correct performance of a system and the to be 5% [11, 12]. This gives some perspective on the seri-
other is to detect deterioration of the system in order to take ousness of, for example, the Exeter accident in 1988 [13]
corrective action. Demonstration and detection are, in fact, when a 25% overdose was delivered to many patients
two sides of the same coin. The boundary between each between February and July of that year. Systems of quality
side is set in accordance with appropriate limits chosen control checks endeavour to ensure that treatment equip-
with regard to the distribution of a measured parameter ment operates both safely and effectively.
as shown in Figure 13.1 for the example of a 10 10 field.
Quality control immediately following a repair of equip-
ment demonstrates that performance has been restored or A COMMITMENT TO QUALITY
detects problems with the repair. CONTROL
In radiotherapy, quality control has become increasingly
significant over the past 20 years. It has been recognized
For quality control to be effective, there must be a commit-
that, in order to achieve and maintain high standards of
ment to examine aspects of a machines operation. It is self-
safe and effective dose delivery, there is a need for not only
evident that provided an aspect does not show itself up in
quality assurance systems which ensure safe, effective and
clinical practice and is never measured, it is never a prob-
traceable processes, but also for effective quality control
lem. The saying leave well alone comes to mind.
checks to demonstrate and ensure satisfactory operation
The Exeter overdose was apparent in skin reactions and
of equipment. In 1985, the ICRP [6] recognized the role
raised concerns. However, that in itself did not prompt a
that quality control played in the protection of the patient
measurement check, yet this was an overdose of 25%.
in radiotherapy. The hazards of radiation to normal tissue
were well known and the risk of oncogenesis [79] further
. . . it is seen that even a person whose treatment had
complicates the use of radiation in cancer treatment. These
started as early as mid February would not necessarily have
concerns were reinforced by accidents [10], some of which
shown any abnormal signs until about mid May [13].
were due to safety failures, others due to performance fail-
ures and, of course, some due to human error. It has been
clear that the absence or deficiencies of quality control had An underdose may well go on for a much longer period of
time and the incident at Stoke [14], when an underdose of
approximately 20% continued for several years, serves as a
demonstration of this.
Number of measurements
At Exeter, there were clinical concerns by the end of May
and the beginning of June 1988. On July 4, the calibration
of February 12 was still thought to be correct by the Physics
Department and it was not re-measured. No further mea-
surement would have taken place until August. The IPEM
dosimetry survey [15] measurement, which revealed the
error, was done on July 12.
This indicates that it is essential that the staff group
responsible for the equipments performance must look,
measure and check. Measurements can reveal problems
much quicker than clinical outcome will reveal them.
The difficult decision that needs to be made is what to look
at, how to look at it, how often to look at it and how to
judge what we find and what to do about it.
Figure 13.1 Illustration of limits chosen to encompass what is There are two aspects to dose delivery. First, the physical
considered to be satisfactory performance within the amount of dose and, secondly, is it in the correct position.
distribution of measurements of a parameter. For example, one Both aspects are significant and, in addition to safety sys-
side of a field size dimension, such as the X jaw of a 10 10 field. tems, are the key to satisfactory radiotherapy performance.
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Chapter | 13 | Quality control
When we consider the many and various components t Total treatment time (T) or greater
within the radiotherapy process, these two aspects are If t is long, say several times as long as a total course treat-
identifiable as where uncertainty in the treatment delivery ment time, T, where typically that can be between 3 to 6
can occur. For example, the calibration of CT number for weeks, the following occurs compared to having t equal
dose prediction is a dose aspect while the movement accu- to T. The variation in the dose is shown in Figure 13.3.
racy of the scanner and processing of the image matrix will This shows that the final batch of patients could be
be a positional aspect. receiving a dose difference up to almost double that for
a period of t which is about as long as a fractionation
regimen. The deterioration may not be controllable.
FREQUENCY, TOLERANCES AND There is, therefore, a need to choose a tighter tolerance
FAILURE TRENDS for this parameter.
Indeed, the performance deterioration is likely to be far
The classical assumption for performance deterioration is a from linear and more likely to be non-linear as in
linear change with time. Consider a tolerance of 3% in Figure 13.4.
dose delivered with action being taken at that level to restore This has significance for the interval between checks,
the performance to the required value. Figure 13.2 illus- although that needs to be balanced against resources. For
trates such a change in performance with time. example, frequent recording of parameters on a machine
Considering the effect of the length of the time period t: will perhaps pick up the deterioration in a parameter as
t 1 day it begins. However, in order to do this effectively without
any automated recording and analysis system requires suf-
If t was one day then, depending upon when a patient ficient staff to run-up a machine, taking note of parameters
was treated and assuming they attended at the same time
each day, then their dose for the entire treatment will be
different by between 0% and 3% over the full course of T=t
treatment.
t 5 days All mean differences approx 1.5%
0%
For all treatments of duration greater than or equal to
5 days, the variation from the required dose will be
approximately 1.5%. For treatments of 4 days or less,
3%
the variation will be between 0% and 3% depending
upon the day and the number of days treated. For example,
a 3-day treatment on days 2, 3 and 4 will have a mean
difference of (0.6% 1.2% 1.8%)/3 1.2%. How-
t = 5T
ever, an 8-day treatment on days 1 to 8 will have a mean
difference of 1.575% 0.3% 0.9% 1.5% 2.1% 2.7%
t 20 days 0%
For treatments of duration greater than or equal to 20 days,
the variation from the required dose will be about 1.5%.
For treatments of 19 days or less, the variation will be 3%
between 0% and 3% depending upon the day and the
number of days treated. Figure 13.3 Change in performance represented by a linear
change of a parameter over a time period when tT, (upper)
Hence the length of t can have a variable effect on the
and t5T, (lower).
dose delivered to the patient.
t t
0% 0%
3% 3%
Figure 13.2 Change in performance represented by a linear Figure 13.4 Change in performance represented by a non-
change of a parameter over a time period t after which linear change of a parameter over a time period t after which
corrective action is taken to restore the performance. corrective action is taken to restore the performance.
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Walter and Millers Textbook of Radiotherapy
NULL HYPOTHESIS 2 +2 2 +2
M M
This is an essential aspect of all statistical analysis. The null
R R
hypothesis (H0) is the hypothesis that the measurement
M is not different from the reference value R. Consider a Figure 13.7 A mean of a measurement M with respect to a
measurement with a best estimate mean M and standard reference value, R.
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Chapter | 13 | Quality control
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Walter and Millers Textbook of Radiotherapy
D M:O:W:T:S:C 13:3 There are three major categories of quality control. Each
where D is the dose, M the number of monitor units and involves drawing conclusions from measurement data
the other terms, O, W, T, S and C represent output, wedge, obtained from different methods of monitoring: immedi-
tray, source to surface and machine calibration factors ate monitoring, short-term and long-term monitoring.
respectively. For treatment machines, each method provides different
If we assume that the variation in the factors is indepen- but appropriate means by which to evaluate and maintain
dent, it is appropriate to apply the same method of combin- performance as follows.
ing the tolerances as was applied for standard deviations in Immediate monitoring. In this category, the immediate
equation 13.1. Therefore, the variation in the dose D can be effect on the performance of the machine is determined from
written as follows, assuming that the variation on M is zero: the response to changing a control parameter. Using this
approach, the optimum tuning of a circuit or system can
sD 2 sO 2 sW 2 sT 2 sS 2 sC 2 be determined. The monitoring of the machine can involve
13:4 both external and internal output signals. Internal para-
If we choose D to be within 2%, then the tolerance on C meters which alter as a consequence of the changed param-
needs to be less than 2% if all the other factors are not eter can provide system response information and externally
required to have zero tolerance, which of course is impos- monitored characteristics of the beam, such as beam sym-
sible. If we allow D to lie within 3%, take the tolerance on metry and energy, can also provide response information.
C to be 1% and let all the other tolerances be equal then a Long-term monitoring. Many parameters on a machine
value for the tolerance on each of the other factors would alter slowly as components age or their performance dete-
be 1.4%. If they are all equal then the tolerance on all fac- riorates. In order to correct and compensate for the deteri-
tors are 1.3%. oration, including replacement of a component, long-term
data trends provide an indication as to when action is
required. For example, this may be used to indicate the
need to adjust a parameter which requires adjustment con-
MAINTENANCE AND CATASTROPHES tinuously over time in order to maintain the performance
within an adequate value. Or it might indicate when the
It is important to bear in mind that not all aspects of equip- end of life of the device can be expected in order to schedule
ment performance can be maintained. Catastrophes are replacement and avoid treatment delays and interruption
inevitable and these are usually exhibited by component due to machine breakdown or lack of component availabil-
failure. They can also occur due to human error. Although ity. The data might again come from internal parameters of
some devices and components can be replaced, or action the machine or from measurements made independent of
taken to monitor performance and replace components the machine. Inevitably, data are difficult to record, log and
before failure, not everything can be maintained. Provision process. In particular, for measurements on the radiation
needs to be made as best as possible for catastrophes. Such beam, the results cannot be gathered in an entirely auto-
provision is to enable routine treatment provision to be matic manner and any system which can assist with the
maintained while equipment repair is completed. recording and processing of these data is invaluable.
Short-term monitoring. In contrast to immediate and long
term, short term endeavours to determine the performance
of the machine during a treatment day. Only internal para-
SHORT-TERM, LONG-TERM AND
meters of the machine are recorded during the day for
IMMEDIATE MONITORING subsequent processing. By analysis of such recorded data, it
is possible to identify deteriorating overall performance of
Constantly monitoring a parameter demonstrates perfor- the machine and schedule periods for attending to the
mance up until the point at which it is considered that machine. Although only internal parameters are monitored,
unacceptable performance has been detected. Hence, the it can be useful to compare the processed results with appro-
data collected through QC measurements can be used priate daily measurements of external beam characteristics.
not simply in a pass or fail fashion but to examine trends
in performance and, if possible, use these as predictors
for maintaining the performance of equipment.
One routinely used but simple trend technique is when THE RADIOTHERAPY PROCESS
a double tolerance level is set to monitor a parameter. Let
these levels be a% and b% where b>a. Results outside Quality control has a role throughout the entire radiotherapy
b% are considered to require immediate attention while process due to the significant technology that each aspect
results outside a% and also within b% must occur on a relies upon. The purpose of quality control in each aspect
number of subsequent occasions in order for action to be can be identified in terms of dose, position or safety and it
taken. contributes to ensuring effective overall treatment delivery.
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Chapter | 13 | Quality control
Acquisition CT scanner
Patient information that is not determined from clinical The quality control for the CT scanner relates to ensuring
examination and physiological and biochemical testing is the alignment of the patient with respect to the scanner
almost entirely obtained through imaging. The focus of is appropriate and accurate and also that any patient den-
the information is the computed tomography (CT) scan sity information is appropriate for dosimetry calculations.
which forms the basis for dose prediction. This is supple- Table 13.1 lists areas of consideration which are typical but
mented with magnetic resonance imaging (MRI) and posi- not comprehensive.
tron emission tomography (PET) imaging, the use of which
relies upon accurate image registration in order to ensure in MRI, PET and image registration
turn accurate target localization.
with CT
The radiotherapy simulator still continues to contribute
significantly to gathering data about the patient in many The CT image data set forms the basis for dose prediction
clinical situations. However, the manipulation of large CT and the MRI and PET images aid target volume localization.
data sets with virtual simulation has proved to be increas- Hence, the MRI and PET registration with the CT image
ingly useful. In brachytherapy, localization of the radioactive data needs quality control checks which will ensure that
sources or the applicators is readily obtained radiographi- the geometric alignment between these images and the
cally with a simulator or with a C-arm radiographic device CT images is accurate and that volume sizes and dimen-
and it is also done with CT imaging supplemented by MRI. sions are not transferred incorrectly from one to the other.
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Walter and Millers Textbook of Radiotherapy
4 Beam energy
Isocentric linear accelerators
and cobalt machines 5 Dose variation with tube angle
Besides ensuring the satisfactory operation of safety inter- 6 Dose linearity and reproducibility
locks, there are many aspects concerning the performance
7 Absolute dose
of these machines that require routine quality control.
These aspects concern mechanical and optical alignment
as well as the performance of the radiation beam in terms
of its alignment to the optics and mechanics of the machine to the megavoltage machines. One fundamental aspect is
and the relative dose distribution within the beam, normally the alignment of the focal spot to the mechanical assembly
referred to as symmetry and uniformity. Both the mechanical of the applicators and tube attachment. Once this is accu-
and radiation performance are prerequisites for the correct rately established then accurate mechanical alignment of the
delivery of absolute dose and the final quality control checks applicators will ensure adequate performance. Table 13.3
are to ensure that an accurate dose is delivered. With linear lists checks that are typical but not comprehensive.
accelerators, there may well be multiple energies for both
photon and electron modes. Quality control needs to be per-
Afterloading brachytherapy
formed for all energies and radiation modes. Table 13.2 lists
checks that are typical but not comprehensive. machines
High, medium and low dose-rate machines all require
quality control checks for safety and performance. With
Orthovoltage teletherapy machines
this equipment, the mechanical aspects concern the posi-
Orthovoltage treatment machines require mechanical, tional accuracy of the radiation source and then ensuring
radiation field and dosimetry checks in a similar fashion that the dummy source indicators, which are used for
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Chapter | 13 | Quality control
planning radiographs, accurately reflect the source positions. GETTING THINGS IN BALANCE
Finally, of course, measurement of the absolute dose checks
source activity, timer and positional accuracy. Table 13.4
lists checks that are typical but not comprehensive. There are three aspects which need to be balanced when
dealing with a problem:
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Walter and Millers Textbook of Radiotherapy
Clinical
CONCLUSION
Clinical Quality control and planned maintenance are a require-
Figure 13.10 Illustration of the split between the three aspects ment of IRMER [1]. They are both often seen as an unnec-
to be considered in equipment problems and restoring essary intrusion into the routine treatment of patients. It
performance for two extreme situations. can become very frustrating for treatment personnel when
the performance of a treatment machine needs to be
On the one hand, if the clinical significance is small and checked and confirmed following the repair after a break-
the resource and/or part availability is large, then the work down. It is, however, apparent from previous incidents that
can be scheduled for planned maintenance (PPM). How- measurement of a physical parameter could have averted
ever, on the other hand, if the clinical significance is great, incorrect treatment over a lengthy period before clinical
then an immediate repair will be appropriate. indicators indicated a problem.
There is no easy answer to the numerous situations It is important to be able to put the checks on perfor-
between the two extremes. This has to rely on the skill, mance into context. This can be done in relation to the
knowledge and insight of the scientists and technicians treatment planning and dose prediction undertaken for the
involved in the work. treatment of a patient. For example, considerable effort is
Quality control coupled with planned maintenance used on occasions to achieve a dose distribution satisfying
forms an essential component in ensuring that safe and the ICRU 50 [16] criteria of 5% to 7% across the target.
effective radiotherapy is achieved. The performance of the machine can compromise this
due to several factors. A non-uniform beam due to energy
change or tilted beam due to poor steering could change
QUALITY CONTROL CHECKS AND this by 6%. The variation in the factors used for calcula-
SCHEDULING FOR MEGAVOLTAGE tion of the monitor units in combination with the dose cal-
ibration of the machine could also change this by up to
MACHINES 6%. Geometric misalignment between the radiation
beam and the beam indicators can result in dose differ-
The scheduling of routine quality control should be chosen ences, particularly in regions of high dose gradient such
to suit the local circumstances. For many types of equip- as wedged or modulated fields. It is worth bearing in mind
ment, this can be accommodated within normal working that, typically, within 5 mm of a radiation fields geometri-
hours. However, in the case of treatment machines, this cal edge, a dose variation of up to 10% can result from the
may not be possible due to the lack of treatment capacity order of a 1 mm discrepancy.
and patient demand. Suitable guidance as to the frequency A random combination of these many factors throughout
of checks and the types of tests can be found in both the treatment cannot be guaranteed and the performance
IEC60601:9076 [6] and IPEM81 [5]. Both documents pro- variation that might result without adequate quality control
vide guidance for checks to be conducted on a monthly to and planned maintenance could well negate or even swamp
12-monthly frequency. The IEC document does not specify the variation expected from the planned dose prediction.
weekly checks. An estimate of the total time for the checks A comprehensive system of quality control for all the
suggested is approximately the same based upon experience equipment used in radiotherapy will ensure that accurate
of nominal times. This amounts to between 117 and 128 and reproducible treatment is being delivered.
REFERENCES
[1] Statutory Instrument 2000 No. [2] British Standards Institute. BSEN requirements for medical electrical
1059. The Ionising Radiation 6061-1-1:2002. Medical electrical systems.
(Medical Exposures) Regulations. equipment. General requirements [3] British Standards Institute. BSEN
2000. for safety. Collateral standard. Safety 60976:2001. Medical electrical
220
Chapter | 13 | Quality control
equipment Medical electron [8] Lorigan P, Radford J, Howell A, [13] The Exeter District Health Authority.
accelerators Functional Thatcher N. Lung cancer after The Report of the Committee of
performance characteristics. treatment for Hodgkins lymphoma: Enquiry into the overdoses
[4] British Standards Institute. BS 5724- a systematic review. Lancet Oncol administered in the Department of
3.1: Supplement 1: 1990: Medical 2005;6:7739. Radiotherapy in the period February
electrical equipment Part 3: [9] Amemiya K, Shibuya H, to July 1988. 28 November, 1988.
Particular requirements for Yoshimura R, Okada N. The risk of [14] West Midlands Health Authority.
performance Section 3.1 Methods radiation-induced cancer in patients Second Report of the Independent
of declaring functional performance with squamous cell carcinoma of Enquiry into the conduct of
characteristics of medical electron the head and neck and its results of isocentric radiotherapy at the North
accelerators in the range 1 MeV to 50 treatment. Br J Radiol Staffordshire Royal Infirmary, 1994.
MeV Supplement 1. Guide to 2005;78:102833. [15] Thwaites DI, et al. A dosimetric
functional performance values. [10] IAEA Safety Report Series No 17 intercomparison of megavoltage
[5] Institute of Physics and Engineering Lessons learned from accidental photon beams in UK radiotherapy
in Medicine. IPEM Report 81. exposures in radiotherapy. 2000. centres. Phys Med Biol
Physics Aspects of Quality Control [11] Dutreix A. When and how can we 1992;37:445661.
in Radiotherapy. improve precision in radiotherapy? [16] ICRU Report 50 Prescribing,
[6] ICRP Publication 44. Protection of Radiother Oncol 1984;2:27592. recording, and reporting photon
the patient in radiation therapy. [12] Herring DF, Compton DMJ. The beam therapy. International
Pergamon Press. degree of precision required in the Commission on Radiation Units
[7] Travis LB, et al. Cumulative absolute radiation dose delivered in cancer and Measurements. 1993.
breast cancer risk for young women radiotherapy. Br J Radiol 1971;
treated for Hodgkin lymphoma. (Suppl. 5):518.
J Natl Cancer Inst 2005;97:13945.
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Chapter | 14 |
Quality management in radiotherapy
Jill Emmerson, Julie Clark, Caroline Mansell
important to describe from the outset. Quality may be a focus on the prevention of problems
defined as fitness for purpose or conformance to require- recognition that quality is a continual process.
ments, but it is more than this. The steps to achieving any quality initiative must include
the following stages:
Quality is the totality of features and characteristics of a
product or service that bear on its ability to satisfy stated analysis of current service
or implied needs [3]. identification of recommendations for change
implementation of change
In other words, it is the degree to which a product or service evaluation of the impact of change.
satisfies the requirements of the user. Some definitions do The main aim of quality in radiotherapy is safe and effective
not take costs into account. However, quality is about treatment. In addition to ensuring that all treatments are
meeting customer requirements, stated or implied, while optimized, a quality system should ensure that all possible
also keeping costs to a minimum. measures are taken to prevent inappropriate exposures
Another often used term is quality control (QC): the part from occurring [6].
of quality management focused on fulfilling quality
requirements, [4].
In radiotherapy, quality control does not only apply to
controlling the performance of the equipment, but also
HISTORY OF QUALITY IN
to controlling the performance of radiotherapy processes. RADIOTHERAPY
Quality assurance (QA) refers to the part of quality man-
agement focused on providing confidence that quality There are a number of well-documented radiotherapy inci-
requirements will be fulfilled [4] or: a systematic process dents [712], which have occurred both in the UK and
of verifying that a product or service is meeting specified internationally (Table 14.1). These have led to hundreds
requirements [5]. of patients receiving incorrect doses of radiation which,
Quality assurance incorporates risk assessment, deter- in turn, may have led to the possibility of the treatment
mining what might go wrong, or what is critical to get right, intent being compromised or causing unnecessary and dis-
then planning the process and putting procedures in place tressing acute and late side effects of treatment. Subsequent
to ensure that a reliable service is provided. Aspects to be outcomes in the UK have included key reports which have
included should be operational, including legislative and contributed to the development of quality management
educational requirements; physical and technical checks systems in radiotherapy.
to verify correct functioning of equipment; and clinical It is notable that, throughout numerous reported inci-
aspects, including patient care and management. This can dents, a number of recurring themes can be identified as
be achieved through activities such as documentation, contributing factors. These include:
training and ongoing review of existing processes.
Quality management (QM) is the coordinated activities
lack of communication, especially at staff group
interfaces
to direct and control an organization with regard to quality
[4]. The underpinning philosophy, to get the process and
training, competency and supervision issues
the service right first time, applies to all parts of the organi-
lack of up-to-date procedures, protocols and
documentation
zation, involving managing all functions and activities to
achieve quality.
no independent check/calibration
A quality system (QS) is the organizational structure,
inadequate identification of clear responsibilities.
responsibilities, procedures, processes and resources which It is of the utmost importance that the radiotherapy com-
must be in place to implement quality management. munity shares information and learns from past mistakes
A quality management system (QMS) is a management [6,20]. Departments should also search for, correct, moni-
system to direct and control an organization with regard tor and learn from their own incidents. Departments open
to quality [4]. themselves up to risk if there are workload or time pressures
There are a number of documented approaches to or if there is an insufficiency in:
quality, including total quality management (TQM), con- attention to detail, alertness or awareness
tinuous quality improvement (CQI) and business process procedures or checks
re-engineering. From these different approaches, it is possi- resources, e.g. qualified and well-trained staff
ble to identify a number of recurring key themes: coordination, communication and clear
management commitment responsibilities [6].
staff involvement All of these factors are encompassed by ISO 9001 and should
identification of clear requirements or standards be incorporated into a departments quality management
identification of clear processes, broken down into system. They are areas that should be kept under regular
identifiable steps review with a view to continual improvement.
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Chapter | 14 | Quality management in radiotherapy
DoH working party, chaired by Professor Bleehen, to investigate the application of quality assurance
to radiotherapy to reduce the probability of incidents occurring in other centres.
1991 Bleehen Report: Quality assurance in radiotherapy (QART). Took the form of a quality standard and [14]
provided a formal system for managing quality in radiotherapy. It was based on the Quality Standard
BS 5750, Part 2, 1987 (the predecessor of ISO 9001), a quality standard which was generic to a range
of industries and services and thus, open to a degree of interpretation and translation.
1994 Sample documents from two pilot sites published and DoH recommendation for all departments to [16]
develop their own quality management system (QMS)
2008 Redacted Independent review of the circumstances surrounding a serious adverse incident [12]
225
Walter and Millers Textbook of Radiotherapy
Management Commitment
Quality Policy
LEADERSHIP
Quality Objectives
CONTINUAL
Trained IMPROVEMENT
competent staff
INVOLVEMENT Definition of
OF PEOPLE processes and
responsibilities
Communication Appropriate
and feedback environment Monitoring
PROCESS
APPROACH
Customer
focused service FACTUAL APPROACH
TO DECISION MAKING
CUSTOMER FOCUS
ISO 9000
QMP 6 Continual improvement
Systems, such as audit, should be in place for continual ISO 9000 is a family of documents that provides an inter-
measurement, review and improvement of a departments national standard code of practice for quality management
processes and service. systems. It is designed to be generic so that it is independent
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Chapter | 14 | Quality management in radiotherapy
of any specific industry and therefore applicable to both the quality management principles which underpin the
manufacturing and service industries, including healthcare. clauses of ISO 9001. The ISO 9001:2008 requirements
It consists of: are very much based on the Plan Do Check Act cycle
ISO 9000 Quality management systems [22], as illustrated in Figure 14.2. Clauses 48 and their
Fundamentals and vocabulary (last published requirements are described further below, with the relevant
2005 [21]) quality management principles (QMP) indicated in
ISO 9001 Quality management systems brackets.
Requirements (last published 2008 [22])
ISO 9004 Quality management systems Guidelines Clause 4 Quality management system
for performance improvements (last published 2000
[23], due for republication 2009 [24] with a new focus
(QMP 2, 4, 5, 6, 7)
on sustained success). This describes the basic requirements for establishing a
The standards themselves are subject to a review pro- QMS and does include some duplication of requirements
gramme to ensure that they remain relevant. There were contained in other clauses, but this serves to emphasize
major changes when ISO 9001:2000 was introduced, the key actions required. Although the 2000 version of
whereas the publication of ISO 9001:2008 included only ISO 9001 shifted the emphasis from documentation to a
minor amendments. process-based approach, implementation of a QMS does
The scope of a departments QMS defines the activities require a certain amount of documentation. ISO
included within the QMS and is determined by the organi- 9001:2008 stipulates that there must be a quality manual,
zation. There are variations between oncology depart- often referred to as the Level 1 document, containing docu-
ments: some include just radiotherapy whereas others mented statements of a quality policy and quality objec-
include planning and dosimetry, medical physics, chemo- tives. In addition, there should be written procedures for:
therapy, clinical trials and clerical areas. ISO 9001 is the 1. control of documents (Clause 4)
standard against which an organization is assessed. It spe- 2. control of records (Clause 4)
cifies the requirements a QMS must meet but not how the 3. internal audit (Clause 8)
organization should meet them. 4. control of non-conforming product (Clause 8), e.g.
The ISO 9001:2008 [22] standard comprises nine complaints, clinical incidents
clauses, listed in Box 14.1. 5. corrective action (Clause 8)
Clause 0, Introduction, describes a process approach 6. preventive action (Clause 8).
and compatibility with other management systems. Clause
1, Scope, specifies the type of organization that the stan-
dard is applicable to. Clause 2, Normative references, gives
reference to the document ISO 9000:2005 [21], which is Table 14.2 Quality management principles underpinning
necessary for the application of the ISO standard. Clause 3, ISO 9001 clauses
Terms and definitions, defines what particular terms,
e.g. product, mean within the concept of ISO 9000. The QUALITY MANAGEMENT
remaining clauses, 48, contain the requirements against PRINCIPLE (QMP)
which departments are assessed.
These requirements are based on the eight quality man- CLAUSES OF 1 2 3 4 5 6 7 8
agement principles outlined above. Table 14.2 illustrates ISO 9001:2008
4. Quality
management
system
Box 14.1 The clauses of ISO 9001:2008
5. Management
0 Introduction
responsibility
1 Scope
2 Normative references 6. Resource
3 Terms and definitions management
4 Quality management system 7. Product
5 Management responsibility realization
6 Resource management
7 Product realization 8. Measurement
analysis &
8 Measurement, analysis and improvement
improvement
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Walter and Millers Textbook of Radiotherapy
Establish the
objectives and Implement the
processes necessary processes.
to deliver results in
accordance with customer
requirements and the
organizations policies.
Monitor and
measure
Take actions to processes and service
continually against policies,
improve process objectives and
performance. requirements for the
service and report
the results.
ACT CHECK
A QMS will also contain all or some of the following: Clause 5 Management responsibility
department procedures (QMP 1, 2, 4, 5, 6, 7)
process flow charts
Specific areas of management responsibility outlined in
clinical protocols
this clause include:
work instructions (detailed instruction about how a
task should be carried out) evidence of management commitment
forms determining, meeting and enhancing customers
data requirements
reference documents. an established quality policy which reflects the vision
Control of all these documents includes regulating their of the organization
development, approval, issue, identification, amend- established quality objectives which are based on the
ments, distribution, storage, security, obsolescence, reten- quality policy and business objectives, and aim to fulfill
tion and disposal. Similarly, records produced, such as the needs of the customers
training records, patient treatment records, equipment management review meetings to review the
maintenance records and records of complaints and inci- effectiveness of the QMS and the departments
dents, must be regulated for the duration of their life cycle. performance against objectives, and to identify further
A record may be any document that provides evidence improvements
of activities performed. Records must be legible, identifi- ensuring the availability and effective allocation of the
able and retrievable. A department must define what its resources required to fulfil the departments objectives.
quality records are, how they are stored, who has respon-
sibility for them, how long they should be retained and
Clause 6 Resources (QMP 1, 2, 3, 4, 7)
the method of disposal. Departments must ensure they
incorporate legislative [25, 26], national [2729] and The resources required to provide a service and fulfill
local requirements into their control of documents the departments objectives are categorized by ISO
and records policies. 9001:2008 as listed below. The management team is
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Chapter | 14 | Quality management in radiotherapy
responsible for determining and then providing the improve its service, it must be able to identify standards
resources to implement and maintain the QMS, continually to strive for, measure its performance and monitor
improve its effectiveness and enhance customer satisfaction. outcomes against requirements and expectations, analyze
n Human resources. For example: there should be the findings and identify potential improvements.
sufficient numbers of staff who are trained and Departments should develop indicators and measures
competent [30] which are meaningful to them and which they can use to
n Infrastructure. This includes buildings, utilities, measure improvement. Key requirements of this clause
IT and support services. It includes not only include:
the purchase of but also the correct maintenance monitoring customer satisfaction to assess whether the
of treatment machines and other equipment service provided has met with customers expectations,
n Work environment. This encompasses physical, e.g. using information from customer surveys,
social and psychological factors associated with the complaints [32], compliments and user groups
work environment. For example, health and safety, internal audit. Quality audits are the measurement
local rules and radiation protection. component of a QMS and, through independent
examination, should provide objective evidence of:
n effective implementation of the organizations
Clause 7 Product realization (QMP 1, 2,
processes
3, 4, 5, 6, 7, 8) n achieving the organizations objectives
n conformance to ISO 9001 requirements
This clause, the largest of ISO 9001:2008, describes and
includes the processes and steps involved from identifying monitoring systems at identified points of a process to
the need for a service, to creating and providing it. In detect any problems or faults and prevent errors from
planning the provision of a particular service to fulfill occurring, e.g. calculation checks
requirements, consideration must be given to: measurement systems to verify performance against
targets, e.g. waiting time targets
customer requirements and how they are identified
control of a non-conforming product. If any problems,
resources required, e.g. skill mix of staff, equipment such as complaints, are detected by the monitoring
documentation requirements, e.g. are detailed work systems in place, there should be clear systems in place
instructions required?
to record and correct them and to prevent them
the activities required to verify, validate and monitor escalating
the process at critical stages, e.g. what checks should be
in place at each stage?
analysis of data. Organizations need to identify
sources of data, for example, clinical incidents,
records that should be maintained, e.g. patient records,
machine down time and waiting time data, which give
equipment records [27]
an indication of performance. These data should be
statutory and regulatory requirements, e.g. radiation
analyzed to identify whether there are opportunities for
protection [31]
improvement
customer communication, e.g. obtaining customer
feedback and handling complaints
improvement. The previous requirements lead on to
implementing continual improvement. Immediate
purchasing, e.g. equipment specifications, and use of
remedial action is required in response to an error,
reliable suppliers
non-compliance with a procedure or a complaint.
service provision, including, for example, the use of work
Corrective action is necessary to identify the cause of a
instructions, suitable equipment, monitoring and
problem and prevent it recurring. Methods of
checking processes, identification and traceability issues.
preventive action should be in place to identify
Examples could include the identification of the patient
any potential faults or risks in processes in order that
and their accessories throughout the treatment process,
action can be taken to reduce the likelihood of
traceability of any equipment used and the storage of
occurrence.
records such as patient notes
the control of measuring and monitoring devices. This Further reading on ISO 9000 should include the standards
applies to any method used to monitor whether the themselves. In addition, there are many textbooks which
service provided meets the determined requirements. It interpret how to apply the requirements [33]. Figure 14.3
could be applied to satisfaction surveys, but also to the illustrates the process of implementation of a QMS through
calibration of measuring equipment. to ongoing surveillance visits.
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Walter and Millers Textbook of Radiotherapy
Assessment Assessment
unsuccessful successful
Assessor recommends
department for registration.
Registration body approve
recommendation.
The ISO 9001:2008 standard adopts a process-based what are the outputs?
approach and requires systematic identification and man- how are they measured?
agement of an organizations processes and the interaction what are the critical interfaces with other processes?
between them. To adopt a process-based approach, a radio- have responsibilities been clearly identified?
therapy department should consider the following: Processes are best illustrated with a diagram or flow chart.
identify each process carried out An example, relating to the treatment process, is shown
what are the inputs? in Figure 14.4. It is important to remember that a process
230
Chapter | 14 | Quality management in radiotherapy
Prescription
National and Activity data
local clinical from Oncology
guidelines Information
Treatment preparation System
(e.g. mould room, simulation, planning,
calculations, checking, data entry etc.)
Statutory
requirements, Data for
e.g. IR(ME)R Confirm patient Identification clinical audit
Equipment:
availability of Treatment Information
safe and to Cancer
accurate Registry
machines
Continual patient monitoring
and communication
Trained and Continual
competent reporting of
staff working complaints and
Completion of treatment
as a team incidents
Infrastructure,
Treatment record completed.
including patient Request for
information and follow up
support, clerical
support etc.
can be defined at many levels. A core process (e.g. treat- are staff trained and competent?
ment) will be made up of a number of subprocesses. are training records up to date?
Figure 14.5 illustrates an example of the interaction between how do you know if your customers expectations have
a departments core processes. For each process, it is impor- been fulfilled?
tant to consider the key elements of the ISO 9001 require- how are complaints or other problems
ments, for example, in addition to the list above: resolved?
are resources allocated effectively? how could potential improvements
is the work environment suitable for the task? be identified?
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Walter and Millers Textbook of Radiotherapy
TREATMENT
Radiotherapy
equipment
maintenance
and QC
Radiotherapy
Brachytherapy
Unsealed Source Therapy
Dosimetry
Measurement, Departments
Documentation Management Resource Service
analysis and within the Trust
requirements activities management provision
improvement external to the
scope of the QMS
what are the arrangements for ensuring calibration complement each other or have common characteristics,
equipment remains within specification? and should not be considered in isolation. They reflect the
is identification and traceability, e.g. of equipment and same principles that underpin quality management systems
patients, maintained throughout the process. and are all designed with the same ultimate objective
to improve the patients experience [34], whether this is
by, for example, improving treatment outcome, reducing
waiting times, reducing the risk of incidents, improving
AN INTEGRATED APPROACH TO communication with patients or improving patient facil-
QUALITY AND OTHER INITIATIVES ities. Meeting such standards gives an indication that an
acceptable level of quality has been achieved and allows
inter comparison. Obviously, getting the right measure of
Quality in the NHS
quality is important. For example, waiting times measure
Quality may be measured in a number of ways and there the speed of throughput for patients but have no bearing
are a number of standards, measures, targets and improve- on the standard of treatment delivered. This chapter has
ment initiatives within the NHS, both generic and specific discussed the principles of quality management systems
to cancer services. Key examples of this include Clinical but this is only part of developing and maintaining a qual-
governance (Box 14.2) and National Cancer Peer Review ity service. An effective QMS should be a tool to help imple-
(Box 14.3). Table 14.3 lists a number of other initiatives ment, integrate and measure any new initiative introduced
and documents that have contributed to the development into a department. For example, most UK radiotherapy
of quality in UK radiotherapy departments. Many of these departments who have undergone the peer review process
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Chapter | 14 | Quality management in radiotherapy
as part of the National Cancer Peer Review programme have on risk management, clinical incidents, audit and patient
found that using documentation describing working prac- focused care give more detail on some of the most important
tices, which was already present in the QMS, has made areas where a robust QMS can ensure smooth interfaces
the whole experience much easier. The following paragraphs between different initiatives.
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Walter and Millers Textbook of Radiotherapy
234
Chapter | 14 | Quality management in radiotherapy
7. July 1998 A First Class Document which set out the http://www.dh.gov.uk/en/Publicationsandstatistics/
Service: Quality governments strategy for Publications/PublicationsPolicyAndGuidance/
in the New NHS reorganizing and DH_4006902
modernizing the NHS. www.cgsupport.nhs.uk
Defined the concept of
Clinical Governance see
Box 14.2
10. September NHS Cancer Plan Set out a 5- year plan. Main http://www.dh.gov.uk/en/Publicationsandstatistics/
2000 areas identified were: Publications/PublicationsPolicyAndGuidance/
reducing waiting times DH_4009609
in the system
promoting the
empowerment
and involvement
of patients
adoption of national
standards of practice
Cancer Research
Networks
Cancer Information
Strategy
Cancer Services
Collborative
Cancer Networks
Continued
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Walter and Millers Textbook of Radiotherapy
236
Chapter | 14 | Quality management in radiotherapy
Continued
237
Table 14.3 Overview of quality initiatives in oncology and the NHScontd
23. September NHS Next Stage A review of the way the NHS http://www.ournhs.nhs.uk/
2007 Review Our delivers healthcare, looking
NHS, Our Future at how it can become fairer,
more personalized, effective
and safe, setting out
immediate and longer term
priorities.
Final report launched June
2008
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Chapter | 14 | Quality management in radiotherapy
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Walter and Millers Textbook of Radiotherapy
Audit
Box 14.4 Clinical audit
Audit is a key requirement of a quality management system
and has a long history both in the NHS, including medical, Clinical audit is a quality improvement process that seeks to
improve patient care and outcomes through systematic
clinical and multiprofessional audit, and in oncology [56].
review of care against explicit criteria and the
There are many definitions of audit [57]. For example:
implementation of change. Aspects of the structures,
processes and outcomes of care are selected and
A systematic, independent and documented process systematically evaluated against explicit criteria. Where
for obtaining audit evidence and evaluating it objectively indicated changes are implemented at an individual, team,
to determine the extent to which audit criteria are or service level and further monitoring is used to confirm
fulfilled [4] improvement in healthcare delivery [58].
Clinical audit, initially termed Medical Audit, was
where, in the above definition, audit criteria are a set of introduced to the NHS by the 1989 White Paper, Working
policies, procedures or requirements and audit evidence for Patients. It has continued to evolve and is now well
consists of records, statements of fact or other information established in the NHS, forming a key component of the
relevant to audit criteria which is verifiable. A definition of clinical governance framework. Guidance on audit is
clinical audit is included in Box 14.4. available from NICE [58] and the NHS Clinical Governance
It is important to distinguish audit from research. In the Support Team [59]. It is monitored by the Healthcare
most simplistic terms, research tells us the most effective Commission as a requirement of the Standards for Better
way to do things and how to achieve the best results and Health [60].
audit tells us if we are doing that [1]. Clinical audit:
is a specific form of audit that involves measuring clinical
All audits are cyclical in nature (Figure 14.6) and have the
practice against standards
same key features, such as defining audit criteria to evaluate
findings against. Audits are a valuable tool for ensuring provides a framework to improve the quality of patient
care in a collaborative and systematic way
continual improvement. Many departments will have a
clinical audit programme that is developed independently should be owned by healthcare professionals. They carry
out the audit, discuss the results and then make
to the QMS internal audit programme. Whereas clinical
improvements to practice. Other forms of audit, to a
audits may focus more on outcomes, for example, the effect
greater or lesser extent, may involve someone coming in
on health or on patient experience, QMS audits aim to ver-
to audit you
ify processes, particularly at the interfaces, highlight any
should be patient focused, develop a culture of
areas of concern and identify areas for potential improve-
continuous evaluation and improve clinical effectiveness
ment. An integrated approach to both QMS and clinical
by examining patient outcomes
audits could encompass a range of audit projects and pro-
is essentially all about checking whether best practice is
vide a comprehensive audit programme.
being followed and making improvements if there are
shortfalls in the delivery of care.
Patient focused care A good clinical audit will identify or confirm any problems
and then lead to changes that should result in improved
Patient focused care is an approach to quality improve- patient care.
ment which is geared specifically to health, rather
than derived from industry [1]. It is underpinned by a phi-
losophy which puts patients at the centre of the health
service. In todays world, patients expectations have
increased [61], as too has their intolerance of failure involvement in cancer services was driven by the
or complications. Their final perception of the quality CalmanHine report [63] and then re-emphasized in
of service received will result from a comparison of their the NHS Cancer Plan [34]. At the heart of the current
expectations with their actual experience. The most com- modernization agenda is the empowerment of the cus-
mon complaints concern delays, incorrect treatment tomer or user while the hopes, fears, aspirations and
and morbidity [55], perception of professional compe- expectations of patients need to be central to decisions
tence and efficiency of process. There is a long history about their care. Current national policies make it clear
of public and patient participation in the UK [62], leading that all NHS cancer services are responsible at a local
to user involvement being at the centre of the develop- level for developing user involvement in service evalua-
ment and evaluation of services, extending from the tion, planning and delivery. In practical terms, the devel-
establishment of Community Health Councils in 1974, opment of patient and carer input can be achieved in
and including a number of the initiatives included various ways including questionnaires, complaint moni-
in Table 14.3. In particular, the development of user toring, focus groups, interviews, websites, newsletters,
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Chapter | 14 | Quality management in radiotherapy
Risk management,
e.g. complex or Customer
high risk activities, expectations
incident trends.
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Walter and Millers Textbook of Radiotherapy
Project team
Identify and review:
Current technique / technology
Alternative options
Evidence base
Implications of new tech. to all areas & staff
Potential problems / risk assessment
Set clear aims, timescales, responsibilities
and methodology
Ensure clear two way communication
with all involved
REQUIREMENTS Consider OUTPUTS
May arise from: requirements Monitor may include:
Stakeholders, e.g. PLAN Management ACT Stakeholder
& implications implementation
Purchasers / Patients Responsibility satisfaction,
& carers / Staff. Financial Audit new technique e.g. Purchasers /
National initiatives / Multidisciplinary Evaluate and Patients & carers /
recommendations. Staff, e.g. training, Resource Measurement, analyse results Staff.
Legislation. competency, Management Analysis, Continual review Increased
Evidence based role extension Improvement and improvement effectiveness /
practice (EBP) - Equipment, e.g Effective efficiency.
results of clinical additional checks. communication with Implementation
Process
audit or research. Environment all involved of EBP.
DO Management CHECK
Trust Policies. Achievement of
national targets,
e.g. waiting
Implement new technique times, clinical
or technology guidelines.
Figure 14.7 Principles of ISO 9001:2008 applied to the introduction of new techniques or technology.
developing clear guidelines as to when and how new comprehensive quality management systems. Depart-
techniques/technology may be used ments must build on what they have in place and develop
identifying and developing clear documentation a culture of continuous improvement, encouraging
detailing procedures to be used all staff to be involved. A multidisciplinary approach
a review of the number of staff and training needs. will generate service wide problem identification [2]. It
Figure 14.7 illustrates how the principles of ISO 9001 can may be argued that a QMS is costly to implement and
be applied to the safe introduction of new techniques or maintain and that there is a risk of running a system with-
technology. It is vital that attention is paid to the recurrent out addressing vital quality issues. However, if a system
themes identified in error reporting as outlined in this has management commitment and is run effectively,
chapter. For example, provision of adequate training and although it may not prevent disasters or eliminate human
assessment of competency. error [46], it will:
reduce an organizations exposure to the common
elements behind disasters
CONCLUSION ensure that an organization has systems in place to
prevent problems escalating into disaster
There is a long history of technically focused QA pro- provide the tools to react quickly to put things right
grammes in radiotherapy. However, in response to a num- reduce the risk of major errors and reduce the frequency
ber of pressures, the emphasis has shifted towards more of minor errors [2].
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Chapter | 14 | Quality management in radiotherapy
Historically, ISO 9001 has received criticism for being too are provided within the resources available. Departments
generic since it is up to the organization to set a number of with systems in place should continue to improve and
its own standards. To implement a system effectively, and develop their QMS, incorporating recommendations from:
gain the most benefit, oncology and radiotherapy depart- the investigations and reports of publicized errors
ments should implement the ISO 9001 requirements in national and international multidisciplinary working
such a way as to provide a framework which ensures an parties, such as the group set up to develop incident
integrated approach to the numerous quality standards, reporting [41], the NPSA working party developing a
targets and initiatives that they are required to fulfill. A safety package for radiotherapy and the World Health
quality management system is not just about achieving cer- Organization [65].
tification, it is to ensure that the best possible treatments
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[1] Parsley K, Corrigan P. Quality [10] IAEA Safety Report Series No 17. [17] BS EN ISO 9001. Quality
improvement in healthcare, putting Lessons learned from accidental management systems
evidence into practice. Stanley exposures in radiotherapy. Requirements. British Standards
Thornes; 1999. International Atomic Energy Institute; 2000.
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[8] Borras C. Overexposure of radiation of isocentric radiotherapy at the
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245
Intentionally left as blank
Section | 2 |
Melanoma 260
CHAPTER CONTENTS
Head and neck 260
The cancer problem 249 Lymphoma 260
Cancer in the USA 250 Leukaemia 261
Cancer in Europe 250 Reducing the risks of developing cancer 261
Epidemiology of cancer 250 Reducing tobacco smoking 263
Terminology 250 Modifying alcohol consumption 263
Survival and cure in cancer 251 Ultraviolet light 263
Outcome of palliative care 252 Occupational exposure 263
Epidemiology and the prevention of cancer 252 Diet 263
Criteria for causality 252 Ionizing radiation 265
Aetiology 253 Pollution 265
Lung cancer 253 Chemoprevention 266
Tobacco 253 Conclusion 266
Involuntary smoking 253 Further reading 266
Asbestos 254
Radon 254
THE CANCER PROBLEM
Chemoprevention 255
Colon cancer 255
In 2000, malignant tumours were responsible for 12% of
Screening 255 the nearly 56 million deaths worldwide from all causes.
Breast 256 In many countries, more than a quarter of deaths are attrib-
Screening 257 utable to cancer. In 2000, 5.3 million men and 4.7 million
Stomach 257 women developed a malignant tumour and altogether
6.2 million died from the disease. Cancer has now emerged
Screening 258
as a major public health problem in developing countries,
Prostate 258 matching its effect in industrialized nations.
Screening 258 Cancer rates could further increase by 50% from 10 mil-
Cervix 259 lion new cases globally in 2000 to 15 million new cases in
the year 2020. This increase will mainly be due to steadily
Screening 259
ageing populations in both developed and developing
Oesophagus 259 countries and also to current trends in smoking prevalence
249
Walter and Millers Textbook of Radiotherapy
and the growing adoption of unhealthy lifestyles. However, diagnoses. This has been attributed to the successful imple-
there is clear evidence that healthy lifestyles and public mentation of more effective adjuvant treatment and the
health action by governments and health practitioners increased use of mammography screening. However,
could stem this trend, and prevent as many as one third higher rates of late-stage disease exist in some population
of cancers worldwide. groups such as women who lacked health insurance and
Lung cancer is the most common cancer worldwide, recent immigrants.
accounting for 1.2 million new cases annually; followed Prostate cancer death rates have been declining since
by cancer of the breast, just over 1 million cases; colorectal, 1994, while incidence rates have increased dramatically
940 000; stomach, 870 000; liver, 560 000; cervical, 470 000; since this time. Much of the increase is due to the wider
oesophageal, 410 000; head and neck, 390 000; bladder, use of prostate specific antigen (PSA) screening rather than
330 000; malignant non-Hodgkins lymphomas, 290 000; a major increase in symptomatic disease. Colorectal cancer
leukaemia, 250 000; prostate and testicular, 250 000; pan- death rates have been declining since the 1970s with
creatic, 216 000; ovarian, 190 000; kidney, 190 000; endo- steeper declines beginning in the mid-1980s. This is prob-
metrial, 188 000; nervous system, 175 000; melanoma, ably due to improving surgical techniques and, more
133 000; thyroid, 123 000; pharynx, 65 000; and Hodgkins recently, the introduction of adjuvant treatment regimens.
disease, 62 000 cases.
In developed countries, the probability of being diag-
nosed with cancer is more than twice as high as in develop- Cancer in Europe
ing countries. However, in rich countries, some 50% of The International Agency for Research on Cancer has
cancer patients die of the disease while, in developing recently produced estimates of the number of new cancers
countries, 80% of cancer victims already have late-stage developing and the number of deaths due to cancer
incurable tumours when they are diagnosed, pointing to which are likely to have occurred in 2004. Of an estimated
the need for much better detection programmes. The main total of 2 886 800 incident cases of cancer (excluding
reasons for the greater cancer burden of affluent societies non-melanoma skin), the most common forms were lung
are the earlier onset of the tobacco epidemic, the earlier expo- (381 500 cases), colorectal (376 400 cases) and breast
sure to occupational carcinogens, and the Western nutrition (370 100 cases). Among men, the top five cancers were
and lifestyle. However, with increasing wealth and industri- lung, prostate, colorectal, bladder and stomach. Among
alization, many countries undergo rapid lifestyle changes women, the most common cancers were breast, colorectal,
that will greatly increase their future disease burden. lung, endometrium and ovary. In terms of mortality, it is
estimated there were 1 711 000 cancer deaths, with the
main causes being lung (341 800 deaths), colorectal
CANCER IN THE USA (203 700 deaths), stomach (137 900 deaths) and breast
(129 900 deaths). With nearly 3 million new cancers and
1.75 million deaths each year, cancer remains one of the
Cancer, after heart disease, is the second leading cause most important public health problems in Europe. As the
of death. One of every four deaths in the USA is due to European population ages, these numbers will increase even
cancer. It is estimated that, in 2003, 1.33 million Americans if the age-specific rates remain constant. Lung, colorectal,
would receive a new diagnosis of invasive cancer (excluding stomach and breast cancers account for nearly half of all can-
basal and squamous cell skin cancers) and over 0.5 million cer deaths in Europe and point very clearly to the priorities
Americans will die of this disease. The most common can- for cancer control action.
cers among men were prostate, lung and colorectal and While many countries, particularly in the European
among women were breast, lung and colorectal. For both Union, have seen falls in the age-standardized mortality
sexes, these cancers made up over 50% of the new cases rates for cancer over the past 20 years, there are a few nota-
diagnosed in 2000. Age-adjusted incidence rates for all ble exceptions (Greece, Spain, Portugal). Many of the
cancer sites combined were essentially stable from 1995 countries from Central and Eastern Europe exhibit increas-
through to 2000 with increases in breast cancer among ing trends with lung cancer a particular problem.
women and prostate cancer in men being offset by long-
term decreases in lung cancer among men.
The four most common cancer killers lung, breast,
prostate and colorectal all declined in the late 1990s. EPIDEMIOLOGY OF CANCER
The steep decline in lung cancer rates in men and the recent
slowing of an increase in rates in women are steps in the
Terminology
right direction and further progress will require rigorous
application of strategies known to be effective in reducing Epidemiology is the study of the occurrence, distribution
tobacco use. Death rates from breast cancer are falling and causes of disease. It can be divided into three main
despite a gradual, long-term increase in the rate of new components descriptive, analytical and experimental.
250
Chapter | 15 | Epidemiology of cancer and screening
251
Walter and Millers Textbook of Radiotherapy
An alternative method for dealing with the problem of relationship than isolated observations from single
intercurrent deaths or mortality from natural causes of studies
the patients studied is to introduce an age correction if the risk of the disease increases with the amount of
(age-corrected survival rate), which adjusts for the fact that exposure, this is considered to be a strong indication
some deaths would be expected in the cohort normally, of causality
and that this will vary with age and sex. Thus, the age- demonstration of a decline in risk after cessation of or
corrected survival rate enables direct comparisons between reduction in exposure in individuals or in whole
cohorts of patients with different age and sex distributions. populations also supports a causal interpretation
although a carcinogen may act upon more than
one target organ, the specificity of an association
Outcome of palliative care (an increased occurrence of cancer at one anatomical
Survival figures are essential for estimating the success site or of one morphological type) adds plausibility
of treatment aimed at cure but are of limited value in asses- to a causal relationship
sing the effects of palliative treatment. The main aim of where an increase in exposure in a population and an
palliative treatment is the relief of distressing symptoms. increase in the incidence of a cancer are apparent, there
Palliative radiotherapy or chemotherapy may sometimes must be a sensible latency (20 years for solid
restrain tumour growth sufficiently to prolong the patients tumours, 3 years for blood-borne cancers) between
life for a few months or sometimes years. In this case, a bet- the timings of the two increases
ter measure of survival would be the median survival time. there is evidence from animal models of a link between
This is calculated by ranking the survival times in ascending the exposure and the occurrence of the cancer
order and choosing the middle value. It is subject to the there is a biological mechanism in humans for a link
proviso that all survival times for patients still alive, which between the exposure and the cancer
are less than the middle value, are excluded and the median bias and confounding can be ruled out as possible
recalculated. explanations for the association.
252
Chapter | 15 | Epidemiology of cancer and screening
253
Walter and Millers Textbook of Radiotherapy
information collectively, in particular from those studies and never smoked, asbestos exposed and never smoked,
with a limited number of cases, meta-analyses have been con- no asbestos exposure and ever smoked and exposed to both
ducted. The excess risk of lung cancer has been identified as carcinogens. These results clearly favoured the multiplica-
being of the order of 24% and this excess could not be tive model but it has not proven to be generalizable to other
explained by chance, potential biases or confounding. More- studies. Indeed, a recent analysis of the Quebec chrysotile
over, a recent international working group of 29 experts miners and millers cohort concluded that an additive
convened by the IARC Monograph Program concluded that model provided the best fit to their data but cautioned that
second-hand smoke is carcinogenic to humans. there seems no good reason to believe that interactions
Interestingly, an association has also been shown between should conform to any simple theory.
exposure to environmental tobacco smoke (ETS) in infancy The situation with regard to mesothelioma is far simpler
and risk of lung cancer in adulthood among 60, 182 life- in that asbestos exposure is a causal factor but cigarette
long non-smokers who participated in the EPIC (European smoking is not. The disease is rapidly fatal, most of those
Prospective Investigation into Cancer and Nutrition) study. affected dying within a year of diagnosis. There is a long
With passive smoking now implicated as a cause of lung latent period between first exposure to asbestos and diag-
cancer as well as being a contributing factor in increasing nosis of mesothelioma that is seldom less than 15 years
coronary heart disease, the emphasis has now moved to and often exceeds 60 years. In all, 85% of deaths are among
what action public health policy makers should advocate men, and the risk is highest in occupations with substantial
and what legislation government should enact. The whole exposure to asbestos. Shipyard workers have been a partic-
of the UK and Ireland have imposed bans on smoking in ularly susceptible group in that considerable exposures were
enclosed workspaces to protect the health of workers and to be found during the 1940s, 1950s and into the 1960s
a number of other countries are actively considering or when ships were being repaired and the merchant fleet
recommending legislation. One of the additional benefits was being rebuilt after the World War II. Incidence rates
of such restrictions has been a reduction in the rate of of mesothelioma in Clydebank, one of the main centres
active smoking among the population at large. of shipbuilding in Scotland, reached such a peak in the early
1990s that it registered as the fourth most common male
cancer in the local population.
Asbestos While mesothelioma is almost exclusively due to inhala-
It has been known for many years that exposure to asbestos tion of asbestos fibres, it is of note that, in specific areas
is a major cause of lung cancer. In 1999, a meta-analysis of of Turkey, a high incidence of mesothelioma has been
69 cohort studies found a standardized mortality ratio observed in conjunction with environmental exposure to
(SMR) of 163 for lung cancer, but a substantial heterogene- erionite. Erionite occurs as a fibrous component of some
ity existed largely attributable to the different cumulative zeolite deposits and has been identified as a component
exposure to asbestos in various cohorts. These cohorts com- of soil and building materials in these areas.
prised workers from a variety of industries mining, textile With asbestos clearly established as an occupational
and manufacturing, insulation, asbestos-cement factories carcinogen, more interest surrounds the issue of whether
and shipyards and risk was closely related to level of expo- domestic or environmental exposure poses an increased
sure in the different industries. Type of asbestos was also risk. Domestic exposure and increased risk has been observed
observed to be relevant, with chrysotile fibres being consid- among the wives of South African Cape miners who
ered less carcinogenic than amphiboles. brought home contaminated working clothes for cleaning.
Asbestos dust and cigarette smoke are both causes of Air pollution from asbestos mines and factories does repre-
lung cancer. What is less clear is the effect of the combina- sent exposure. Fibre concentrations in the lungs of (non-
tion of the two carcinogenic agents. Initially, two hypoth- mining) residents near the chrysotile mines in Quebec
eses existed about the way asbestos and cigarette smoking are up to 10 times higher than the average Canadian. The
interact. In one, it is assumed that asbestos produces the critical question is whether this level of exposure represents
same additional risk in men who smoke cigarettes as an increased risk of the disease. The answer to this question
in those who do not (additive hypothesis); in the other, is almost certainly yes as there appears to be no evidence
it is assumed that asbestos produces an effect that is pro- that a threshold level exists below which there is no (excess)
portional to the effect of the other agent (multiplicative risk of mesothelioma. There might exist a background level
hypothesis). The additive hypothesis explains the data less of mesothelioma occurring in the absence of exposure
well than the second, but the fit to the latter is not par- to asbestos, but there is no proof of this and this natural
ticularly convincing. Until recently, no other hypotheses level is probably lower than 1 case/million/year.
have been considered even though the multiplicative
hypothesis is just one of infinitely many putative forms
of synergism. Radon
One often quoted study by Hammond et al estimates Underground miners exposed to radioactive radon and its
relative risks of 1, 5, 11 and 53 for no asbestos exposure decay products have been found to be at an increased risk
254
Chapter | 15 | Epidemiology of cancer and screening
of lung cancer. Indoor exposure to radon has been asso- energy. Thus, dietary associations with colon cancer are
ciated with a marginal increase in risk of lung cancer. characterized as typical of the western diet, without being
able to tie in any specific components. The recurring prob-
lem has been to explain the association of colon cancer
Chemoprevention
with a disparate group of dietary and lifestyle factors.
Chemoprevention is defined as the reduction of the risk of More recently, epidemiological studies have started to
cancer development through the use of pharmaceuticals or demonstrate a close association between colon cancer risk
micronutrients. There has been consistent evidence that and evidence of insulin resistance. Insulin resistance is a
high intake of fruit and vegetables is associated with some condition in which higher levels of insulin are needed to
reduction in risk of lung cancer. Thus, it has been suggested dispose of plasma glucose, and it is associated with an
that micronutrients and macronutrients present in our diet increased risk of type 2 diabetes. The mechanism begins
may act as cancer inhibiting substances. Epidemiological with the excess dietary energy provided by the high-risk
studies have verified that B-carotene is inversely related diet. This excess energy elevates the intravascular levels of
to lung cancer risk and a number of randomized controlled insulin and energy substrates. The excess hormone expo-
intervention trials have been undertaken. The settings have sure and excess energy available to epithelial cells stimulate
varied but the largest trials have targeted high-risk smokers cell signalling pathways to increase the proliferation, pre-
(ATBC study, Physicians Health Study) or asbestos workers sumably favouring cells with defective cell cycle control.
(CARET study). None of these trials showed a reduction in Also, agents are now being identified that significantly
lung cancer incidence or mortality, and two of them even inhibit experimental colon carcinogenesis. The following
suggested an increased risk, albeit small. Clearly, our under- mechanism has been proposed: focal loss of epithelial bar-
standing of the mechanism by which relatively short-term rier function resulting from a failure of terminal differenti-
intake of retinoids and carotenoids affects the development ation results in the leak of an undefined toxin and a local
of cancer in large populations is insufficient to use this inflammatory response characterized by evidence of the
approach as a specific lung cancer control procedure. activation of the COX-2 enzyme and an oxidative stress with
the release of reactive oxygen intermediates. The resulting
focal proliferation and mutagenesis give rise to aberrant
Colon cancer
crypt foci and adenomas.
Incidence rates for cancer of the colon vary greatly across These two mechanisms, insulin resistance acting through-
the world. High rates are found in some states in the out the body and focal epithelial barrier failure acting
USA, Australia and Argentina. Incidence rates in northern locally, can describe most of the known relationships
and western Europe are generally somewhat lower. In between diet and colon cancer risk.
developing countries, incidence rates are substantially While the vast majority of colon cancer cases occur spo-
lower. Studies of migrants suggest that environmental fac- radically in the general population, a number of specific
tors rather than ethnic or genetic factors play a major role in disease groups Crohns disease, ulcerative colitis and
its aetiology. Most studies have involved migrants moving familial polyposis are subject to increased risks. For exam-
from low-risk to high-risk areas, such as Chinese and ple, colorectal cancer in ulcerative colitis only accounts for
Japanese to Hawaii or the rest of the USA, or southern 1% of all colorectal cancer cases, it accounts for one-sixth of
Europeans to North America or Australia. In general, the all deaths in ulcerative colitis patients. The overall preva-
risk in migrants approximates that of the new country with lence of colorectal cancer in any ulcerative colitis patient
rates increasing with increasing duration of stay, presum- is estimated to be 3.7%. However, there is general agree-
ably as their lifestyles merge with that of the host country. ment that the colorectal cancer risk is highest in those with
Over time, the incidence of colon cancer has been rising, extensive disease of long duration. Overall, incidence rates
slowly in high-risk areas but more rapidly in areas where build to cumulative probabilities of 2% by 10 years, 8% by
the risk was formerly low. These changes have been accompa- 20 years and 18% by 30 years.
nied by changing ratios between the subsites within the colon
at which tumours occur, with left-sided tumours (of the des-
cending and sigmoid colon) becoming more frequent. Screening
Risk of colon cancer is closely related to diet and other Colorectal cancer is one of the few internal cancers that are
lifestyle factors. International comparisons have suggested amenable to secondary prevention, that is, prevention by
increased risks with increased intakes of dietary fat and a detection of preclinical lesions. The precursor of advanced
decreased intake of cereal grains and dietary fibre. Analyti- colorectal cancer is either an adenomatous polyp or a
cal studies within populations have shown a deficiency of flat neoplastic area. In order to prevent premature death,
vegetables and fruits and a sedentary lifestyle as being asso- people aged 5069 years are the main focus of attention.
ciated with an increased risk. However, attempts to identify Screening by the fecal occult blood test (FOBT) is
independent roles for specific macronutrients have proved currently considered the optimal screening strategy in
unsuccessful, with the exception of over-consumption of terms of cost-effectiveness. FOBT identifies persons at risk,
255
Walter and Millers Textbook of Radiotherapy
though falling short of being definite for cancer. In general, time and it may well be that pre-menopausal and post-
the test is positive in about 2% of those screened. The sen- menopausal breast cancer should be considered as two
sitivity of the test is around 50% for cancer (i.e. of all separate diseases in etiological terms.
screened persons who have cancer, 50% will be detected) Reproductive factors have been consistently related to
and around 10% for polyps. The predictive value of a posi- (post-menopausal) breast cancer in that early age at first
tive test is around 10% (i.e. out of 10 persons with a full-term pregnancy and high parity are associated with
positive test, only one will have cancer). lower levels of the disease. Furthermore, risk is increased
Endoscopy, using either the flexible sigmoidoscope or in women who have early menarche or who have late men-
the colonoscope is the most definitive means of detection opause. Obesity, related to various alterations in plasma
but has limitations. The major weakness is the limited levels of total and bioavailable sex steroids, is also a strong
reach of the former (somewhere between the sigmoid risk factor. As circulating levels of sex steroids are regulated
colon and the splenic flexure). The colonoscope permits by a range of factors, including insulin and insulin-like
exploration of the colon with a low false negative rate for growth factors, this may provide the link between many
polypoid lesions of at least 10 mm in diameter. However, observations regarding excessive energy intake and increased
patient compliance is poor, the cost of the procedure is risk of cancer.
high and perforation is an acknowledged morbidity which, The oestrogen excess hypothesis stipulates that risk
although uncommon, may be of consequence in large depends directly on breast tissue exposure to oestrogens.
series. Oestrogens increase breast cell proliferation and inhibit
FOBT has been assessed in randomized trials. In two apoptosis in vitro and, in experimental animals, cause
European, population-based, trials conducted in the UK increased rates of tumour development when oestrogens
and Denmark with a biennial non-rehydrated FOBT, the are administered. This theory is consistent with the epide-
compliance was about 60%, about 4% of individuals tested miological evidence showing an increase in breast cancer
underwent colonoscopy and the reduction in mortality was risk in post-menopausal women who have low circulating
about 15%. Screening by sigmoidoscopy has been evaluated sex hormone-binding globulin and elevated total and
in case-control studies. Less compliance has been observed bioavailable oestradiol.
but a higher yield of detection with mortality reductions Two developments in the second half of the 20th cen-
of up to 50% being claimed with good compliance. tury, the oral contraceptive pill and hormone replacement
Options for population based screening in countries therapy (HRT), have impacted on the risk of breast cancer.
with high rates of colorectal cancer include: annual Oral contraceptives, in the form of oestrogenprogestogen
FOBT, biennial FOBT, annual FOBT sigmoidoscopy combinations, were introduced in the early 1960s and
every 5 years, sigmoidoscopy every 5 years, colonoscopy rapidly found widespread use in most developed countries.
every 10 years, and colonoscopy once in a lifetime. Cost Preparations of oral contraceptives have undergone substan-
and compliance will be the major determining factors. tial changes over time, reducing the potency of the oestro-
gens, adding in different progestogens and using biphasic
and triphasic pills. A small increase in risk has been observed
Breast
in current and recent users of combined oral contraceptives
The majority of cancers exhibit a consistently increasing (a relative risk of about 1.2), but this association is
rise in incidence rates with age. Breast cancer is one of a unrelated to duration of use or type and dose of prepara-
number which do not adhere to this rule, highlighting tion, and 10 years after cessation of use, the excess risk dis-
the fact that the frequency of a disease is a function of appears. Causation has not been clearly established and
duration of exposure rather than age per se. Among pre- one suggestion has been that it could be the result of detec-
menopausal women, incidence rates steeply with age. tion bias due to the increased attention to the occurrence
For those women in their fifties, the incidence rate remains of breast abnormalities in women regularly visiting their
relatively steady (sometimes referred to as Clemmensens doctor for contraceptive prescriptions.
hook) and thereafter starts to rise again but at a much HRT is used to treat the symptoms of menopause
less steep gradient than is observed for pre-menopausal and, during the 1990s, up to one-third of all menopausal
women. The examination of the shape of age-specific inci- women in the USA and many European countries used
dence curves can give indications as to causal factors, par- HRT for some period. A small increase in breast cancer risk
ticularly those that change over a persons lifetime, such as is correlated with longer duration of oestrogen replacement
hormonal factors. Thus, for breast cancer it would seem to therapy use in current and recent users. The increase seems
indicate that the factors related to pre-menopausal breast to cease several years after use has stopped. Initially, there
cancer may well be different to those which cause post- appeared to be no difference in breast cancer risk between
menopausal breast cancer. Add to this the observation that long-term users of all hormone replacement therapy and
the incidence of pre-menopausal breast cancer has users of oestrogens alone, although two recent studies have
remained stable over time while post-menopausal breast suggested that HRT may pose a greater risk than oestrogens
cancer rates have been slowly, but steadily increasing over alone.
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Chapter | 15 | Epidemiology of cancer and screening
A second oestrogenprogestogen hypothesis postulates pathway for breast cancer generally. Now, designated surgical
that compared to an exposure to oestrogens alone (as in units provide specialist expertise to manage breast cancer,
post-menopausal women not using any exogenous hor- particularly those women with impalpable tumours, and
mones), risk of breast cancer is increased further in women pathologists and oncologists with a special interest in breast
who have elevated plasma and tissue levels of oestrogens cancer and clinical nurse specialists combine to form a mul-
in combination with progestogens. This theory is supported tidisciplinary team for the management of the disease.
by observations that post-menopausal women using The effectiveness of routine national breast screening
oestrogen-plus-progestogen preparations for HRT have a programmes has been questioned. There is general agree-
greater increase in risk than women using oestrogens alone. ment that the extent of the reduction in mortality has been
lower than that experienced in the trial situation. Under
optimal conditions with a high compliance rate, a mortal-
Screening ity reduction of 20% appears achievable. In reality, this
No practical strategies exist which can be recommended for may be more in the region of 1015% on current data.
the prevention of breast cancer and so considerable effort One of the major problems in trying to assess the reduction
has been aimed at developing methods of early detection. in mortality due to screening now is that other factors
Mammography can detect preclinical cancer, that is, before it have come into play, which were not operating at the
is palpable or before it causes symptoms. Tumours detected time when the trials were being conducted. Before the
and treated at an early stage would be expected to be late 1980s, no decline in mortality had been seen, but then
associated with a better survival rate than those detected a smooth downturn occurred in Europe, North America
symptomatically. However, as some breast cancers are char- and Australia. These changes accelerated in the early 1990s
acterized by early systemic dissemination, the actual effec- but the fall occurred too soon after the widespread avail-
tiveness of screening is not at all clear. In this context, a ability of mammography to be a consequence of it. More
number of large randomized trials were undertaken to eval- likely, the success of adjuvant therapy based on tamoxifen
uate its effectiveness on a population basis. The analysis of and chemotherapy was the major cause of this trend.
these trials has shown that in women aged 50 to 69 years, Thus, the concurrent changes in improved adjuvant ther-
mammography screening can reduce mortality from breast apy, better and more focused surgical services, protocol
cancer by 2530%. For women in the age group 4049 driven management and a better awareness of breast cancer
years, screening efficacy is significantly less. and its symptoms among the general population make it
The only true measure of success of a screening programme almost impossible to isolate the contribution that breast
is an associated reduction in mortality. Survival rates can screening is now making. However, there is no denying
theoretically improve without extending length of life the fact that more women are being diagnosed with smaller
by the simple expedient of bringing forward the date of tumours and consequently can safely be offered conserva-
diagnosis while the date of death remains the same. This tion surgery rather than radical mastectomy.
is known as lead-time bias. Analysis of trial data suggests
that screening brings forward the date of diagnosis by an
Stomach
average of about 3 years, but this will vary considerably
on an individual basis depending on how long the tumour On a global scale, mortality from stomach cancer is second
remains in the screen-detectable phase. This raises a sec- only to lung cancer. The areas with the highest incidence
ond phenomenon known as length-time bias. The argument rates are in Eastern Asia, the Andean regions of South
is based on the well-founded assumption that tumours America and Eastern Europe. There is marked geographical
grow at varying speeds in different women. Slow-growing variation in incidence between countries and among differ-
tumours will therefore remain in the screen-detectable win- ent ethnic groups within the same locale. Migration studies
dow for longer than fast-growing tumours. Hence, a screen- show that the risk of cancer changes within two generations
ing programme will tend to pick up slow-growing tumours when people move from high-incidence to low-incidence
disproportionately more than fast-growing tumours. If slow- areas. For example, Japanese immigrants to the USA retain
growing tumours are also more amenable to cure then sur- their original risk, whereas subsequent generations share
vival rates will tend to be artificially inflated as they will tend the incidence of the host country. No matter what level
to include a larger proportion of better prognosis tumours. of incidence, there has been a general decline worldwide.
A sizeable number of developed countries have now In most European countries, it has fallen by more than
established national or subnational screening programmes. 60% during the past 50 years.
Eligible age ranges vary, the repeat interval varies, some use Dietary risk factors include inadequate intake of fresh
single view mammography, others use two view and inde- fruits and vegetables, high salt intake and consumption
pendent double reading of mammograms is recommended of smoked or cured meats or fish. There is good evidence
but not always adhered to. One of the side effects of the that refrigeration of food also protects against this cancer
introduction of national breast screening programmes has by facilitating year-round consumption of fruit and vegeta-
been the necessity to overhaul the referral and management bles and probably by reducing the need for salt as a
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Walter and Millers Textbook of Radiotherapy
preservative. Vitamin C, contained in vegetables and fruits of many of the risk factors proposed suggests a significant
and other foods of plant origin, is probably protective and role for geneticenvironmental interactions in determining
so too are diets high in whole-grain cereals, carotenoids patterns of disease. The role of hormones, particularly andro-
and allium compounds. gens, is obviously important given the impact of orchidectomy
Conditions that cause an excessive rate of cell prolifera- on progression. Genetic polymorphisms in the androgen
tion in the gastric epithelium, thus increasing the chance of receptor may be more important than any imbalance of
fixation of replication errors induced by dietary and endog- hormones in the circulation. A diet characteristic of Asian
enous carcinogens, include Helicobacter pylori infection, countries, essentially a low fat intake with consequent low
gastric ulcer, atrophic gastritis and autoimmune gastritis body weight and an intake of relatively high levels of phytoes-
associated with pernicious anaemia. Gastritis is associated trogens, may provide the means of restraining the growth
with increased production of oxidants and reactive nitro- and progression of prostate cancer. A strategy for prevention
gen intermediates, including nitric oxide. There is increased would be to increase the intake of phytoestrogens, essentially
expression of the inducible isoform of nitric oxide synthase isoflavonoids, lignans and possibly certain flavonoids.
in gastritis. Gastritis and atrophy alter gastric acid secretion,
elevating gastric pH, changing the gastric flora and allowing
anaerobic bacteria to colonize the stomach.
Screening
Secondary prevention of prostate cancer is feasible, but is
Screening subject to controversy, since the capacity to detect early dis-
ease must inevitably result in the overtreatment of some
About 80% of western patients with stomach cancer present
individuals with substantial costs to society in exchange
with advanced tumours. Screening for early disease by x-ray
for decreased mortality. PSA testing is widely used for the
(photofluoroscopy), followed by gastroscopy and biopsy of
early detection of prostate cancer. Elevated levels of PSA
suspicious findings, has been widely used in Japan since the
are closely, but not definitely, associated with the presence
1960s. It is a costly approach to prevention and the results
of a tumour. Using a cut-off level of 4 ng/ml for normality,
have been controversial. With the background incidence
25% of patients diagnosed with prostate cancer will have
now falling substantially, screening has not been consid-
levels below this value. Of men with moderately raised
ered as a national priority in most other countries.
levels (410 ng/ml) 25% will have cancer but this rises
to 60% when PSA levels are greater than 10 ng/ml.
Prostate
In order to improve the sensitivity of the PSA analysis,
Prostate cancer is the third most common cancer in men in it should be combined with a digital rectal examination.
the world. In the majority of developed and developing This will provide an assessment of the volume of the gland
countries, prostate cancer is the most commonly diagnosed since PSA is also released into the bloodstream of patients
neoplasm affecting men beyond middle age. In recent with benign prostate hyperplasia and other prostatic dis-
times, incidence rates of prostate cancer have been influenced eases. Additionally, different age-specific reference values
by the diagnosis of latent cancers whose presence has been for the cut-off threshold are of value 2.5 ng/ml for age
suggested by screening of asymptomatic individuals. In the group 4049 years and 3.5 ng/ml for age group 5059 years.
USA, for example, the introduction of screening using Any patient who asks for a PSA test should be counselled
prostate-specific antigen (PSA) testing has led to an enor- about the risks and benefits in relation to the procedure
mous increase in the diagnosis of prostate cancer, making and its outcome.
it by far the most commonly diagnosed cancer in men. Some national authorities have recommended screening
The distribution of mortality rates is less affected than for the detection of prostate cancer, starting at the age of
incidence by the effects of early diagnosis of asymptomatic 50 for men with at least a 10-year life expectancy. A slight
cancers and is thus a more reliable way of comparing rates but definite decrease in mortality has been observed in
of the disease. High rates are found in North America, countries where PSA has been widely used in screening dif-
northern and western Europe, Australia/New Zealand and ferent cohorts of men, although the reason for the decrease
the Caribbean. The difference between China and the USA in mortality has become a major subject of controversy.
is 26-fold and, within the USA, black populations have The general expectation that the earlier detection of pros-
higher rates than white, who in turn have rates considerably tate cancer inevitably provides a unique chance for cure
higher than populations of Asian origin. has to be balanced against the clear prevalence of over-
The causes of prostate cancer are not well understood. diagnosing a disease which may never become symptom-
Development of this malignancy is a multistep process asso- atic during a mans lifetime.
ciated with a long natural history. The initiation of pre- Ultimately, resolution of the true benefit of screening
neoplastic lesions and microscopic cancer is probably influ- will only be achieved on the basis of the results of large
enced by environmental factors which implies a case for life- randomized controlled trials. One such trial in Europe
style causes and primary prevention. The strong association has recruited 180 000 men randomized between diagnosis
of race, familial and geographic patterns and the weak link and treatment in screened men versus controls. In the USA,
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Chapter | 15 | Epidemiology of cancer and screening
74 000 men have been enrolled in a trial of screening screening programmes using the Pap smear were initiated
for prostate, colorectal and other cancers. Collaboration in British Columbia in 1949 and in regions of Norway in
has led to the development of the International Prostate 1959 and Scotland in 1960. Since then, programmes based
Screening Trial Evaluation Group which will provide a on the Pap smear have been introduced in many developed
sound basis for the scientific evidence to decide on the countries.
merit of large population-based screening programmes. No randomized trials have ever been performed to
assess the efficacy of such a method of cervical screening.
The main evidence is indirect, being based on the trends
Cervix in the incidence of, or mortality due to, cervical cancer
Cancer of the cervix is the second most common cancer in relation to screening intensity and the risk of cervical
among women worldwide with about 470 000 new cases cancer in individuals in relation to their screening history.
diagnosed each year. Eighty percent of cases of cervical can- Nationwide programmes were established in Finland, Ice-
cer occur in developing countries where, in many regions, land and Sweden; in Denmark, programmes covered about
it is the most common cancer of women. The highest 40% of the female population and in Norway only 5%.
incidence rates are in South America and the Caribbean, In Iceland, cervical cancer mortality fell by 80% between
sub-Saharan Africa, and South and South-Eastern Asia. 1965 and 1982, compared with 50% in Finland, 34% in
Incidence and mortality have declined markedly in the Sweden, 25% in Denmark and 10% in Norway. More
last 40 years in western Europe, USA, Canada, Australia recently, the effect of cytologic screening on the incidence
and New Zealand, mainly in relation to extensive screening of cervical cancer has been examined in 17 populations cov-
programmes based on exfoliative cervical cytology, typically ered by cancer registries between the early 1960s and late
by means of the Pap smear. Nevertheless, in several 1980s. Compared with the time before the introduction of
countries, notably the UK, Australia, New Zealand, and in screening, the age standardized incidence rates decreased
central Europe, there have been increases in risk in younger by at least 25% in 11 of the 17 populations, with the largest
women, probably the result of changes in exposure to risk effect occurring in the 4555 year age groups.
factors. These changes are most evident for adenocarcino-
mas, which share to some extent the same aetiological Oesophagus
agents of squamous cell carcinomas, but for which cytologi-
cal screening is ineffective in countering the increase in risk. Cancer of the oesophagus is the sixth most frequent cancer
Molecular studies have shown that certain human papil- worldwide. About 412 000 new cases occur each year, of
lomavirus (HPV) types are the central cause of cervical can- which over 80% are in developing countries. While squa-
cer and cervical intraepithelial neoplasia (CIN), the pre- mous cell carcinomas occur at high frequency in many
invasive state. It is now clear that the well-established risk developing countries, adenocarcinomas are essentially a
factors associated with sexual behaviour, such as multiple tumour of more developed, industrialized countries. Dif-
sexual partners and early age of starting sexual activity, ferences between the incidence of oesophageal cancer in
simply reflect the probability of being infected with HPV. distinct geographical areas are more extreme than observed
HPV DNA has been detected in virtually all cervical cancer for any other cancer. An oesophageal cancer belt in Asia
specimens. The association of HPV with cervical cancer is stretches from northern Iran through the central Asian
equally strong for the two main histological types: squa- republics to Henan province in north-central China. Inci-
mous cell carcinoma and adenocarcinoma. Over 100 HPV dence rates are as high as 200 per 100 000 per year and,
types have been identified and about 40 can infect the gen- in some areas, there is a female predominance. In Europe,
ital tract. Fifteen of these have been classified as high-risk, high rates occur in Normandy and Brittany in France and
three as probably high-risk and twelve as low-risk. How- in the north-east of Italy. In these areas, high rates occur spe-
ever, since only a small fraction of HPV-infected women cifically in males.
will eventually develop cervical cancer, there must be other Consumption of tobacco and alcohol, associated with
exogenous or endogenous factors which, acting in conjunc- low intake of fresh fruit, vegetables and meat, is causally
tion with HPV, influence the progression from cervical associated with squamous cell carcinoma of the oesopha-
infection to cervical cancer. In assessing of the role of these gus worldwide. In developed countries, about 90% of the
co-factors, it should be recognized that HPV is very much squamous cell cancers are attributable to tobacco and alco-
the dominant effect. Co-factors which have been identified hol, with a multiplicative increase in risk when individuals are
as being associated with an increased risk include high par- exposed to both factors. Risk factors for oesophageal cancer in
ity, smoking and long-term use of oral contraceptives. developing countries vary by region, with oral consumption
of opium by-products an important factor in the Caspian
Sea area, betel chewing in South-East Asia, drinking of scalding
Screening hot beverages, such as mate, in South America and environ-
By far the best-established screening method for cervical mental factors including nitrosamines, contamination with
cancer is the Papanicolaou (Pap) smear. Population-based fungi and deficiency of vitamins A and C in parts of China.
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Walter and Millers Textbook of Radiotherapy
Lymphoma
Head and neck Lymphoma covers a heterogeneous group of neoplasms of
Cancers of the oral mucosa and oro- and hypopharynx can lymphoid tissue. Traditionally, lymphomas have been cate-
be considered together, as there are similarities in epidemi- gorized as either Hodgkins disease (HD) or non-Hodgkins
ology, treatment and prognosis. The geographic patterns lymphoma (NHL), these distinct entities having different
and trends in incidence for these cancers vary depending patterns of behaviour and response to treatment.
upon the anatomical subsites concerned, a phenomenon Geographically, NHL is most common in developed
that is often explicable by the influence of risk factors, such countries (52% of the total cases globally, and the seventh
as tobacco use and alcohol consumption. A high incidence most common cancer in more developed countries),
of these cancers is observed in the Indian subcontinent, although in the developing world, there are areas of
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Chapter | 15 | Epidemiology of cancer and screening
moderate to high incidence in some Middle-Eastern Leukaemia has a peak in incidence in the first four years of
countries (Saudi Arabia, Israel) and in parts of sub-Saharan life, which is predominantly due to acute lymphoblastic
Africa. Much of the latters high rate is due to the high leukaemia (ALL), the most common paediatric malignancy,
incidence of Burkitts lymphoma, an aggressive subtype accounting for nearly 25% of all such disease. After infancy,
of NHL. there is a steep decline in rates of leukaemia with age, lowest
NHL incidence rates have risen dramatically in the last incidence being at 15 to 25, after which there is an expo-
20 years, particularly in developed countries, including west- nential rise up to age 85.
ern Europe, North America and Australia. In part, this The usual form of the disease in adults is acute myeloid
reflects better diagnosis and changing classification systems. leukaemia (AML), accounting for 70% of all cases. The
However, this is by no means the complete explanation. more differentiated, or chronic forms of leukaemia are pre-
Also, the fact that NHL is a complication of AIDS (occurring dominantly adult diseases, rarely occurring below the age
in up to 510% of AIDS cases in developed countries) does of 30, and then increasing progressively in incidence with
not completely account for the increasing trend. In contrast age. Chronic myelogenous leukaemia (CML) accounts for
to incidence, mortality rates have, in general, been declining 1520% of all case of leukaemia. For patients over 50,
as a consequence of improvement in therapy. chronic lymphocytic leukaemia (CLL) is the dominant type
In developed countries, HD incidence reaches a peak of leukaemia.
in young adults, whereas in developing countries, HD The cause of most leukaemias is not known. A range of
occurs mainly in children and in the elderly. In developed risk factors has been predominantly, although not exclu-
countries, incidence has fallen over the last 20 years. sively, associated with particular leukaemia subtypes. Ion-
Patients with HIV/AIDS or who have received immuno- izing radiation (nuclear bombs, medical procedures), and
suppressant therapy have a higher risk of developing NHL. occupational exposure to benzene are associated with acute
Viral infection such as HIV-1, HTLV-1, and Epstein-Barr myeloid leukaemia.
virus (EBV) are also associated with NHL. Infection of the Leukaemia (mainly acute myeloid) may occur in a small
stomach with Helicobacter pylori is associated with gastric proportion of cancer patients treated with chlorambucil,
lymphoma. There is also an increased risk of NHL among cyclophosphamide, melphalan, thiotepa, treosulphan or
persons with a family history of lymphoma or haematologi- etoposide, as well as certain combination chemotherapy.
cal cancer. Leukaemia has followed induction of aplastic anaemia
A subtype of HD cases, the mixed cellularity type, has by the antibiotic, chloramphenicol. Certain risk factors,
been linked to the EBV. Overall, around 45% of cases such as Downs syndrome, have been identified for child-
may be attributable to EBV. The presence of EBV in tumours hood leukaemia but, generally, the causes of the disease
seems also to be related to age and socioeconomic cir- are not known. Some studies have shown a risk of child-
cumstances. EBV is involved in the aetiology of Burkitts hood leukaemia with exposure to high-level residential
lymphoma, especially in cases in tropical Africa, where over extremely low frequency electromagnetic fields, but causal-
95% of tumours contain the virus. The proportion of EBV- ity has not been established.
positive tumours is much less in the sporadic cases of HD Infection with the virus HTLV-1 has been established as a
occurring in Europe and North America. The singular cause of leukaemia. This virus is responsible for adult T-cell
geographic distribution of Burkitts lymphoma is not expli- leukaemia, a disease mainly observed in tropical countries
cable on the basis of EBV alone, however, since infection by and Japan, and rarely in the USA and Europe. In experi-
the virus is ubiquitous, suspicion has fallen upon intense mental animals, particularly in mice, there are many retro-
malarial infection as predisposing to Burkitts lymphoma viruses, which can cause a variety of leukaemias, but such
in the presence of EBV infection. The risk of HD is also retroviruses have not been identified in humans.
increased in patients with HIV infection.
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Walter and Millers Textbook of Radiotherapy
Diet Rich in animal fat and protein, Colon, breast, prostate and 30%
low in fresh fruit and vegetables endometrium
Obesity and sedentary lifestyle
contributing factors
Chronic infections
Epstein-Barr virus (EBV) Lymphoma and
nasopharynx cancer
Human papilloma virus Cervix and oropharynx 20%
(HPV)
Hepatitis B and C Liver
Schistosomiasis Bladder
Helicobacter pylori Stomach
Food contamination
Aflatoxins Liver Varies up to 20% in hot/
humid parts of the world
Pesticides Pancreas, breast,
lymphoma/leukaemia
Pollution of air, water Arsenic in water Lung Varies
and soil Asbestos, specific Skin 14 %
Pollutants such as Bladder
benzopyrene, engine
exhaust Tobacco smoke
Medicinal drugs
Hormones, cytotoxic Kidney, bladder Leukaemia
chemotherapy
Phenacetin Uterus, breast
Sunlight
Ultraviolet radiation Melanoma and Skin cancer Up to 80% of all cases of
non-melanomatory melanoma
Occupation See Table 15.2 45%
Ionizing radiation See Table 15.3
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Chapter | 15 | Epidemiology of cancer and screening
The EC has produced a 10-point code for the general be expected. The principal culprits are the chlorofluorohydro-
public, summarizing the ways in which certain common carbons (CFCs). These are components in, for example,
cancers can be prevented. aerosol sprays, refrigerants, and solvents for cleaning elec-
tronic equipment. However, to put the contribution of
commercial sources of CFCs into context, one volcano in
Reducing tobacco smoking Antarctica emits 100 tons of chlorine every month, sub-
Every country should give high priority to tobacco control stantially more than the combined output of CFCs from
in its fight against cancer. Unchecked, smoking will cause deodorants over the same period. Nitrogen oxides from
more than 10 million deaths from cancer (mostly lung can- vehicle exhaust fumes also deplete the ozone layer. Interna-
cer) in the next decade. tional agreements have been reached, aimed at eliminating
The UK Government has made health warnings manda- the use of CFCs.
tory on commercial tobacco products and on advertise-
ments for tobacco. To achieve substantial reductions in Occupational exposure
tobacco consumption, additional measures will be required.
These could include banning advertising of tobacco, its A wide variety of occupations are known to carry the risk of
consumption in public places and working environments, exposure to carcinogens. However, they only represent
increasing taxation on tobacco, reducing tar content in cigar- a relatively small number of cases of cancer deaths (4%
ettes and setting up clinics for smokers to help them break in the USA). In 1987, 246 agents were classified by the
the habit. International Agency for Research on Cancer as definitely
There is a great need for effective and carefully evaluated (50), probably (37) or possibly (159) carcinogenic to
school education programmes which include tobacco humans. These included industrial processes, industrial
abstinence as a major goal. chemicals, pesticides, laboratory chemicals, drugs, food
ingredients, tobacco smoking and related stimulants.
Drugs and industrial chemicals represent the largest risks.
Modifying alcohol consumption There are many other occupations where an agent is
thought to be carcinogenic to workers but a causal link
After smoking, alcohol is the second most important cause
has not been established. Some of the known occupational
of cancer. It may be responsible in some countries for up to
hazards are listed in Table 15.2. Of these, exposure to asbes-
10% of deaths from cancer. Cancers of the mouth, larynx,
tos dust, aromatic amines and the products of burning
pharynx, oesophagus and liver are certainly caused in part
fossil fuels are the commonest. Measures to prevent occu-
by alcohol. It probably has a role in the aetiology of some
pational exposure include labelling of products as carcino-
breast and rectal cancers. For several tumours, the risk rises
genic, and prohibiting the marketing and use of certain
with the quantity consumed to more than tenfold for life-
substances, e.g. the four aromatic amines (naphthylamine,
long non-drinkers. Alcohol and tobacco smoking act as
4-aminobiphenyl, 4-nitrodiphenyl and benzidine) and
synergistic carcinogens (i.e. the combined effect is greater
blue asbestos (crocidolite).
than that of either alone). This combination accounts for
It is thought that preventive methods are likely to have
the very high incidence of these tumours in France, where
little impact on the mortality from occupational cancers
they are often multifocal. Alcohol probably acts as a co-
in the near future. The detection of tumours at an early
carcinogen rather than a carcinogen (i.e. it promotes rather
stage by screening is likely to have a greater effect on mor-
than initiates carcinogenesis). Spirits may have a slightly
tality. Screening of urine by cytology among workers in the
stronger carcinogenic effect than other alcoholic beverages.
dyestuff and rubber industries has long been practiced.
Any policy on moderating the consumption of alcohol
has to take account of a number of facts. First, many people
find it pleasurable. Secondly, moderate amounts (23 units Diet
per day) protect against coronary thrombosis, though Diet influences carcinogenesis in a variety of ways: carcino-
heavy drinking has other undesirable social consequences gens may be eaten; food substances may be converted to
(e.g. violent behaviour and road accidents). Thirdly, its car- carcinogens once ingested; and dietary components may
cinogenic effects are largely in conjunction with smoking modify the ways in which the body metabolizes and
tobacco. Thus, the risk of cancer induction by alcohol in responds to carcinogens. The only component of food that
non-smokers is relatively small. has been found to be strongly linked to the development of
cancer is aflatoxin. This is a product of the fungus Aspergillus
fumigatus, which often contaminates damp cereals in tropi-
Ultraviolet light
cal countries. It causes primary liver cancer, although the
Exposure to ultraviolet light has been increasing with the data are unclear since there is a high incidence of hepatitis
reduction of the ozone layer, caused by chemical pollution. B, itself associated with liver tumours, in the same group of
An increase in the incidence of all forms of skin cancer can patients.
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Walter and Millers Textbook of Radiotherapy
Table 15.2 International Agency for Research on Cancer (IARC) Class I, Occupational carcinogenesis (strong evidence of an
association with human cancer)
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Chapter | 15 | Epidemiology of cancer and screening
Bracken fern containing nitrates is suspected of causing occupants to 20 mSv per year. The lifetime risk of fatal
oesophageal cancer, particularly among the Japanese. cancer from this exposure is about 10%. The carcinogenic
Salted fish is implicated in the aetiology of nasopharyngeal risks of ionizing radiation have been revised upwards
cancer, possibly as a co-carcinogen with the Epstein-Barr since 1988. Current estimates of risk are two to five times
virus. higher. However, it is unclear whether these revised esti-
Diet may be indirectly related to carcinogenesis. One mates apply to very low levels of exposure to natural
example is fibre, which seems to have a protective effect background radioactivity.
against colorectal cancer. A second is obesity, which is asso- The role of ionizing radiation in the causation of cancer
ciated with an increased incidence of cancer of the endome- is mainly derived from occupational exposure. Early evi-
trium and of the gallbladder in women. Consumption of dence came from the development of lung cancer among
saturated fat is implicated but not proven as a cause of miners at Joachimstal in Czechoslovakia and Schneeberg
breast cancer. A third is vitamin A (retinol) and its deriva- in Germany. Lung disease had been known to occur among
tives, retinoids, which may inhibit the full malignant trans- these workers since the 16th century. It was subsequently
formation of cells and prevent tumour formation. appreciated that the disease was lung cancer due to radio-
Dietary measures likely to reduce the risk of cancers are: active radon gas in the mines.
high-fibre diet The main source of evidence of the effects of ionizing
reducing saturated fats radiation in man are the survivors of the atomic bombs
plenty of fresh fruit and vegetables (owing to the dropped on Hiroshima and Nagasaki in 1945. The inci-
presence of antioxidants such as vitamin E). dence of acute and chronic leukaemia was significantly
raised within a radius of 1.5 km from the epicentre.
The highest incidence occurred 68 years afterwards.
Ionizing radiation For cancers other than leukaemia, the latent period
was longer (1520 years) among victims who received
The whole spectrum of sources of ionizing radiations, both
1 Gy or more; indeed the incidence is still higher over
natural and man-made, has been calculated to contribute
50 years later.
1.5% of all fatal cancers. The sources of radiation exposure
It is assumed that there is no threshold below which can-
in the UK are shown in Table 15.3.
cers cannot be induced by ionizing radiation. Indeed, chil-
It is estimated that exposure to radon gas from domes-
dren who received only 0.010.02 Gy in utero when their
tic buildings may be responsible for 1% of lung cancer
mothers were irradiated had an additional 1 in 2000 risk of
in Europe. Concentrations of radon gas in excess of
cancer. At low doses, the risk of developing cancer is prob-
400 Bq/m3 (about 1 in 1000 homes) will expose the
ably proportional to dose, although much uncertainty
remains.
Reducing the levels of radon gas from domestic buildings
requires a number of measures. First, systematic surveys are
Table 15.3 Estimated annual dose of ionizing radiation needed to identify buildings which pose a hazard. Levels of
received by a member of the general public (mSv) radon gas can be reduced by alterations to the floors and
installation of extractor fans.
External terrestrial radiation 0.4
265
Walter and Millers Textbook of Radiotherapy
FURTHER READING
Boyle P, Ferlay J. Cancer incidence and Hackshaw AK, Law MR, Wald NJ. The Quebec chrysotile miners and millers.
mortality in Europe, 2004. Ann Oncol accumulated evidence on lung cancer Ann Occup Hyg 2002;46:513.
2005;16:4818. and environmental tobacco smoke. Br
Harris JE, Thun MJ, Mondul AM, et al. Med J 1997;315:9808. Colon cancer
Cigarette tar yields in relation to International Agency for Research on Potter JD, Slattery ML, Bostick RM, et al.
mortality from lung cancer in the Cancer IARC Monograph 83: Tobacco Colon cancer: a review of the
cancer prevention study II prospective smoke and involuntary smoking. epidemiology. Epidemiol Rev
cohort. 19828. Br Med J IARC Lyon 2002. 1993;15:499545.
2004;328:72. Bruce WR, Giacca A, Medline A. Possible
Doll R, Peto R, Boreham, et al. Mortality Asbestos mechanisms relating diet and risk of
in relation to smoking: 50 years Goodman M. Cancer in asbestos-exposed colon cancer. Cancer Epidemiol
observations on male British doctors. occupational cohorts: a meta-analysis. Biomarkers Prev 2000;9:12719.
Br Med J 2004;22 Jun. Cancer Causes Control
1999;10:45365. Breast cancer and hormones
Doll R, Peto R, Wheatley K, et al. Mortality
in relation to smoking: 40 years Hammond EC, Selikoff IJ, Seidman H. International Agency for Research on
observations on male British doctors. Asbestos exposure, cigarette smoking Cancer IARC Monograph 72.
Br Med J 1994;309:90111. and death rates. Ann N Y Acad Sci Hormonal contraception and post-
1979;330:47390. menopausal hormone therapy. IARC
Passive smoking Liddell FD, Armstrong BG. The Lyon 1999.
Boffetta P. Involuntary smoking and lung combination of effects on lung cancer World Health Organization. Guidelines
cancer. Scand J Work Environ Health of cigarette smoking and exposure in for controlling and monitoring the
2002;28(s):3040. tobacco epidemic. WHO; 1998.
266
Chapter | 16 |
Biological and pathological introduction
John R. Goepel
CHAPTER CONTENTS
Precancerous lesions 272
Growth: proliferation, differentiation and Field change 272
apoptosis 268
Natural history and spread of cancer 273
Growth disorders 268
Local invasion 273
Neoplasia 268
Functional effects 273
Benign and malignant neoplasms 268
Metastasis 273
Carcinogenesis 269
By lymphatic vessels 273
Initiation 269
By blood vessels 274
Promotion 269
Across cavities (transcelomic) 274
Progression 269
Implantation 274
Clinical cancer 269
Functioning tumours 274
Oncogenes and tumour suppressor genes 269
Cause of death from cancer 274
Blood vessels 270
Staging of cancers 274
Heredity and cancer 270
TNM classification 274
Physical agents 270
Histological grading: differentiation 275
Ionizing radiation 270
Limitations of grading 275
Chemicals 271
Growth rate of cancers 275
Coal tars, oils and cigarette smoke 271
Spontaneous regression of cancer 276
Aniline dyes and the rubber industry 271
Classification of neoplasms 276
Asbestos 271
Undifferentiated tumours 277
Hormones 271
Viruses and cancer 271 Radiotherapy is used almost exclusively for the treatment of
Infectivity and cancer 271 cancer and related conditions. It is thus very important to have
Immunity and cancer 271 a reasonable understanding of this disease. This chapter
contains an outline of the basic characteristics of cancerous
Immune surveillance 272
cells, and the conditions that can cause cancer. There is con-
Injury and cancer 272 sideration of the natural history of untreated cancer, and of
the ways that different types of cancer are named and the organ in which the neoplasm is situated. This, com-
classified. bined with loss of control of the normal relationships
between cells, often results in the new tumour cells repla-
cing and insinuating themselves between the adjacent
GROWTH: PROLIFERATION, normal tissues, a process called invasion. Loss of differen-
DIFFERENTIATION AND APOPTOSIS tiation accompanies, and often correlates with, failure of
proliferation control and invasiveness. Failure of apopto-
Growth is the process of increase in size and maturity of sis may also be a major contribution to the survival of
tissues from fertilization through to the adult. When abnormal cells.
normally controlled, the different parts of the body take
on their correct size and specialist functions, and relation- Benign and malignant neoplasms
ship to one another. Furthermore, throughout life these Neoplasia is not a single disease, but rather a common path-
attributes continue despite the need for replacement and ological process with a multitude of different varieties and
repair. This is all a reflection of accurate control of the timing clinical outcomes. One fundamental division is between
and extent of cellular proliferation, cell-to-cell orientation benign and malignant tumours. Benign tumours will remain
and organization, and differentiation. Differentiation is localized, with generally relatively little effect on the patient.
the process of a cell taking on a specialized function; this In contrast, other tumours are locally destructive, may
is usually associated with a change in its microscopic appear- spread to involve other parts of the body, and ultimately
ance. It is also usually a one-way commitment, with relative result in the death of the patient. Figure 16.1 and
or complete loss of the ability to continue proliferating. Table 16.1 show some of the differences between benign
Also important is the ability to delete cells which are no and malignant neoplasms. Further aspects of the classifica-
longer needed, by a process called apoptosis or programmed tion of tumours are discussed later in this chapter.
cell death. This is used in the development of the fetus,
and in maintaining or adjusting the size of a structure in
the adult. Apoptosis is also used to delete defective cells. A
Growth disorders
Hypertrophy is an increase in the size of an organ due to an
increase in the size of its constituent cells. The left ventricle
of the heart becomes hypertrophic if it has to work harder B
because of hypertension.
Hyperplasia is an increase in size because of an increase in
the number of cells. The adrenal cortex will become hyper-
plastic if there is excessive adrenocorticotrophic hormone
to stimulate it. However, it will return to normal if the stim-
ulus is reduced again.
Metaplasia is a change from one type of tissue to another.
Smoking induces a change of the bronchial lining from the Figure 16.1 The difference between a benign tumour A
usual respiratory mucosa to a squamous epithelium, with contained by a definitive capsule and a malignant tumour B
resultant loss of mucus-producing and ciliated cells. It is actively invading the tumour bed.
also potentially reversible.
Neoplasia (literally a new growth), in contrast, is an irre-
versible process once initiated: it is the main subject of this Table 16.1 Characteristics of neoplasms
chapter. It is also called cancer, or a tumour, though the lat-
ter is sometimes used to denote any swelling.
FEATURE BENIGN MALIGNANT
268
Chapter | 16 | Biological and pathological introduction
The term cancer (Latin for crab) is very ancient, and there are Progression
several explanations for its usage. Some say it reflects the tena-
cious grip the disease has on its victim, some that it describes Neoplasms are clonal, i.e. are derived from a single cell. For
the radiating prominent veins that may surround an advanced this to happen, a cell and its progeny must acquire and sus-
superficial tumour. Others contend that it describes the tain a growth advantage over other cells throughout suc-
irregular infiltrative profile of some tumours, e.g. of breast. Suf- ceeding cell divisions. This eventually results in visible
fice it to say that cancer is a common colloquial term that alterations at the microscopic level. Not all the daughter
is generally applied to any malignant neoplasm. cells will be identical, giving rise to differences between
Though the behaviour of tumours, particularly malignant individual cells or subclones; this is called pleomorphism.
ones, may seem very odd, it can generally be explained by the
excessive or inappropriate expression of genes that are pres- Clinical cancer
ent in all cells. The tumour continues to be dependent upon
an adequate blood supply (though many acquire the capac- Finally, the neoplasm becomes manifest as a clinically sig-
ity to induce new vessels). Also, many of those which arise nificant tumour. Unless removed, it will continue to prog-
from hormone-dependent tissues (e.g. breast, prostate) con- ress with a general tendency towards further loss of growth
tinue to show a degree of dependence on those hormones. restraint, and acquisition of the capacity to spread to other
This can be exploited to therapeutic advantage by giving anti- parts of the body (metastasize).
hormone treatment.
Oncogenes and tumour suppressor
CARCINOGENESIS genes
The function of a cell is critically dependent on the
The causes of cancer are numerous, and mechanisms of its expression of its genes. In cancer, it has been observed
production are complex, but some of the principles will be that there may be both inappropriate levels of expression
presented. There are two avenues of thought to follow: one of otherwise normal genes, and abnormalities of genes.
at the molecular and genetic levels, the other concerned Though copying of the genetic code from one cell gener-
with causative associations. It is not always easy to relate ation to another is very accurate, it is not perfect. An
these to each other. Underlying the mechanistic approach abnormal copy or mutation may give rise to a protein
is the assumption that cell behavior is controlled by the with excessive function or reduced function, or may fail
genes expressed (which ones, and how strongly), bearing to produce a protein at all, resulting in no function. Alter-
in mind that these can be influenced by chemical messages natively, it may be the control of the gene which is
relayed from outside the cell. Every cell contains the entire altered, so that there is increased or decreased expression
genetic code, but only expresses those genes appropriate resulting in excess or deficient protein product and hence
to its own situation. In cancer, this has gone wrong, partic- function. An oncogene is an altered gene which contri-
ularly with respect to proliferation, differentiation or apo- butes to cancer development when its expression is
ptosis. We can generalize to say that multiple abnormalities increased. The normally functioning counterparts of
need to have occurred between normality and cancer, and these genes are often concerned with control of cell
that this reflects a multistep process. Only those cells capable proliferation.
of division are at risk of transforming into a neoplasm. This In contrast, tumour suppressor genes are those which, when
excludes terminally differentiated cells such as circulating totally absent or non-functioning in a cell, permit the emer-
red cells, the uppermost keratinized cells of the skin, and gence of neoplasia, i.e. their presence prevents neoplasia.
adult voluntary muscle and nerve cells. Given that all normal cells will have two copies of each
gene (one on each chromosome pair), the development
of neoplasia by this means requires loss or mutation of
Initiation both copies.
This describes the first step towards neoplasia. It reflects a It must be stressed that clinical cancer does not reflect a
change at the molecular level of how a cell can function, solitary abnormality of one of these genes, but rather the
escaping in some small way from a control mechanism. final result of a combination of several errors of function.
Nothing can be seen microscopically at this stage. Substances The gradual accumulation of multiple genetic defects is
that can initiate neoplasia are called initiators or carcinogens. typified by the progression of a benign polyp in the colon
to a cancer over about 10 years. How is it that a cell can
acquire so many abnormal genes? The explanation in sev-
Promotion
eral situations is that there is failure of the screening of the
No more will come of the initiated cell unless it continues cells genetic code for abnormalities, or defective repair
to divide. Further abnormalities of cell function (i.e. gene of incidental genetic damage. The protein p53 is important
expression) arise over a period of time. Substances that in assuring the integrity of the genome, and it is frequently
enhance this process are called promoters. defective in cancer cells. Similarly, the failure of DNA
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Walter and Millers Textbook of Radiotherapy
repair can result in much more rapid accumulation of inherited risk of malignancy does not imply that it is certain
mutations the mutator phenotype. that a cancer will arise in a particular individual.
Defective apoptosis has several consequences with
regard to cancer. Inappropriately increased expression of
BCL-2, which inhibits apoptosis, is a major reason for cell Physical agents
accumulation in some tumours, for example follicular lym- Ionizing radiation
phoma. Failure of apoptosis may contribute to survival of
defective cells and also cell survival in abnormal environ- There is no doubt that ionizing radiation can cause cancer.
ments such as occurs during invasion and metastasis. Direct damage to DNA (i.e. the chemical basis of genetic
Finally, many cancer treatments rely on induction of apo- information), and damage mediated via ionization of
ptosis to kill tumour cells, so these will be less effective if water can result in mutation of genes. The damage is ran-
apoptosis is defective. domly scattered throughout the genetic code, but can
include sites critical to the development of cancer by the
usual sequence of initiation, promotion and so on. Tradi-
Blood vessels tionally, it has been thought that radiation causes a somatic
The development of cancer cells into a clinically important mutation in a normal cell. The earliest event is probably
mass requires establishing a blood supply, a process called genomic instability. Subsequently, there is a multistep
angiogenesis. New capillaries form under the influence of sequence of genetic events. This typically results in an inter-
vascular endothelial growth factors (VEGF); platelets are val of many years between exposure and clinical cancer.
the main source of VEGF in the blood. VEGF may be The source of radiation does not matter from the point of
secreted directly by tumour cells, particularly when stimu- view of causing cancer, though it will affect the sites at risk.
lated by hypoxia, but also when tumours abnormally Ionizing radiation can lead to loss of tumour suppressor
express a range of other oncogenes, for example epidermal genes and activation of proto-oncogenes. Oncogenes may
growth factor receptor (EGFR) and Her2. Her2 is important also be activated as result of point mutations. Gene ampli-
in many breast cancers, and is a therapeutic target for tras- fication can lead to activation and overexpression of a
tuzumab (Herceptin). Drugs are also becoming available to proto-oncogene. It had previously been thought that muta-
target angiogenesis, for example the VEGF antibody bevaci- genesis only occurred in normal cells traversed by radiation
zumab (Avastin). particles. However, normal cells can undergo change with-
out such damage by virtue of what is termed the bystander
effect. The mechanism of this bystander effect is not clear
Heredity and cancer but it could be due to secretion of factors (as yet unidenti-
fied) from irradiated cells that influence the survival of
The great majority of common tumours do not seem to
adjacent non-irradiated cells.
have any relationship to hereditary factors. However, some
The dose at which carcinogenesis occurs may be tissue
rare tumours do, and have led to an understanding of
specific. Actively proliferating tissues within or adjacent
tumour suppressor genes. The pioneering work of Knudson
to the irradiated volume (e.g. in the pelvis), and having
on families of patients with multiple retinoblastomas (a
a high capacity for proliferation not inhibited by radia-
tumour of the eye) indicated first that there must be two
tion, will carry a risk of radiation-induced malignancy at
genetic events. In due course, it became clear that one
lower doses than in slowly turning-over tissues such as
defective gene was inherited by the patient, while its
connective tissue.
corresponding gene on the opposite chromosome became
defective, or was lost, in some cells during the growth of the
eye. With both retinoblastoma (Rb) genes now defective, Industrial exposure
the cells proceeded to neoplasia. Early workers with x-rays unknowingly induced tumours,
It is apparent that a minority of common tumours run in and other radiation damage, in their hands. Today, diag-
families because of the same sort of mechanism. For exam- nostic and therapeutic radiation also carry this risk to
ple, breast cancer kindreds may be passing on the BRCA-1 patients and staff alike, necessitating stringent safety reg-
or BRCA-2 genes, and also be associated with carcinoma ulations. Some mineworkers are exposed to high levels
of the ovary or colon, (these genes code for DNA repair). of radon, which is inhaled and may cause lung cancer
In familial adenomatous polyposis, a defective APC gene (a risk increased by cigarette smoking). Radon- induced
results in adenomas and colon cancers, while in hereditary lung cancer has been linked to mutations of p53, a tumour
non-polyposis colon cancer (HNPCC), one of a number of suppressor gene. This mutation differs from those seen in
mismatch repair genes or abnormal hypermethylation is lung cancer induced by smoking. Another industrial asso-
involved, giving rise to colon cancer by a different molecu- ciation was with the painters of luminous watch dials.
lar biology route. These issues are taken further in the rele- These ladies pointed their brush with their lips, thereby
vant sections about breast cancer or colon cancer. An taking in minute quantities of radium. Some of the
270
Chapter | 16 | Biological and pathological introduction
material remained near the jaw, while some was absorbed pleura (malignant mesothelioma); they also correlate
and passed to bone marrow, where the alpha emissions with bronchial cancer, particularly if associated with
resulted in bone necrosis, tumours and marrow failure. smoking.
In all cases, there was the usual long time delay between
exposure and clinical cancer. Hormones
Atomic bomb survivors have been followed up very care-
fully. There has been an excessive number of cases of leu- Are endogenous chemicals such as hormones carcinogenic?
kaemia, mainly 712 years after exposure, and also a There is no doubt that hormone levels are important in
larger number of other cancers from about 20 years later hormonally responsive organs and their cancers. Whether
onwards. the hormone is actually carcinogenic, or simply contributes
to the process of carcinogenesis by promoting cell prolifer-
ation is debatable; the latter is more probable. The relation-
Ultraviolet light ship between oestrogens and endometrial cancer is discussed
The shorter wavelengths of solar ultraviolet light, UVB, are in Chapter 27. Breast and prostate cancers are also likely
capable of damaging the DNA of various skin cells, result- to relate to hormonal influences. As mentioned earlier, hor-
ing in mutations and eventually cancers. Melanin pigment monal manipulation is an important therapeutic tool in
protects against UV penetration to the deeper layers of cancer treatment.
cells. The common tumours, basal cell and squamous cell
carcinomas, seem to result from chronic overexposure;
Viruses and cancer
malignant melanoma correlates better with acute and
intense exposure. As viruses contain genetic material, and gain access to the
inside of cells, they have long been suspected of having
a role in carcinogenesis. This speculation has been fuelled
Chemicals by finding close similarity between some viral genes and
Coal tars, oils and cigarette smoke oncogenes. Viruses are clearly responsible for a variety
of tumours in several species, such as leukaemias in mice
Percival Pott, in 1775, described carcinoma of the scrotal and cats and sarcomas in chickens. In humans, common
skin in chimney sweeps, and attributed it to the soot. Simi- skin warts are self-limiting benign tumours caused by a
larly, mule-spinners in mills developed tumours due to the virus. Over recent years, these human papilloma (wart)
oil that soaked their clothing and, even today, motor viruses (HPV) have been found to be a large family of
mechanics are at risk from lubricating oils. However, the related organisms, some of which correlate closely with
greatest problem at present from this group of chemicals cancer of the uterine cervix and similar tumours. Simi-
is cigarette smoke. This contains many known carcinogenic larly, Epstein-Barr virus, which is very widespread and
substances, including benzo[a]pyrene, a potent carcinogen causes infectious mononucleosis, is closely associated
also present in coal tars. Not only do smokers have a very with tumours such as Hodgkins Lymphoma, Burkitts
greatly increased incidence of lung cancer, they also have a lymphoma (a high-grade non-Hodgkins lymphoma),
higher risk of cancer at several other sites, such as the blad- and nasopharyngeal carcinoma.
der. Chemicals that are able to cause tumours are called
direct carcinogens, but most require metabolism to the active
chemical so are called procarcinogens. Infectivity and cancer
Some patients, or their relatives, worry that cancer
Aniline dyes and the rubber industry may be infectious. It is possible to allay these fears and
Workers in the chemical industry, particularly those assure them that this is not the case. The association
involved in making dyes, were found to develop bladder with viruses mentioned above is a rare sequel to agents
cancer. A similar risk was noted in the rubber-processing widely present in the community; the cancer cannot be
industry. The chemical implicated, b-naphthylamine, passed on.
needs to be metabolized in the kidney, thus releasing the
active ingredient into the urine.
Immunity and cancer
Asbestos The immune system exists to detect and eliminate
Many particulate minerals are now recognized as carci- foreign substances, from isolated molecules to whole
nogenic, including asbestos. The blue asbestos (crocido- organisms. This is effected by antibodies and cells, prin-
lite) particles used for insulation are easily inhaled when cipally lymphocytes. In the development of a tumour, it
very small but are then retained within the lung. Over a is quite possible for new or inappropriate substances
period of decades, they may then cause tumours of the to be produced. From this one would predict that
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Walter and Millers Textbook of Radiotherapy
272
Chapter | 16 | Biological and pathological introduction
Blood Spread to
Distant Organs Circulating Spread across Body Cavities
Tumour Cells (Pleura, Peritoneum)
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Walter and Millers Textbook of Radiotherapy
By blood vessels In other cases, the primary site remains undetected despite
widespread metastatic deposits. Some tumours show relent-
Thin-walled blood vessels are similarly at risk of tumour
less progression, and run their course in a few months; others
invasion, and again fragments of tumour float passively
take many years, with long intervals of apparent dormancy.
downstream. (Single tumour cells are generally destroyed
Many patients with locally advanced or metastatic cancer
by non-specific defense mechanisms in the blood.) These
become bedridden and die from bronchopneumonia, ina-
then lodge in the next capillary bed, where they may
nition and/or metabolic disturbance. Sometimes there
develop into metastases. Though this can happen in any tis-
may be liver failure due to numerous liver secondaries.
sue, the liver, lungs and bone are by far the most frequent
Often the actual cause of death is unclear. It is important
sites for secondaries (Figure evolve 16.5 ).
to consider carrying out a post-mortem examination
if there is reasonable doubt about the cause of death.
Across cavities (transcelomic) Patients with cancer are still at risk of non-neoplastic
conditions such as coronary artery disease. This is particu-
Access to the pleura enables tumour cells to seed themselves
larly likely in patients who smoke. Indeed, smoking may
around the pleural cavity, forming numerous further
have given rise both to the primary tumour (e.g. in the lung,
deposits or seedlings. These may be associated with secre-
oral cavity or pharynx) and to ischemic heart disease.
tion of fluid into the cavity, with resultant impairment of
It is important to make a judgment as to whether the
respiration. An identical process may occur in the perito-
patient died from cancer or from an unrelated condition,
neum; the fluid accumulation is called ascites. Malignant
since this influences cancer mortality statistics. Where a
cells may settle on the ovaries, or all over the omentum.
patient has remained disease free from cancer for more
Related to this, some intracranial tumours, such as medul-
than 5 years, and the cause of death is said to be cancer, this
loblastoma of the cerebellum, may disseminate by the cere-
conclusion should be questioned. However, late relapses
brospinal fluid, seeding over the surface of the brain and
can occur after 5 years, in breast cancer, for example. Alter-
down the spinal canal (Figure evolve 16.6 ).
natively, a new primary may develop, especially in head
and neck cancer.
Implantation
Occasionally cells may be implanted in the scar by the sur-
STAGING OF CANCERS
geons knife while removing a tumour, or through a pleural
or abdominal paracentesis drainage site.
It is of the greatest practical importance in many cases to
estimate the extent of the spread of a tumour at the time
Functioning tumours of initial diagnosis. This process is called staging. Staging
Many tumour cells continue certain cell functions related to often influences the choice of treatment, and can provide
their tissue of origin but, in some, this has a profound effect valuable information on prognosis. Staging may include
on the patient. Tumours of endocrine glands typically pro- clinical, pathological, radiological, and biochemical infor-
duce an excess of their hormone. The problem is that the mation. This enables similar groups of patients to be com-
tumour is no longer responsive to the usual control of pared between different oncology centres nationally and
secretion. Thus, an adrenal cortex tumour will produce ster- internationally. A number of staging classifications are in
oids despite switching off its pituitary drive, and Cushings use. The simplest and oldest classification is as follows:
syndrome will result. Stage 1: Tumour confined to the organ of origin
In other circumstances, the hormone production is quite Stage 2: Local lymph nodes invaded
inappropriate for the tumour site. Many lung tumours pro- Stage 3: Distant nodes invaded, or local spread beyond the
duce substances that mimic the function of parathyroid organ of origin
hormone, antidiuretic hormone, or adrenocorticotrophic Stage 4: Blood-borne metastasis present.
hormone. Again, it is not subject to the normal control This is still used with some cancers, though often with slight
of secretion, and the clinical consequences may be severe. modification to bring in subcategories, as with the FIGO sys-
Some of the other effects that tumours may have, such as tem for cervix cancer. The UICC (International Union Against
profound weight loss, could be due to secretions as yet Cancer) has worked towards international agreement on the
unidentified. staging of many tumours, coding them on the TNM system.
274
Chapter | 16 | Biological and pathological introduction
T13: Generally based on the size and/or extent of the Limitations of grading
primary
T4: The most advanced local disease, often with invasion Some tumours show a tight correlation between histologi-
of adjacent structures cal grading and behavior, such that treatment is guided by
N0: No nodes palpable this information. Cancer of the bladder is one of these.
N1: Mobile nodes on the same side as the primary However, the tumour stage is of overriding importance.
N1a: Nodes not considered to contain tumour Some tumours (e.g. pancreatic islet) have a very variable
N1b: Nodes considered to contain tumour rate of clinical progression, but uniform histology: grading
N2: Mobile nodes on the opposite side (N2a and N2b in this circumstance is misleading if attempted. Other
as above) tumours vary considerably from one microscopic field to
N3: Fixed, involved nodes another: in general, the outlook will depend upon the
M0: No evidence of distant metastasis worst areas, but these could be missed without adequate
M1: Distant metastasis present sampling. Finally, the organ of origin is important: a
well-differentiated cancer of the skin carries an excellent
Thus, a very early cancer would be categorized as T1N0M0,
prognosis, whereas in the lung it may not.
and a very advanced one as T4N3M1. The details of how to
categorise a tumour vary between sites; the TNM classifica-
tion for breast cancer is shown in Table 26.3.
The clinical staging may differ from the pathological GROWTH RATE OF CANCERS
staging. For example, a tumour in the breast may be measured
clinically as 2 cm in diameter and thus be staged as T1. How-
ever, when actually measured directly in the mastectomy As indicated in the section on carcinogenesis, there is usu-
specimen it might be 3 cm in maximum diameter, and thus ally a considerable time between initiation of a tumour
be pathologically T2 (abbreviated as pT2). Most staging and its clinical detection. Part of this time is taken by
classifications are based on the clinical extent of spread. the process of becoming a cancer cell, and part by growing
Radiological information may influence staging. For exam- to sufficient size to be found. The latter can be measured as
ple, in carcinoma of the cervix, the presence of an obstructed the time taken for it to double in diameter, its doubling
kidney on ultrasound or other investigation (in the absence time. A mass 1 mm in diameter would represent about
of a non-neoplastic cause), automatically indicates stage 3b. one million cells: this could result from one cell, and each
The staging of testicular cancer is an example where of its subsequent daughter cells, dividing 20 times. A word
biochemical information (the presence of serum tumour of caution is needed before theorizing further. Once a
markers alpha-fetoprotein and human chorionic gonadotro- tumour exceeds about 2 mm it is essential for it to have
phin) is included. If the tumour is clinically confined to the its own blood supply: this, together with other supporting
testis but tumour markers are rising, it is classified as stage 1, structures, is the tumour stroma. In some tumours, the
marker positive (Mk). stroma is very scanty, while in others it constitutes the
majority of the mass. (The character of the stroma also
influences what the tumour feels like on palpation; most
HISTOLOGICAL GRADING: breast cancers are hard because of abundant, dense
stroma.) Thus, calculations about how many cancer cells
DIFFERENTIATION there are in a tumour of a certain size will be incorrect if
they ignore the stroma.
In an effort to predict the future course of a tumour, an esti- Another consideration is that the clinical growth of a
mate is made of how malignant it is for a particular site and tumour will be the result of the balance between cell pro-
type of tumour. Generally speaking, the closer a tumour liferation and loss. It will be influenced too by the growth
cell resembles its normal counterpart, i.e. the better it is dif- fraction or proportion of cancer cells actually proliferating.
ferentiated, the more orderly and slower its growth. Thus, Many cancer cells in a tumour cease to proliferate as they
histological examination allows tumour grading on the differentiate, or produce non-viable daughter cells. Further-
basis of the extent of differentiation. Attention is given to more, if the vascularity of the stroma is inadequate there
the nucleus (how abnormal it is and how often mitosis is will be necrosis.
observed), and the cytoplasm (the extent to which normal Though a cancer produces an expanding mass, this is a
structures are seen) (Figures evolve 16.7 & 16.8 ). reflection of loss of control of growth. The actual rate at
For most of the common tumours, the pathologist divides which individual cancer cells divide is slower than compa-
them into descriptive categories: well differentiated, moder- rable normal tissues. If there is a very sudden increase in the
ately differentiated and poorly differentiated. Undifferenti- size of a tumour, it will probably reflect internal hemor-
ated tumours lack sufficient features to allow more than rhage or fluid accumulation. (On the other hand, a slow-
a broad classification, as do anaplastic tumours (see below growing mass which begins to grow faster may have
under Classification of neoplasms) (Figure evolve 16.9 ). changed from benign to malignant.)
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Walter and Millers Textbook of Radiotherapy
Intracranial
Spontaneous regression of cancer and neural
Occasionally, a tumour may regress and disappear without Supporting Glioma
treatment, though the original diagnosis could have been cells
Meninges Meningioma
erroneous. Most of the reported cases are renal cell car-
Cerebellum Medulloblastoma
cinoma, malignant melanoma and gestational choriocarci-
Retina Retinoblastoma
noma. In all these instances, immunological mechanisms
Sympathetic Ganglioneuroma Neuroblastoma
are thought to be responsible. Some cases of lymphoid
nerve
tumours fluctuate in size, and may temporarily disappear,
only to return later. In some cases of neuroblastoma, a Pigment cells
primitive tumour of nerve cells, there is subsequent differ- Skin or eye Mole or nevus Malignant melanoma
entiation and growth ceases.
Gonad
Germ cells Dermoid cyst Malignant teratoma
(Figure evolve 16.10 )
CLASSIFICATION OF NEOPLASMS Seminoma
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Chapter | 16 | Biological and pathological introduction
and applied only to epithelial malignancy, which makes up under the relevant organ Refer to Figure evolve 16.10
75% of cancer. (Teratoma) (Figure evolve 16.14 ).
Squamous epithelium lines the skin, where it is called
epidermis, the upper aerodigestive tract (mouth, pharynx,
Undifferentiated tumours
larynx, oesophagus), anus, vagina and cervix. It is present
in the bronchi if there is metaplasia. Transitional cell epithe- Some tumours lack obvious features to allow their identifi-
lium, (or urothelium) lines the renal pelvis, ureters and cation or classification. An undifferentiated carcinoma or
bladder. sarcoma cannot be ascribed to any subcategory. An ana-
Glandular (secretory) epithelium lines the gut from stomach plastic tumour could be carcinoma, lymphoma or sarcoma.
to rectum, and forms the related secretory glands (salivary, As these different categories have major therapeutic conse-
pancreas, biliary tract and liver), endocrine glands (pituitary, quences, it is important to attempt a more detailed diagno-
thyroid, parathyroids, adrenals), kidneys, ovarian surface, sis. Simple microscopy can now be supplemented by
endometrium and breast (Figure evolve 16.12 ). special staining procedures, many of which involve detect-
Sometimes the tumour name is combined with a descrip- ing cell components with antibodies. The presence of the
tion of shape or function. If a cyst is formed it may be cysta- leukocyte common antigen (CD45), B-cell (CD20) or
denoma or cystadenocarcinoma, both of which are T-cell (CD3) markers would indicate a lymphoma, whereas
common in the ovary. Mucin-secreting variants would be finding cytokeratins would suggest a carcinoma (Figure
mucinous cystadenoma. evolve 16.15 ). As tumours have deranged genetic func-
Sarcoma denotes any tumour of mesenchymal origin tion there are sometimes unexpected findings. Electron
(supporting structures). They are much less frequent than microscopy sometimes helps. There are other approaches
carcinoma. Metastasis from sarcomas is generally blood- such as cytogenetics, which depends upon finding charac-
borne, and few give rise to lymph node secondaries (Figure teristic abnormalities of the chromosomes. These are most
evolve 16.13 ). often loss or gain of part or the whole of a chromosome, or
Lymphomas are malignant tumours of lymphoid cells; translocations in which two chromosomes break and are
many are classified as Hodgkins lymphoma, leaving the rejoined with the fragments on the wrong chromosome,
remainder as non-Hodgkins lymphoma. Some are closely for example t(11;22).
related to leukaemias (tumours of white blood cells). Most oncology centres arrange for many of their
There are many tumours that do not easily fit the guide- patients tumours to be reviewed before treatment. Diag-
lines mentioned such as testicular teratomas: some are in nosis and classification of rare or undifferentiated
Table 16.2 and others are referred to elsewhere in this book tumours form a considerable part of such work.
Figure evolve 16.2 Benign and malig- Figure evolve 16.7 Adenocarcinoma of Figure evolve 16.12 Adenocarcinoma
nant colorectal tumours breast (Grade 1 & Grade 2) of endometrium
Figure evolve 16.4 Carcinoma of head Figure evolve 16.8 Adenocarcinoma of Figure evolve 16.13 Myxoid liposarcoma
of pancreas breast (Grade 3) Figure evolve 16.14 Teratomas: Ovary
Figure evolve 16.5 Bone metastatic Figure evolve 16.9 Histological features benign, testis malignant
carcinoma of an anaplastic carcinoma Figure evolve 16.15 Immunocytochem-
Figure evolve 16.6 Peritoneum meta- Figure evolve 16.10 Teratoma istry to distinguish lymphoma from
static carcinoma Figure evolve 16.11 Squamous papilloma carcinoma
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Chapter | 17 |
Molecular, cellular and tissue effects
of radiotherapy
George D.D. Jones, Paul Symonds
H 2O H3O+
(H2O)n
H eaq e
O2
O2 (H / O2 / eaq) e
H2O+ h
h
H2O R+
H3O+
OH
B
A
Figure 17.1 The (A) indirect and (B) direct effects of ionizing radiation. In the indirect effect, radiation interacts with water to produce
hydroxyl free radicals (OH) which, in turn, react with the DNA producing damage. In the direct effect, the radiation interacts directly
with the DNA to produce damage. While both direct and indirect effects damage DNA, it is suggested that only indirect events
happening within 2 nm of the DNA damage the DNA. Indirect effects dominate for low LET ionizing radiations. (The dot refers to
an unpaired electron of a free radical, and the dashed lines reflect the lower reactivity of the reducing species with DNA, as compared
to the high reactivity of OH).
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Chapter | 17 | Molecular, cellular and tissue effects of radiotherapy
Double strand
break
DNA-DNA
crosslink
B
A
Figure 17.2 (A) The types of damage produced by radiation. (B) The concept of multiply damaged sites being produced by a cluster
of ionizations impinging on the DNA and its local environment. Energy deposition for x-rays is not uniformly absorbed, but
deposited in discrete events of high energy sufficient to generate a number of ion-pairs. Should this happen in pure water this
will generate locally several OH e pairs, however, should these events overlap the DNA both the direct and indirect effects will
contribute to MDS formation.
species, may damage DNA via the so-called indirect effect Table 17.1 Types and frequency of radiation-induced
(Figure 17.1A). Radiation can also directly ionize the DNA damage
leading to direct damage of the DNAs bases or sugar-
phosphate backbone (R) (Figure 17.1B); although the
TYPE OF DAMAGE APPROXIMATE NUMBER
distinction between direct and indirect damage is not always PER Gy PER CELL
clear as electrons and radical cations produced in the DNA
and DNA-associated water may lead to further ionizations/ DNA double-strand breaks 40
oxidations in the DNA macromolecule and its surrounding
microenvironment. DNA single-strand breaks 1000
Through direct and indirect effects, radiation causes a wide DNAprotein cross-links 150
range of damage in DNA, including strand breaks, base or
sugar damage and cross-links between macromolecules DNADNA cross-links 30
(i.e. DNADNA or DNAprotein cross-links) (Figure 17.2A);
the frequency of these DNA lesions is shown in Table 17.1. Base damage 2000
In general, it is considered that the DNA double-strand break Sugar damage 1500
(DSB) is the most critical for the lethal effects of radiation;
evidence for this is a follows:
under a variety of experimental conditions, it is the
relative level of induced or unrepaired DSBs that best However, not all DSBs are the same, as the chemical nature
correlates with cell killing of the strand break ends and the separation between the
a single DSB is lethal to yeast constituent single strand breaks can vary considerably,
enzymatically produced DSBs (produced by inserting as can the proximity of other types of lesions. Indeed, the
DNA restriction enzymes into cells) gives the same influence of the proximity of induced lesions has been
pattern of chromosome damage and lethality as shown to affect the reparability of damage and this is rele-
radiation vant because low LET radiation (x-rays and g-rays) can pro-
microbeam irradiation has shown the cell nucleus to be duce multiple ionizations in isolated events (termed spurs
the most radiation sensitive site in the cell and blobs). When these isolated events occur close to or
the extreme radiosensitivity of some mutant cell lines is overlap the DNA molecule (see Figure 17.2B), several
due to defects in DSB repair. lesions may be formed within a region of a few base-pairs
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Asymmetrical
interchange
Dicentric Inter-arm
Centric ring intrachange
Symmetrical
interchange
Interstitial
deletion Terminal deletion Intra-arm
intrachanges
Figure 17.3 Some examples of radiation-induced chromosomal structural changes solid stained. (A) Chromosome-type
aberrations all breaks and rejoins affect both sister-chromatids at the same locus. Only forms that produce acentric fragments are
visible with solid staining. However, there is much hidden damage present, some of which is transmitted to future cell generations.
(B) Chromatid-type aberrations all breaks and rejoins affect only one of the sister chromatids at any one locus. Compared with
chromosome-type changes, many more forms are visible with solid staining, but hidden damage still occurs. The observed frequencies
always vary with post-irradiation sampling time, so there is never a fixed yield to set against a given exposure dose. Ionizing radiation
can produce both types; the type recovered at first post-irradiation division depends upon the duplication status of the target
chromatin, chromosome-types arising from pre-replicated chromatin. (C) Many forms lead to mechanical separation problems at
anaphase (inter-cell bridges) and acentric fragments are usually excluded from the daughter nuclei, leading to micronuclei in their
cytoplasm. (D) The exclusion of any visible fragment means the loss of many megabases of DNA. These bridges and fragments are the
primary cause of cell lethality and genetic imbalance.
(Courtesy of Dr John Savage)
producing so-called multiply damaged sites (MDS), as irradiated cells (Figure 17.3). As these events appear to cor-
described by Ward. relate radiation-induced cell killing, such damage is consid-
On a larger scale, radiation damage to chromosomes and ered an important aspect of the radiation-induced effects in
chromatids leading to aberrations involving breakage and many cells. Furthermore, chromosome damage may be a
rejoining of chromosome/chromatid fragments (e.g. trans- very sensitive indicator of environmental radiation expo-
locations and ring formations) are observed in many sure in an individual.
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Chapter | 17 | Molecular, cellular and tissue effects of radiotherapy
AP, abasic site; BD, base damage; CL, cross-links; DSB, double strand break; SSB, single strand break.
(From Steel 2002, with permission of Hodder Education.)
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Walter and Millers Textbook of Radiotherapy
End processing
Rad51 Rad50
Rad52 Mre11
Nbs1
RPA Rad52
Joint molecule formation Rad51 Rad54
Rad55 Rad57
Ku DNA-PK
Rad50 Ligase IV
Mre11 XRCC4 ATM
Nbs1
p53
Ligation, branch migration,
holiday junction resolution Bax p21
Cell cycle
Arrest/
Progression
Apoptosis
B
A
Figure 17.4 DNA double strand break repair; (A) homologous recombination repair (HRR) and (B) non-homologous end-joining
(NHEJ). NHEJ is error prone while HRR uses a non-damaged homologous template and is therefore error free.
seals the breaks by forming a phosphodiester bond. Impor- Epigenetic radiation signalling
tantly, however, DNA-PK also appears to trigger signal mechanisms
transduction pathways that are involved in stress responses
leading to apoptosis (leading to the elimination cells bear- Although, traditionally, nuclear DNA has been considered
ing excessive or irreparable damage), cell cycle arrest to be the key target for the biological effects of ionizing
(allowing cells more time for repair) or cell progression. radiation, numerous studies have now revealed several
This is an example of an important concept, developed non-genomic epigenetic targets that influence a cells
from studies in molecular radiobiology, that cells possess response to ionizing radiation. Radiation-induced damage
sensors of induced damage and that these act to link dam- to cytoplasmic, mitochondrial and membrane structures,
age to a cells ultimate response through intricate cell sig- changes in redox balance and protease activity have all
naling pathways. Patterns are now emerging that allow now been suggested to mediate cellular responses to ionizing
critical molecules and pathways to be recognized linking radiation. These include ceramide production from plasma
DNA damage and DNA damage repair to classical out- membrane-derived sphingomyelin and activation of numer-
comes of radiation exposure. ous signalling pathways including inflammatory-type path-
A major unanswered question, which is now the focus of ways, mediated by proinflammatory cytokines (e.g. tumour
increasing research, is the extent to which variation in the necrosis factor a (TNF-a) and cytokine IL-1) and other
level of expression/activity of DNA repair enzymes plus cytokines and cytokine receptors, plus cell adhesion mole-
enzymes and proteins involved in downstream signalling, cules and proteases/antiproteases. These responses play an
influences the outcome of RT. Given the highly ordered important role in tissue recovery and remodelling following
nature of the described protein machines, small structural irradiation (see later). Another example of the epigenetic
changes introduced by single amino-acid changes in indi- radiation-induced signalling includes expression of epider-
vidual proteins may alter the activity of the complex signif- mal growth factor receptor (EGFR), which has a prosurvival
icantly. Indeed, there is increasing evidence that mild effect. Pharmacological inhibition of this pathway leading to
reductions in DNA repair capacity, assumed to be the con- cell sensitization can be achieved with EGFR-binding antibo-
sequence of common genetic variation in the human pop- dies or small molecule inhibitors of the EGFR tyrosine kinase
ulation (polymorphisms), affect cancer predisposition (e.g. Gefitinib (Iressa) and Tarceva (erlotinib, OSI 774)).
and, by inference, may possibly modulate the response Another factor to consider is the bystander effect, an
to radiation treatment as well. intercellular signalling pathway now described in several
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studies. These responses appear to be cell-type dependent, an important factor following the irradiation of human
and they consist of broad cellular changes including gene tumours. This has been shown by direct and indirect clinical
activation, induction of genomic instability, differentiation, studies. One of the most important studies was by Tomlin-
and changes in apoptotic potential. This appears to be son and Gray in 1955. They examined sections of human
mediated, at least in part, by diffusible substances, since the bronchogenic carcinoma specimens and showed that there
effect occurs when bystander cells are physically separated were cords of viable cells close to blood vessels. By contrast,
from the irradiated cells. While the diffusible substance 150180 mm from blood vessels there were areas of necrosis.
remains to be identified, contenders include nitric oxide The width of the viable tissue (150180 mm) was equal to
and/or cytokines being released to mediate membrane the calculated diffusion distance of oxygen from blood ves-
dependent signaling events. Consequently, the entire tumour sels beyond which cells were unable to survive. They postu-
microenvironment may need to be taken into account when lated that radioresistant hypoxic cells were present within
considering the consequences of cancer cell irradiation. the areas of necrosis. It is possible to measure oxygen ten-
sions in accessible tumours, such as carcinoma of cervix,
by directly inserting Eppendorf electrodes into the tumour.
RADIATION-INDUCED CELL KILLING The degree of hypoxia within tumours has been correlated to
clinical outcome; tumours with large areas of hypoxia tend
to persist after RT, while those tumours that are better oxy-
As already mentioned, the objective of RT is to kill cancer cells
genated are more likely to be controlled.
while limiting damage to the surrounding normal tissue and
In addition to its effects on DNA damage, laboratory
this is achieved in part by exploiting the differences in the
studies have shown that hypoxia can also trigger genetic
response of tumour and normal tissue to irradiation. One
mechanisms that may give tumour cells additional survival
of the best known and most studied differences between
advantages. Hypoxia induces the expression of a number of
tumour and normal tissue is the manifestation of hypoxia
genes, in particular genetic programs that are under the
in tumours.
control of hypoxia inducible factor 1 (HIF-1). HIF-1 is
recognized as a key mediator of gene expression in hypoxic
Tumour hypoxia, oxygen effect
and reoxygenation
N Hypoxic
In order to grow, solid tumours need to develop their own Oxic
blood supply through the process of angiogenesis. However,
the formation of this neovasculature tends to shadow
Dq
tumour growth, consequently, a growing tumours nutrient
and oxygen demands can exceed the capacity of the hosts 1.0
blood supply. Furthermore, the chaotic nature of tumour
Surviving fraction
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Walter and Millers Textbook of Radiotherapy
tumours. The range of its downstream target genes is exten- Cells that are initially hypoxic may become more oxyge-
sive. Some of these (i.e. vascular endothelial growth factor nated during a fractionated course of RT. Following a frac-
(VEGF), erythropoietin and TNF-a) are clearly aimed at tion of RT, most of the radiosensitive aerobic cells in a
increasing angiogenesis and oxygen delivery, so driving tumour will be killed and the surviving fraction will be pre-
tumour growth. HIF-1 regulated mechanisms also control dominantly hypoxic. If sufficient time is allowed before the
the acidity of tumour tissue and may further enhance next fraction of radiation, some of the tumour cells will
tumour growth and radioresistance. Importantly, hypoxia oxygenate through the process of reoxygenation and, if this
can induce apoptosis by a mechanism dependent upon a is efficient, the presence of hypoxic cells does not greatly
drop in extracellular pH. Although, intuitively, this process affect the response of the tumour. However, the speed of
would be expected to reduce the tumour cell population, it reoxygenation varies widely, occurring within a few hours
can in fact provide a selective pressure for the emergence of in some tumours and several days in others.
apoptotic-resistant subclones (see Figure 17.6B). In this In order to reduce the number of hypoxic cells in a tumour,
way, hypoxia may select for cells with p53 mutations (since in the past, patients have been irradiated in hyperbaric oxygen
cells expressing wild-type p53 tend to undergo apoptosis chambers breathing oxygen at three atmospheres pressure.
more readily) and these tumours will have an anti- Breathing in hyperbaric oxygen has been shown to be advan-
apoptotic, more malignant phenotype. tageous in some tumours (locally advanced head and neck
Irradiation
(Damage fixation)
H2O
DNA-OO
OH H2O O2
DNA DNA
RSH
Normoxia [O2] DNA
A RS (Damage repair)
Hypoxia
Ca IX activity
Fixation of radiation
Apoptosis EC pH ECM Breakdown
induced DNA damage
Figure 17.6 (A) The pivotal role of oxygen in the fixation of radiation-induced DNA damage. Ionizing radiation generates
hydroxyl free radicals (OH) that lead to the formation of DNA-centered radicals (DNA). In the presence of oxygen, this
damage becomes fixed. However, under hypoxic conditions, endogenous thiols (RSH) are able chemically to repair this
damage (by donating hydrogen), effectively contributing to radioresistance. (B) Schematic diagram showing the role of hypoxia
in causing radioresistance. In addition to its physical effects on the fixation of radiogenic DNA damage, hypoxia triggers
specific patterns of gene expression, mediated by HIF-1a. CA IX is pivotal in this response, causing acidification of the
extracellular space, promoting extracellular matrix breakdown and apoptosis which, in turn, may provide a selective pressure
favoring apoptosis-resistant subclones.
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Chapter | 17 | Molecular, cellular and tissue effects of radiotherapy
Surviving fraction
compounds and the ability to identify tumours with signif- 0.5 s
icant hypoxic fractions has restored faith in the potential
for this approach. One potentially fruitful opportunity
for further development in this area centres on the recogni-
0.4
tion that cells can react to hypoxia by switching on specific
genes (i.e. glucose transporter 1 (GLUT-1) and carbonic
anhydrase 9 (CA 9)). This will not only allow the identifi-
cation of hypoxic cells but may allow the specific targeting
0.3
of hypoxic cells in gene therapy approaches. In addition,
the use of drugs that are specifically activated in hypoxic
areas (i.e. tirapazamine (SR4233) and AQ4N) have also
been studied.
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Walter and Millers Textbook of Radiotherapy
Patterns of cell death after irradiation Within a few hours there is no trace of the dead cell. For this
reason, apoptosis was underestimated in the past as a
Historically, radiation has been considered to kill cells source of cellular loss. The frequency by which cells
largely by means of a mitotic cell death in which proliferat- undergo apoptosis varies in different tumour types. For
ing cells undergo a general breakdown (i.e. necrosis, see example, lymphomas have a high incidence of both sponta-
below) when they attempt to divide with radiation- neous and treatment-induced apoptosis, whereas high-grade
damaged chromosomes. This holds true for many cells gliomas do not.
but it is clear that some cells, notably those of some normal Necrosis is a pathological process that is not a compo-
tissues, die via a morphologically distinct mechanism nent of normal tissue haemostasis and may occur in
known as apoptosis. The differences between apoptotic tumours due to prolonged nutrient and oxic deprivation.
and necrotic cells are listed in Table 17.3. Cells lethally This involves the loss of membrane integrity, an increase
injured by radiation typically execute one or more divisions in cell size with the release of lysosomal enzymes with a
before dying. The number of divisions depends on the size subsequent inflammatory response. Necrosis can follow
of the radiation dose but after a dose of 2 Gy, two or three vascular injury, changes in pattern of perfusion through
attempts to divide may be made. The progeny of these cells the tumour or may be the mode of death of cells that lack
may all die or a proportion may survive to contribute to the an adequate apoptotic pathway.
reproductive (clonogenic) pool. In the interphase death
process, whereby cells die before they divide, cells die
26 hours after irradiation. These tend to be radiosensitive Models of radiation cell survival
cells such as lymphocytes, spermatagonia and hair follicles As radiation-induced cell killing is exponential rather than
and only relatively low doses of radiation are required. arithmetic in nature, it is traditionally illustrated as the log-
Apoptosis is an important mechanism of normal tissue arithm of survival plotted against linear dose. A typical
homeostasis and is a form of programmed cell death. It survival curve produced by low LET radiation (x- or g rays)
is a mechanism for eliminating cells that have sustained is shown in Figure 17.5. There are two components to this
high levels of potentially deleterious, irreversible damage. curve. First, there is an initial slope (designated D1) and
It is now recognized as being the outcome of a sequence shoulder, then at higher doses the curve becomes steeper
of biochemical signals, usually requiring the involvement and straighter as survival decreases exponentially with
of p53 gene products, that ultimately result in the activa- dose. Cell killing is measured in the exponential part of
tion of a series of enzymes (caspases) that degrade cellular the curve by using the value D0, which is the dose sufficient
proteins and DNA endonucleases that cut DNA in regularly to reduce the survival fraction by 37% (1/e) and in so doing
repeated regions that are not protected by nucleosomal the radiation induces on average one lethal event per cell.
proteins. The latter results in the fragmentation of DNA The size of the shoulder is regarded as giving an indication
into multiples of 80100 base pairs which produce a char- of the repair capacity of the cell and can be quantified by
acteristic ladder pattern when the DNA is separated in an the quasi threshold dose Dq.
agarose gel. The significance of this is that apoptosis is There have been several mathematical models developed
under specific genetic control and, therefore, susceptibility to describe cell survival curves, including the multitarget
to radiation-induced apoptosis may be amenable to equation, the multitarget with single hit equation and the linear
manipulation. Apoptotic cells undergo phagocytosis by quadratic equation. The oldest, the multitarget theory, pre-
neighbouring cells and inflammation is not induced. sumed that the cell contained a number of critical targets
all of which have to be inactivated to bring about lethality.
However, studies with human tumour cells indicate that
the initial shoulder is not absolutely flat, so the simple mul-
Table 17.3 A comparison of some of the morphological titarget equation is not appropriate. The linear quadratic
features of apoptosis and necrosis model is a better description of cell killing, particularly at
lower dose. This assumes that radiation can produce both
NECROSIS APOPTOSIS non-recoverable and repairable lesions. Non-repairable
damage is referred to as the alpha component (represented
Cells swell Cells shrink as aD on a logarithmic scale) and is considered induced lin-
Mitochondria dilate and Organelles retain definition early by single hit mechanisms, while the beta component
other organelles dissolve for a long time (bD2) describes the quadratic cell inactivation by the accu-
mulation and possible interaction of repairable damage
Plasma membranes Cells dissociate from induced by multiple hits. When plotting cell survival,
rupture surrounding cells alpha-type damage is represented by a straight line and beta
damage by a curve (Figure 17.8). The ratio of alpha-beta
Nuclear changes Chromatin condensation and
(a/b) is the dose at which single and multi-hit mechanisms
unremarkable regular DNA degradation
contribute equally to cell killing; that is aD bD2.
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Chapter | 17 | Molecular, cellular and tissue effects of radiotherapy
Late responding tissues repair saturation models, though the actual mechanisms are
Acute/early responding tissues rudimentary and poorly defined. Furthermore, the recently
discovered phenomenon of low-dose HRS (see above) deems
D
that the older (and indeed some of the more current) models
D2 of radiation cell killing cannot be considered as adequate.
Log (surviving fraction)
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Walter and Millers Textbook of Radiotherapy
of the skin stem cells, which usually regenerate most of their settle without any late effects. However, if there has been
number before differentiating to restore function. This pro- marked depletion of the epidermal proliferating cell com-
cess is normally complete within a few weeks. A similar effect partment, the skin may be thin (atrophic) and may be white
is seen within the mucosa of the upper aerodigestive tract. owing to loss of pigment-producing cells. There may be also
Cells are lost from the mucosa following RT leading to a char- permanent loss of hair. The tissues of the dermis may be
acteristic radiation reaction. Initially, there is erythema of the replaced with fibrous tissue leading to thickening of the
mucosa followed by mucosal cell loss. This denuded area is subcutaneous tissues and loss of elasticity. The thickening
covered by a white membrane containing inflammatory exu- of tissues around joints, such as the shoulder, may lead
date and dead cells and is usually white in colour. In the nor- to marked reduction in shoulder movement. The walls of
mal mucosa, only about 15% of stem cells are undergoing arteries may be replaced by fibrous tissue leading to narrow-
cellular division to replace normal cell loss. The majority ing of the lumen and thrombosis. This is often followed by
are in the resting phase (G0) of the cell cycle. After about compensating dilation of skin capillaries leading to telangi-
1012 days into a standard course of RT, virtually all surviving ectasia of the skin. These red blood vessels on the skin
stem cells are dividing to replace cell loss from RT. Usually surface may be very disfiguring.
within a few weeks of completing a standard dose of RT the Ultimately, perhaps following a minor insult such a
mucosa has healed, but if a very high dose has been given suf- trauma or infection, the skin may necrose leading to
ficiently to destroy the stem cell pool, the patient may be left a non-healing ulcer.
with a persisting area of ulceration within the treated area.
The tolerance of normal tissues
Subacute reactions of normal tissue The dose that can be given to tumours is limited by the toler-
Some tissues, such as neural tissue, have a much longer nor- ance of normal tissues. The tolerance depends on the overall
mal turnover time than skin or oral mucosa. The effects of radiation dose, fraction size and the time between fractions.
radiation may not be seen until several months after treat- Overall treatment time and the volume irradiated are lesser
ment. A typical example is Lhermittes syndrome following factors, but the type of radiation used is also very important.
irradiation of the spinal cord. A few weeks after treatment Megavoltage x-rays spare the skin compared to kilovoltage
the patient complains of electric shocks radiating down to (250300 kV). Absorption in bone and cartilage is also much
fingers and toes especially if they flex their neck. This is due less with megavoltage x-rays and there is less risk of necrosis.
to partial temporary demyelination of the spinal cord. There By and large, acute reactions settle with simple medical
is often an interval of 918 months before late effects are seen measures. It is the late effects that are most feared as target
in cell populations with a slow rate of proliferation such as organ damage can be severe and capacity for recovery is
nervous tissue, kidney, blood vessels, subcutaneous tissue usually small. Such injuries are very difficult to treat surgi-
and bone or cartilage. Initially, damage to the slowly prolif- cally as the blood supply to heavily irradiated tissues is very
erating vascular endothelium was thought to be the common poor. The frequency of late effects depends upon the site
cellular injury linking most late effects. Undoubtedly, dam- and the stage of the tumour. The aim of RT following lump-
age to blood vessels is important but, for example, with late ectomy for breast cancer is local control of the breast cancer
demyelination of the brain there is also loss of oligodendro- plus a cosmetically acceptable breast. The late serious com-
cytes and subsequently neurons as well as damage to small plication rate following breast irradiation should be very
blood vessels. Similarly, in the kidney, there is loss of renal small (less than 0.5%). In early larynx cancer, the incidence
tubular cells as well as vascular injury. In late responding tis- of serious necrosis is only 12%, although the incidence
sues, such as jejunal mucosa, cell loss is rapid and there may rises with more advanced disease. One of the highest fre-
be evidence of radiation-induced cell loss within 24 hours of quencies of late effects is seen in the treatment of cancer
irradiation. By contrast, in the kidney there may be no histo- of cervix. In a national audit of patients treated in 1993,
logical evidence of cell depletion for many months after RT. If the incidence of serious late injury was 6%.
a high enough radiation dose has been given to destroy all the The tolerance of organs that have rapidly proliferating
clonogenic tubular cells, the tubules will not regenerate. If cells may be quite low. The tolerance of both lungs to mega-
one or more tubular clonogenic cell per nephron survives, voltage RT is 20 Gy given in 15 fractions over 3 weeks. The
the tubule may well regenerate over several months. kidney has a similar tolerance. The tolerance of the whole
liver is 25 Gy given again over 3 weeks. The incidence of
radiation myelitis of the spinal cord is 15% with doses
The effect of radiotherapy of 5054 Gy given in 1.8 or 2 Gy fractions.
upon tissues
Retreatment
All tissues have different cellular populations within them
and may undergo both acute and late damage. A typical Conventional wisdom is that heavily irradiated tissue will not
example is the effects on skin and subcutaneous tissue. tolerate a retreatment. Previous high dose irradiation may
If the radiation dose is moderate, any acute reaction may limit the tolerance of the tissue to retreatment but, in some
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namely, the inability to restrict the treatment beam to the control and/or to decrease late effects by predicting out-
tumour-bearing tissue. However, the move from conven- come on an individual basis to select the most appropriate
tional conformal RT to IMRT involves more fields and treatment for each patient. Also, molecular/biologic stud-
a larger volume of normal tissue being exposed to lower ies should enable development of new combined-
doses. In addition, the number of monitor units is increased modality treatments such as RT and concurrent biological
by a factor of two to three, increasing the total body exposure, therapies or chemotherapy in a scientifically rational man-
due to leakage radiation. Both factors will tend to increase the ner. The advent of the Omic technologies holds great
risk of second cancers, with IMRT estimated approximately to promise for the future development of molecular studies
double the incidence of second malignancies compared with in RT. Gene expression arrays (cDNA and oligonucleotide
conventional RT from about 1% to 1.75% for patients surviv- arrays) allow investigation of large numbers of patients
ing 10 years. The numbers may be even larger for longer sur- genes and show variation in gene expression among
vival (or for younger patients), but the ratio should remain tumours with similar histological features. In diffuse large
the same. Image guided radiation therapy (IGRT) consists of a B-cell lymphomas, there is a very different overall survival
linear accelerator with an integrated 3D volume imaging between two such groups using this assay. Genes that
functionality. This allows an image of the tumour site with would be expected to be good candidates for prediction
CT-like quality to be acquired and reconstructed immediately of radiosensitivity include DNA repair genes and genes
before treatment, with the patient already set up in the treat- related to cell cycle control, growth regulation, and differ-
ment position. Consequently, if the patient needs to be entiation. Proteomic technologies may also have a role in
moved, the treatment table can be controlled remotely to investigation of radiosensitivity as it can provide a more
do so. Alternatively, if the tumour is no longer where it was accurate indicator of protein function than gene expres-
or has changed shape or size, then the treatment plan or con- sion arrays by taking into account post-translational
formal setting can be modified as appropriate. If the tumour modifications.
is likely to move during treatment (for example a lung tumour In summary, radiobiology has reached a stage where spe-
during respiration) then appropriate margins can be set using cific molecular and cellular pathways and responses are
sequential imaging. This allows the radiotherapist to address being related to the various outcomes of RT. Such studies
directly clinical concerns regarding organ motion and defor- are exposing new potential targets for therapeutic manipu-
mation and uncertainties in repeating and maintaining the lation of radiation responses. The well-established efficacy
set-up of the patient, thereby inspiring clinical confidence of RT, together with the accumulated knowledge of many
in the practice of advanced radiation therapy techniques. decades of treatment, provides a robust platform from
which to launch novel approaches to extend the usefulness
and increase the efficacy of RT. Combined with the molec-
ular evaluations of the probability of tumour cure and
Molecular studies
normal tissue complication, as well as the more precise
An important future aim of molecular/biologic studies in delivery of dose, the future of radiobiology in RT research
RT is to increase the therapeutic ratio to increase tumour looks bright.
FURTHER READING
Books biology of cancer. 4th ed. and therapy. Nat Rev Cancer
Hall EJ. Radiobiology for the radiologist. Oxford University Press; 2005. 2005;5:86775.
5th ed. Lippincott Williams and p. 41427. Connell PP, Kron SJ, Weichselbaum RR.
Wilkins; 2000. McBride WH, Doughert GJ, Milas L. Relevance and irrelevance of
King RJB. Cancer biology. 2nd ed. Molecular mechanisms in DNA damage response to
Prentice Hall; 2000. radiotherapy. In: Alison M, radiotherapy. DNA Repair (Amst)
editor. The cancer handbook. 2004;3:124551.
Steel GG. Basic clinical radiobiology.
John Wiley & Sons; 2002. Ward JF. Complexity of damage produced
3rd ed. Arnold; 2002.
p. 135969. by ionizing radiation. Cold Spring
Chapters in books Harb Symp Quant Biol
Kiltie AE. Radiotherapy and molecular Journal reviews 2000;65:37782.
radiotherapy. In: Knowles MA, Barcellous-Hoff MH, Park C, Wright EG. Willers H, Dahm-Daphi J, Powell SN.
Selby PJ, editors. Introduction Radiation and the Repair of radiation damage to DNA.
to the cellular and molecular microenvironment tumorigenesis Br J Cancer 2004;90:1297301.
292
Chapter | 18 |
Principles of management of patients with cancer
Paul Symonds, Cathy Meredith
1. Preparation
Know all the facts before the meeting, find out who the patient wants present and ensure privacy and chairs to sit on.
2. What does the patient know?
Ask for a narrative of events by the patient (e.g. How did it all start?)
3. Is more information wanted?
Test the waters but be aware that it can be very frightening to ask for more information (e.g. Would you like me to
explain a bit more?)
4. Give a warning shot
e.g. Im afraid it looks rather serious then allow for a pause for the patient to respond.
5. Allow denial
Denial is a defence, and a way of coping. Allow the patient to control the amount of information.
6. Explain (if requested)
Narrow the information gap, step by step. Detail will not be remembered but the way you explain will be.
7. Listen to concerns
Ask What are your main concerns at the moment? and then allow space for expression of feelings.
8. Encourage ventilation of feelings
This is the key phase in terms of patient satisfaction with the interview because it conveys empathy.
9. Summary and plan
Summarize concerns, plan treatment, foster hope.
10. Offer availability
Most patients need further explanation (the details will not have been remembered) and support (adjustment takes
weeks or months) and benefit greatly from a family meeting.
.
professionals, who are present in the clinic, can provide use- supplementary investigations may need to be carried out.
ful reinforcement and clarification of patients questions. These may include examination under anaesthetic, endos-
Often the oncologist needs to cover the ground more than copy and appropriate radiological investigations such as
twice. computed tomography (CT), magnetic resonance imaging
This whole process involves relaying information that (MRI) or isotope bone scans. As the diagnosis of cancer has
can severely alter a patients view of their future and is chal- such possible dire implications, all patients should have
lenging for the giver of the information as well as the patient. histological proof of the diagnosis, if this is possible, espe-
A useful guide in this process is the ten-step approach to giv- cially if radical treatment is planned. To make appropriate
ing bad news (Table 18.1). This model advocates good prep- management decisions the clinician must take into account
aration, finding out what patients want to know, allowing tumour and patient factors (listed below).
denial and listening to concerns. It also recognizes the Frequently, the patients management may have been
importance of encouraging the ventilation of feelings and discussed in a multidisciplinary team meeting (MDT)
the important role played by relatives. where the patients pathology and radiological investiga-
The most important decision at this time is whether the tions will have been reviewed. The decision is usually made
patient should be treated radically with cure as the aim of about whether cure is possible and the appropriate treat-
treatment. But radical treatment may be associated with ment modality. However, only one or two of the treating
treatment-induced morbidity and, occasionally, mortality team may have met the patient at this stage and decisions
and it is therefore vital to ensure that it is the appropriate made at the MDT meeting may not survive the consultation
route to be taking. Unfortunately, a number of patients will with the patient and oncologist. When discussing treatment
be unsuitable for a radical approach to treatment and pal- options, the patients wishes are paramount. However, in
liation will be the appropriate option. practice, the majority of patients will accept the careful rea-
The next question is which is the best treatment modality soned advice of their doctors. Very occasionally, patients
or modalities for that particular patient. Clearly, the patient ask for radical treatment when this is futile. Somewhat
needs to have been fully investigated before such decisions more frequently, such requests come from relatives. How-
can be taken and usually these investigations will have been ever, a doctor is not obliged to provide a treatment that they
carried out prior to referral to the oncologist. However, conscientiously feel is not in the patients best interest.
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Chapter | 18 | Principles of management of patients with cancer
295
Walter and Millers Textbook of Radiotherapy
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Chapter | 18 | Principles of management of patients with cancer
construction of an ileostomy, whereas the right treatment paralysis. In the treatment of tumours in the head and neck,
for an unfit, elderly man may be palliative radiotherapy oesophagus and bronchus, care must be taken to restrict the
in order to suppress symptoms from his bladder cancer. spinal cord dose to 4550 Gy in 25 fractions over 5 weeks.
The side effects of radical radiotherapy may be marked. For
instance, the mucositis associated with treatment of head and
Treatment modality neck cancer may prevent the patient swallowing and they
Increasing use of multimodality treatment has rather may require nasogastric or PEG (percutaneous endoscopic
blurred the once clear-cut rules for treatment by the various gastrostomy) feeding. However, acute side effects are nor-
modalities. mally self-limiting and settle in a few weeks with the help
of simple supportive measures. It is a probability of late radi-
Surgery ation damage that limits the dose to the tumour. In the treat-
ment of breast cancer, the incidence of serious late effects
Surgery, traditionally, was important for establishing the should be vanishingly small and certainly less than half a per-
diagnosis and finding the extent of spread of the cancer. cent of those patients treated. As the life-threatening nature
Increasingly, diagnosis is made without operation using of the tumour increases, the patient and the oncologist
sophisticated imaging techniques such as MRI or CT scan- may be persuaded to take greater chances. Serious damage
ning. Histological proof may be obtained by fine needle or is seen in the larynx following treatment for a T3 (fixed vocal
tru-cut biopsy. Radical surgery is still the treatment of cord) tumour in 13% of patients. In patients with inopera-
choice for many adenocarcinomas, particularly arising in ble cervical cancer, the only realistic chance of cure is chemor-
the stomach, colon, thyroid and kidney. adiotherapy. Some of the highest complication rates
associated with radiotherapy are seen following the treat-
Palliative surgery ment of cervical cancer. On average, 6% of patients require
Prior to palliative surgery, the risks and benefits to the surgery to try to correct late damage following treatment.
patient need to be carefully measured and the patients
potential life expectancy needs to be taken into account. Palliative radiotherapy
Surgery is particularly useful in dealing with obstruction
Palliative treatments can make up between one-third and
of an organ. A classical case is the relief of large bowel
one-half of the workload of any department. The aim of
obstruction by a colon cancer by a colostomy. However,
such treatment is to relieve local symptoms in advanced
palliative surgery may be inappropriate in patients with mul-
cancer. An important part of the treatment is that there
tiple small bowel obstruction. This is often the case in ovar-
should be minimal upset. Treatment should be simple
ian cancer where the risks of surgery outweigh the benefits.
and a minimum number of fractions should be used.
Advanced fungating breast tumours are much less common
Symptomatic relief should be rapid.
than they were 25 years ago, but surgery offers a rapid
Up to 80% of patients with bone metastases have signifi-
method of relieving the unpleasant odour and bleeding
cant pain relief within 3 weeks of a single radiation treat-
associated with such tumours. The pinning of the broken
ment of 810 Gy. Pain relief will be complete within half
bone, which is often followed by palliative radiotherapy,
of these patients. Other important indications for palliative
may relieve pain following a pathological fracture.
radiotherapy are the relief of haemoptysis, cough, dys-
pnoea and mediastinal obstruction in lung cancer. These
Radical radiotherapy symptoms can be suppressed in between 50 and 80% of
The decision to treat the patient by radical radiotherapy patients by a course of radiotherapy lasting up to a week,
depends on the tumour and patient factors previously dis- with minimal side effects.
cussed. The precise regimen will depend on the potential However, some symptoms require longer radiotherapy
radiosensitivity of the tumour, the size of the treatment vol- treatments. Tumours involving nerves, such as the brachial
ume and the proximity of dose-limiting critical tissues. Semi- plexus (Pancoast tumours from the apex of the lung) or the
noma of the testes is among the most radiosensitive lumbosacral plexus, produce pain of a very unpleasant
tumours. The doses required to control small volume disease quality that is difficult to relieve with opiate analgesia.
in the para-aortic lymph nodes are 2530 Gy in 15 fractions Relief of such neuropathic pain may require 45 weeks
over 3 weeks. By contrast, large lymph nodes containing radiotherapy treatment. Typically, neuropathic pain from
metastatic squamous carcinoma may not be controlled by advanced rectal cancer can be relieved in two-thirds
doses as high as 70 Gy given in 35 fractions over 7 weeks. of patients with doses of 4550 Gy given in 45 weeks.
What governs radiation dose is the tolerance of the sur- Radiotherapy can prolong life in some incurable tumours.
rounding normal tissues. The small bowel is the most sen- Randomized controlled trials have shown that the average
sitive tissue in the pelvis and the chance of serious small survival of patients with glioblastomas of the brain follow-
bowel damage rises steeply with doses exceeding 50 Gy ing optimal surgery and radiotherapy is only a year. How-
given in 25 fractions over 5 weeks. Radiation damage to ever, 6 weeks radiotherapy increases a patients survival by,
the spinal cord can be catastrophic leading to permanent on average, 9 months compared to treatment with surgery
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Walter and Millers Textbook of Radiotherapy
and best supportive care. When making the decision to There are important support nurses in the community,
offer a patient 6 weeks radiotherapy, one needs to balance such as Macmillan and Marie Curie nurses. As well as
life expectancy that is taken up by the radiotherapy treat- providing advice on symptom control and emotional sup-
ment and the associated fatigue with the survival benefit port for both patient and family, they also have a most
associated with a treatment which is unlikely to cure the important liaison role. They can act as a link between the
patient. Elderly or more infirm patients are probably better patient, the general practitioner and hospital services. Dis-
treated by a simple scheme of 30 Gy given in six fractions trict nurses play an important role of care at home
three times a week over 2 weeks rather than 60 Gy given providing basic services such as bathing, dressing of
over 30 fractions. wounds and giving medicines by injection.
Adequate nutrition is important following both radical
and palliative radiotherapy and hospital- and community-
Chemotherapy
based dieticians help with the special dietary needs of
Chemotherapy can be given as the sole source of treat- patients. Patients may also require the help of the prosthetic
ment when there is a high chance of cure. Only a small services. For some patients, one of the most distressing side
number of tumours are highly chemosensitive and these effects of chemotherapy or radiotherapy to the head is hair
include the lymphomas, testicular teratoma and choriocarci- loss. A good quality wig may help to maintain the patients
noma. Chemotherapy frequently cures children with Wilms appearance and maintain morale. Other cosmetic prostheses
tumours, rhabdomyosarcomas and acute lymphoblastic leu- that are important are replacements for eyes and sometimes
kaemia. Chemotherapy may be given prior to radiotherapy ears or noses. Prosthetic limb fitters may be required to
or surgery to reduce the tumour in size. This is often referred provide replacement limbs following amputation.
to as neoadjuvant treatment. Increasingly, radiotherapy A patient with cancer may be the main breadwinner for
and chemotherapy are given together. This is of proven value the family, therefore, his or her illness may cause acute
in the treatment of carcinoma of cervix and squamous carci- financial problems. Medical social workers and the Depart-
noma of anus. Clinical trials are continuing in other tumour ment of Health and Social Security may be able to provide
sites, particularly in the treatment of carcinoma of oesopha- financial support both from the State and from charitable
gus and squamous carcinoma of the head and neck. Chemo- bodies. Last, but not least, is a range of national and local
therapy may be of palliative value only in advanced breast support services such as Cancer BACUP or Macmillan
cancer or carcinoma of the colon but, in the treatment of Cancer Support.
small volume disease following surgery, adjuvant chemo-
therapy may improve cure rates. Chemotherapy improves
10-year survival in node positive breast cancer by about
Palliative care
10%. A similar survival advantage is seen following adjuvant In a regional oncology centre, at least 50% of the work is
chemotherapy in Dukes stage C colon cancer. the treatment of advanced disease. Patients may be judged
incurable from the outset and the aim of treatment is the
relief of physical and psychological distress. Subsequently,
Support services
patients who were thought initially to be in the curable cat-
During and after cancer treatment, a wide range of services egory (such as carcinoma of breast) may develop advanced
to provide the patient with physical, psychological and disease and may require the same type of care. Oncology
social support should be available. The most important sin- centres will have developed their own systems of care to
gle individual is the general practitioner. The general prac- support these patients and this should interface well with
titioner needs to be appraised of the patients progress, the their home or hospice care.
likely side effects of cancer treatment and what can be done Ideally, patients should be cared for at home with the
at home to treat these side effects. They also need to be help of the general practitioner and district nurses. Specia-
informed of what is the patients likely prognosis. This is list Macmillan nurses make a significant contribution to
especially true if the treatment is palliative, as the general this process and, increasingly, organizations such as Marie
practitioner has a key role to play in the provision of Curie provide hospice at home services.
continuing care. There is a wide range of specialist nursing Patients who have symptoms that cannot be controlled
services. Some have a relatively restricted role, such as stoma at home or when their nursing care is too complex may
care nurses who provide practical advice on the management need admission to hospital or, ideally, to a specialist hos-
of bowel (colostomy and ileostomy) and urinary (urost- pice. Hospices provide a more homely, less institutional
omy) stomas. Increasingly, specialist nurses are attached to and quieter environment than the noisy, busy hospital
multidisciplinary teams in areas such as breast, gynaecologi- ward. The higher staff to patient ratio gives more time for
cal and CNS cancer. They have multiple roles in giving the patients to talk about their illnesses. The hospice team
patient specialist advice and psychological support. Last, has the distinctive knowledge and skills needed to provide
but not least, is a range of national and local support services spiritual and emotional support for patients at this chal-
such as Macmillan Cancer Support. lenging time. Often, after symptoms have been controlled,
298
Chapter | 18 | Principles of management of patients with cancer
patients may be able to return home perhaps to return to is 180 milligrams. This can be given in the form of 90 mg of
the hospice at a later date. Such patients while at home MST every 12 hours to provide sustained pain control. If the
can be helped by attendance at the hospice day centre. patient cannot swallow, diamorphine is a useful substitute.
As well as checking that the patients symptoms are con- This is highly soluble in very small quantities of water and
trolled, hospice day centres provide a social environment can be given subcutaneously either by intermittent injection
for patients and can allow other family members a respite or continuously using a syringe driver. Diamorphine has
from care to continue employment. roughly twice the potency of morphine when given by injec-
One of the main aims of a hospice is symptom control. tion and three times the potency of oral morphine. Virtually
These include pain, anorexia, nausea, vomiting, dysphasia, all opiates cause constipation and patients should be rou-
dyspnoea and lack of energy. tinely prescribed a laxative. A common side effect is nausea
but this usually settles within 5 days.
Respiratory depression is rarely a problem but, if the
Pain control
patient develops significant respiratory oppression, mor-
Up to three-quarters of patients with advanced cancer may phine can be temporarily stopped and restarted at a lower
have some degree of pain. Up to 80% of patients may have dose. Occasionally, very high doses of morphine can cause
pain at multiple sites. The three most common sources of myoclonic twitching of limbs.
cancer pain are bone metastases, compression of nerves About 1015% of patients are intolerant to morphine
and soft tissue disease. because of either prolonged nausea or a dysphoric reaction.
Pain has both physical and psychological dimensions. Alternative preparations are fentanyl patches, hydromor-
Anxiety or depression may accentuate the perception of pain phone or oxycodone. In the treatment of neuropathic pain,
and lower the pain threshold. Physical conditions such as tricyclic drugs, such as amitriptyline, or anticonvulsants such
hypercalcaemia may also physiologically increase the degree as gabapentin or sodium valproate often help symptoms.
of pain. The treatment of hypercalcaemia may be a pain con- Occasionally, patients with neuropathic pain may require
trol measure by itself. The basis of pain control is to establish a nerve block. Sites where this can be carried out are in
the causes of pain and, if possible, eradicate the source of the intercostal nerves in the ribs, the brachial plexus when
pain. The patient may benefit from a single radiotherapy this is involved by an apical lung tumour, coeliac axis plexus
treatment. However, come what may, the pain should be following infiltration by a pancreatic cancer or involvement
controlled by suitable analgesia if this is possible. of the lumbar-sacral nerve plexus by pelvic cancer. These
Ideally, all analgesics should be given by mouth. Mild or nerve blocks are technically very demanding. Usually a
moderate pain may respond to simple analgesias, such as long-acting local anaesthetic is injected to check that nerve
paracetamol or aspirin. The non-steroidal group of analge- block will bring about adequate analgesia. If the pain is
sics, such as diclofenac, may be useful, especially for bone relieved this could be followed by a further injection using
pain. They can, however, cause gastric irritation and should phenol or alcohol to destroy the nerve.
be used with caution in even mild degrees of renal failure.
Codeine or dihydrocodeine are useful for moderate pain
Dyspnoea
but, unlike morphine, the dose of these drugs cannot be
escalated. Increasing the doses above 60 mg four times a Shortness of breath can be more frightening than pain
day just produces toxicity and not an increase in analgesia. and sometimes more difficult to treat. Treatment of the
Morphine is still a standard analgesic for severe pain. underlying cause is often useful, such as aspirating a pleural
In patients with normal renal and hepatic function, the effusion or abdominal ascites. If there is a strong anxiety
metabolic half-life of morphine is two and a half hours. It component, an anxiolytic, such as diazepam, may be help-
therefore needs to be given no less frequently than four ful. Morphine depresses the respiratory centre but this side
hourly. Morphine serum levels are stable after six half-lives, effect is beneficial in reducing tumour-induced dyspnoea.
therefore, in practice morphine doses can be escalated every As in the control of pain, the ideal route of morphine
12 hours. An initial dose of oral morphine should be chosen administration is by mouth but, if necessary, the patient
according to the patients age, size and the degree of pain. may require diamorphine by syringe driver. As in other
This may vary between 5 and 30 milligrams. This is usually forms of dyspnoea, oxygen can be very helpful along with
given in the form of either morphine sulfate tablets or an psychological support from staff.
elixir. The dose can be rapidly escalated if necessary. When
pain control is achieved, the total morphine dose over
Nausea and vomiting
24 hours can then be added up. This is a guide for the pre-
scription of a strong acting analgesic such as MST (morphine There are many causes of nausea and vomiting in advanced
sulfate continuous tablets). These tablets contain morphine cancer patients. Drug-induced vomiting is one of the most
in a cellulose matrix that is slowly released over a 12-hour common. This may be also a symptom of renal or hepatic
period. If the patient has been receiving 30 mg of morphine failure. Vomiting without a headache can be a feature of
elixir every four hours, the total morphine dosage in 24 hours raised intracranial pressure.
299
Walter and Millers Textbook of Radiotherapy
5HT3 antagonists, such as granisetron or ondansetron, At least a quarter of patients with advanced cancer have
are probably the most effective drugs in the treatment significant depression. Virtually all patients with advanced
of radiotherapy- or chemotherapy-induced nausea and cancer have a feeling of sadness and a sense of loss. Antide-
vomiting. Where nausea and vomiting are associated with pressant medication should be considered sooner rather
a strong anxiety component, antiemetic drugs, such as than later. The selective serotonin re-uptake inhibitors,
prochlorperazine or haloperidol, are often useful. such as fluoxetine or sertraline, are better tolerated than
the traditional tricyclic antidepressants. They often work
faster than the 3 weeks often quoted. Counselling, relaxa-
Anorexia
tion therapy and other measures are also useful adjuncts
Anorexia is often multifactorial in origin. The most com- in the treatment of anxiety and depression.
mon cause is the underlying malignancy. It is thought that
the cancer stimulates the release of cytokines from the
immune system, which induce anorexia. Anorexia though
Context of care
may be due to treatment (radiotherapy or chemotherapy)
or the physical effects of cancer, such as pain or intestinal It is apparent that there is a multiplicity of professionals
obstruction. Dietetic advice may be helpful and a small essential to the treatment and care of patients. These indi-
amount of alcohol before meals may stimulate the appe- viduals work across the Health and Social Care sectors
tite. Steroids are the most effective antianorexic agents. where the potential for a breakdown in communications
It is worth trying prednisolone at 30 milligrams over a is obvious. It is one of the challenges facing modern provi-
7-day period. If this increases appetite, the dose can be sion of cancer services that these groups are able to work
reduced to a maintenance dose of 510 milligrams. Proges- together as a team to enable patients to be provided with
terones, such as megestrol acetate, do improve appetite, a seamless service. This is now well recognized and encour-
however, they can cause ankle oedema and have been asso- aged by a host of Government initiatives designed to
ciated with an increased risk of thrombosis. improve cancer services across the UK.
FURTHER READING
Department of Health. The NHS cancer Meredith C, Symonds P, Webster L, et al. NHS Executive. Improving the quality of
plan. HMSO; 2000. Information needs of cancer patients cancer services. HSC/021.
Kaye P. Breaking bad news: a ten in west Scotland; cross sectional NHS Executive; 2000.
step approach. EPL Publications; survey of patients views. Br Med J
1996. 1996;313:7246.
300
Chapter | 19 |
Chemotherapy and hormones
Anne L. Thomas
Hormones 312
CHAPTER CONTENTS
Antioestrogens 312
Introduction 301 Aromatase inhibitors 312
General indications for chemotherapy 302 Gonadotrophin-releasing hormone (GnRH) analogues 313
Development and testing of anti-cancer Antiandrogens 313
agents 302
Female hormones (oestrogens and progestogens) 313
Phase I studies 302
Targeted therapies 314
Phase II studies 302
Epidermal Growth Factor Receptor (EGFR)
Phase III studies 302 signalling pathway 314
Assessing tumour responses 302 Signalling through RAS-RAF-ERK (MAPK)
The evaluation of targeted therapies 303 and PI3K-AKT 314
Principles of cytotoxic therapy 303 Vascular Endothelial Growth Factor (VEGF)
Drug resistance 303 signalling pathway 314
Selection and scheduling of chemotherapy Proteasome inhibitors 315
agents 304 Immunotherapy 315
High-dose chemotherapy 304 Further reading 315
Route of administration 304
Side effects of chemotherapy 305
INTRODUCTION
Classification of cytotoxic drugs 305
Alkylating agents 305 Chemotherapy is the use of cytotoxic (cell poisoning) drugs
Antimetabolites 305 to control tumour growth. Over the last 30 years, there have
Folate antagonists 305 been advances in the management of several solid tumours
Purine antagonists 308 and haematological malignancies, such as testicular tera-
toma, the leukaemias, childhood cancers and choriocarci-
Pyrimidine antagonists 308
noma. Over 70% of childhood cancers are now curable and
Mitotic inhibitors 309 the cure rate for teratoma is over 95%. What has been more
Topoisomerase inhibitors 310 challenging is the use of cytotoxics in the management of
Miscellaneous 311 the common tumours, such as non-small lung cancer,
breast and bowel cancer. These tumours often present in
Platinum analogues 311
the metastatic stage and are relatively resistant to chemo-
Non-anthracycline antibiotics 312 therapy. Despite intense research, chemotherapy for these
Enzymes 312 tumours remains palliative in intent rather than curative.
One of the major drawbacks of cytotoxic agents is that they Phase I studies
affect all rapidly dividing cells, and do not discriminate
between normal tissues and tumours, hence, the toxicity In phase I studies, the main aim is to establish the maxi-
of chemotherapy. We are now entering an exciting era in mum tolerated dose and the safety of the agent under in-
oncology with new targeted therapies becoming available. vestigation. Such studies are often performed with the
These novel agents are designed to exploit our increased informed consent of patients for whom standard therapy
understanding of molecular oncology and will hopefully has no role. The starting dose is determined by preclinical
be more successful in overcoming drug resistance and data and is usually a tenth of the lethal dose (LD10) in
reducing the side effects of treatment. rodents. In phase I studies, pharmacokinetic studies
Hormone therapy is another systemic treatment for can- (how the body handles the drug, for example by metabo-
cer. It may involve inhibiting the production of endoge- lism) and pharmacodynamic studies (assessing the impact
nous hormones or introducing synthetic ones. There are of the drug on the physiology of the body) are conducted.
now many different hormone preparations available and
they play a vital role in the treatment of tumours such as Phase II studies
prostate and breast cancer.
Once a drug is found to have acceptable side effects it is taken
forward into phase II studies to study its efficacy in a specific
General indications for tumour type. The type selected is usually ascertained from
chemotherapy the responses to therapy seen in the cell lines and sometimes
There are four main ways in which chemotherapy can be used from activity demonstrated in the phase I setting. The main
in the treatment of cancer. First, it is used as the primary treat- outcome is to achieve a response rate which is at least com-
ment for patients with advanced cancers for which no alterna- parable with the standard agent in that setting. Now there is a
tive treatment exists. This is sometimes called palliative vogue actually to randomize some phase II studies so that
chemotherapy and is essentially used to palliate the symp- either the drug can be compared with the standard or two dif-
toms of cancer. Adjuvant chemotherapy is the use of cytotoxic ferent dose schedules could be studied. Gaining these data as
drugs after the primary tumour has been controlled by either early as possible in a drugs development obviously enables
surgery or radiotherapy. Here, the rationale is to eradicate sub- the pharmaceutical company to withdraw a drug as soon as
clinical micrometastatic disease and reduce the risk of recur- possible if activity is disappointing or, alternatively, fast track
rence. Examples of this would be in the treatment of bowel drugs with impressive potential.
and breast cancer. Neoadjuvant (or primary) chemotherapy
is used to debulk the primary tumour in an attempt to make Phase III studies
the definitive treatment, for example surgery, successful. An
example of this is neoadjuvant therapy of large breast primary In phase III studies, the new drug is compared against the
tumours so that conservative local surgery rather than mastec- gold standard in a randomized fashion. The main endpoint
tomy is made possible. The fourth setting is to use chemother- is survival but toxicity data are collected and also quality of
apy directly into the tumour site, for example, into the blood life and health economic data. The cost effectiveness of the
supply of liver metastases from colorectal cancer. drug has to be assessed and deemed to be acceptable before
the drug can be licensed and marketed.
Development and testing of
anti-cancer agents Assessing tumour responses
Cytotoxic therapies have been discovered in a variety of It is essential that there is standardization of how tumours
ways. First, some drugs have been developed de novo based are measured and responses defined so that studies can be
on distinct properties that should confer anti-tumour interpreted accurately. A number of different response cri-
effect. Alternatively, a range of compounds are produced teria are available, but the system used most commonly
and then screened against a selection of resistant tumour now is RECIST (Response Criteria in Solid Tumours). In
cell lines. Those with significant activity are then taken for- this system, the lesions are measured in one dimension,
ward. Once this first generation drug is discovered then longest diameter (LD). A complete response is defined as
analogues with superior pharmacological properties (for eradication of all known disease based on two assessments
example less toxicity, more convenient administration), at least 4 weeks apart. A partial response (PR) represents a
are synthesized. Of course, one should not forget the past reduction of at least 30% in the sum of the LD of target
serendipitous discovery of drugs, such as cisplatin. Once lesions maintained for at least 4 weeks. Progressive disease
an agent has been shown in its preclinical assessment to (PD) represents an increase of 20% or more in the sum
have sufficient activity against animal tumours, with of LD of lesions or the development of new lesions. Stable
acceptable toxicity, it can be considered for clinical evalua- disease (SD) occurs when the measurements are either not
tion. There are three phases of clinical assessment. good enough for a PR but also not bad enough for PD.
302
Chapter | 19 | Chemotherapy and hormones
The evaluation of targeted therapies Gompertzian growth curve), it explains the limited effec-
tiveness of chemotherapy for many cancers. The reason
With the advent of targeted therapies, such as anti-angiogenic for tumour cytoreduction (e.g. by surgery) before chemo-
treatment, and epidermal growth factor inhibition, it has therapy is to bring the tumour to a lower point on the
become apparent that there are difficulties in assessing these growth curve when the growth fraction of the tumour rises.
agents using conventional study design endpoints. This is The concept of moving the tumour down the Gompertzian
because the classic endpoint of the maximum tolerated curve underpins the rationale of adjuvant chemotherapy.
dose may not actually be the biologically active dose. More- Unfortunately, it is not only the proliferating cells that
over, these agents may be cytostatic rather than cytotoxic. must be eradicated by chemotherapy but also the small pop-
This means that stabilization of disease is the best response ulation of clonogenic cells mainly in G0 phase. This explains
that can be expected and the classical endpoint of reduction some of the inherent problems of tumour chemoresistance.
in tumour volume is not reached. It is therefore imperative Cytotoxic drugs prevent cell division by inhibiting DNA rep-
that the actual target of these drugs is known and assays are lication. Unfortunately, these agents are not specifically act-
incorporated into the study design as some surrogate end- ing against malignant cells, and damage both normal and
points. An example of this would be the studies that inves- malignant proliferating cells. A careful balance has to be kept
tigated the activity of trastuzumab, the HER-2/erbB2 between toxicity to the tumour and to the patients normal
growth factor inhibitor, in breast cancer. Here, assays were tissues. What distinguishes normal and malignant cells is the
carried out in tumour biopsies to ensure that the HER-2 recep- failure of the malignant cell, unlike normal cells, to recover
tor was indeed being targeted. It is envisaged that over the from cytotoxic damage. It is exploitation of these differences
next few years there is going to be a change in study design that underpins the role of targeted therapies.
with novel validated endpoints.
Drug resistance
PRINCIPLES OF CYTOTOXIC THERAPY
A variety of host factors influence the response to chemo-
therapy, these include the growth fraction of the tumour,
To understand the rationale of cytotoxic chemotherapy it is
the availability of the drug to the tumour and drug resis-
important to recognize the features of tumour growth. The
tance. Resistance to chemotherapy may be intrinsic or
asymmetric sigmoidal growth curve, the Gompertzian
acquired. Some tumours are intrinsically chemoresistant
growth curve (Figure 19.1) describes the natural history
and show no response to treatment de novo. In other
of tumour growth. By the time that a tumour is clinically
tumours, there is an initial response followed by relapse
detectable, the majority of its growth has already occurred.
due to acquired resistance. Acquired resistance may have
In the early exponential phase of growth, the rates of
a variety of mechanisms. These include:
tumour cell growth and tumour cell loss are proportional
to the tumour cell burden at any point. Since most antican- 1. changes in the cell membrane impeding drug transport
cer agents are more toxic to proliferating cells and most (e.g. of methotrexate)
tumours are in a relatively slow phase of growth when diag- 2. DNA repair of drug-induced lesions (e.g. caused by
nosed (i.e. they lie high and towards the plateau of the cisplatin)
3. utilization of alternative metabolic pathways (e.g.
5-fluorouracil)
1E12 4. increased production of a target enzyme (e.g.
1E11 dihydrofolate reductase binding to methotrexate)
1E10 5. modification of the target enzyme, enabling it to
Limit of clinical detection
1E09 recognize the difference between true and false
1E08 metabolites (e.g. 6-mercaptopurine).
Cell number
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Walter and Millers Textbook of Radiotherapy
drug or combination of drugs for a period of time and then can be administered is limited by the tolerance of normal
ceases to do so. It is thought that within many tumour popu- tissue. Toxicity is often cumulative and may be irreversible.
lations there are genetically determined drug-resistant cells. For example, the major dose-limiting toxicity of the anthra-
When the chemosensitive cells have been killed, the resis- cycline, doxorubicin is cardiotoxicity.
tant population may proliferate. Drug resistance to
repeated exposure to a single agent will usually result in High-dose chemotherapy
cross-resistance to other compounds of the same class of
drugs. This is probably due to common transport mechan- Higher than conventional doses of chemotherapy can
isms and pathways of metabolism and intracellular cyto- be delivered if the primary organ toxicity is to the bone
toxic targets. However, cancer cells that have become marrow and there is minimal toxicity to other organs.
resistant to one class of drugs may retain sensitivity to Dose intensity is recognized to be important, particularly
another class of drugs. Most drugs have a variety of in chemosensitive tumours. Bone marrow toxicity can be
mechanisms of drug resistance. overcome by autologous bone marrow transplantation.
Some drugs which show excellent cell kill in vitro fail to Normal bone marrow is harvested from the patient
do so in vivo. There may be multiple reasons for this. For before high-dose chemotherapy. It is then returned to
example, if the tumour is in a sanctuary site, such as the cen- the patient at the time of chemotherapy to support the
tral nervous system (CNS), the drug does not cross the bone marrow through the period of neutropenia and
bloodbrain barrier and is therefore ineffective. There is thrombocytopenia. While high-dose strategies have been
also evidence that some tumours exhibit drug resistance extremely useful in haematological malignancies, the
that is partly due to host factors which modify the pharma- results from similar approaches in solid tumours have
cokinetics of the anticancer agent in vivo. Chemotherapy been disappointing.
is most effective in killing proliferating cells. While the
growth fraction is high in many chemosensitive tumours,
such as the lymphomas and testicular teratomas, it is rela- ROUTE OF ADMINISTRATION
tively low in many common tumours, e.g. colorectal can-
cer. Finally, in parts of the tumour the blood supply The route of administration is governed by the solubility,
tends to be poor. This not only results in an inadequate chemical stability and local irritant properties of the agent.
concentration of drug reaching the tumour, but also the The simplest route, and the one that patients prefer, is the
hypoxia reduces the growth fraction. oral route. Patients can take their tablets at home with inter-
mittent outpatient visits to monitor treatment. Unfortu-
Selection and scheduling of nately, many cytotoxic drugs are unstable and inactivated
in the stomach, rendering them ineffective. Intravenous
chemotherapy agents
injection is the commonest route of administration of cyto-
In an attempt to improve the curative potential of chemother- toxic agents since it gives direct access to the systemic circula-
apy, agents with proven anticancer properties against a partic- tion. It can be done by delivery of a bolus dose or by infusion.
ular tumour but with different mechanisms of action and, Continuous infusions can be given (e.g. 5-fluorouracil)
as far as possible, non-overlapping toxicities are combined. linked to a battery-operated pump worn around the patients
This is known as combination chemotherapy. For example, in waist. The risks of intravenous administration are the intro-
treating breast cancer, three agents cyclophosphamide, duction of infection and damage to the tissues around the site
methotrexate and 5-fluorouracil (known as CMF) all have of administration if extravasation occurs.
activity against breast cancer as single agents. However, their It is possible to administer intraperitoneal chemotherapy,
response rate as a combination (around 40%) is two- to three- for example, in ovarian cancer. However, the drug absorp-
fold that of their response rates as single agents. Thus, the tion is variable and there are concerns about adverse effects,
overall response is at least additive if not synergistic. such as the development of adhesions. Intra-arterial admin-
Most schedules of chemotherapy administer the drugs istration has the advantage of delivering the drug in high con-
on an intermittent basis to take advantage of the growth centration to the tissue supplied by the artery. Its limitations
kinetics of malignant cells and normal tissues. After each are the complexity of administration and the difficulty in cor-
pulse, the normal and malignant cell populations decline rectly identifying the arterial supply of the tumour. Its main
due to killing of cells in mitosis. The lowest level of the use is in the infusion of chemotherapeutic agents into the
blood count is known as the nadir. However, whereas the hepatic artery of patients with liver metastases from colorec-
bone marrow recovers to its previous level, the malignant tal cancer. Intrathecal injection is used to deliver drugs in
cell population does not. With each subsequent course, this high dose into the CNS. Many cytotoxic drugs do not cross
difference is accentuated. If the interval between pulses is the bloodbrain barrier and are therefore unable to kill
too short, toxicity may prevent the delivery of further pulses tumour cells within the CNS. Methotrexate is the agent most
on schedule, conversely, if the interval is too long, the commonly given by this route, for example, when the
tumour may regrow between courses. The total dose that meninges are involved in lymphoma.
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305
306
Cyclophosphamide
Ifosfamide
Chlorambucil
Thiotepa
Busulphan
Procarbazine
CCNU
BCNU
Dacarbazine
Mitoxantrone
Temozoamide
Mitomycin C
Melphalan
Methotrexate
6-Mercaptopurine
Fludarabine
5-Fluorouracil
Cytosine
arabinoside
Chapter | 19 |
Gemcitabine
Vincristine
Vinblastine
Vinorelbine
Paclitaxel
Doxorubicin
Epirubicin
Actinomycin D
Bleomycin
Cisplatin
Carboplatin
Oxaliplatin
Etoposide
Topotecan
Irinotecan
Asparaginase
Hyroxyurea
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patient has genetic deficiency of the dihydropyrimidine Gemcitabine is the standard therapy for pancreatic tumours
dehydrogenase, very severe toxicity can result including neu- and also is used in non-small cell lung cancer.
rological effects. 5-FU is widely used in a number of tumours,
especially those of the gastrointestinal tract.
Mitotic inhibitors
Cytosine arabinoside is an analogue of deoxycytidine.
It is a competitive inhibitor of the enzyme DNA polymer- There are two major classes of mitotic inhibitors, the vinca
ase. Its principal action is as a false nucleotide competing alkaloids and the taxanes. The vinca alkaloids are naturally
for the enzymes which are responsible for converting cyti- occurring or semisynthetic compounds found in the peri-
dine to deoxycytidine and for incorporating deoxycytidine winkle plant (Vinca rosea): vincristine, vinblastine and vinor-
in to DNA. It can be given by intravenous or subcutaneous elbine. They inhibit formation of the microtubule spindle
routes and is used mainly in acute leukaemias. The main on which the chromatids line up during metaphase in mito-
side effects are bone marrow suppression, nausea, vomiting sis and therefore prevent cell division. They are all given
and diarrhoea. intravenously and, despite being similar in structure, have
Gemcitabine is a second-generation pyrimidine analogue. differing side effects. Vincristine is used in lymphomas, leu-
It is metabolized by nucleotide kinases intracellularly to kaemias and breast cancer. It is vesicant locally and neuro-
the active diphosphate and triphosphate and inhibits toxicity is the main dose-limiting toxicity. This presents
DNA synthesis. Side effects include nausea and vomiting, in the form of a sensorimotor peripheral neuropathy (par-
myelosuppression, flu-like symptoms, rashes and oedema. esthaesiae in fingers, muscle cramps, paralytic ileus,
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Walter and Millers Textbook of Radiotherapy
Pyrimidine
synthesis Purine / amino acid
Methylene
tetrahydrofolate
dUMP deoxyuridine
5-FLUOROURACIL monophosphate
dTMP
Dihydrofolate
DNA METHOTREXATE
constipation). Vinblastine is also a sclerosant, but myelo- albumin bound paclitaxel. It has fewer hypersensitivity reac-
suppression, especially thrombocytopenia, is the main tions and is licensed for use in metastatic breast cancer.
dose-limiting toxicity. Neurotoxicity is less severe than with Docetaxel is characterized by a unique fluid retention syn-
vincristine. It is used mainly in lymphoma, testicular drome with the development of oedema and weight gain.
teratoma and non-small cell lung cancer. Vinorelbine is the As with paclitaxel, a premedication is used. Skin toxicity
most recently discovered vinca alkaloid and causes less alope- may occur and this produces a widespread itchy erythematous
cia and neuropathy than the older agents. It can however rash and nail changes characterized by discolouration, ridging
cause significant constipation. It also has the advantage of and onycholysis the nails lift up from the nail bed. Liver
being available for intravenous and oral administration. toxicity can occur if patients with impaired liver function are
The taxanes are an important class of anticancer drugs not given a dose reduction. Stomatitis and diarrhoea are more
in the field of oncology. Although they also have an effect common with docetaxel. All taxanes cause alopecia.
on the formation of the microtubule spindle, they differ Currently, a new group of mitotic inhibitors, the tubulin
from the vinca alkaloids since they promote the assembly polymerizing agents, are in development. These agents
of the microtubules spindle and inhibit its disassembly. show promise as early studies suggest they have a wider
Paclitaxel is an extract from the bark of the Pacific yew. tumour activity profile, for example in tumours that are
Initially, its development was hampered by the limited sup- taxane resistant. To date significant toxicity has been asso-
ply of the primary source and also its poor solubility in ciated with these agents and Ixabepilone is the only agent
water. With the development of docetaxel, the semisyn- to date approved for use in breast cancer.
thetic analogue from the needles of the tree, the supply
was no longer threatened.
Topoisomerase inhibitors
The most important antitumour activity of these drugs
has been seen in breast and ovarian cancer. Both drugs are Topoisomerases are enzymes involved in the coiling and
given intravenously and there has been a great deal of work uncoiling of DNA. There are two types. Topoisomerase I
involved in optimizing the scheduling. Despite being closely inhibitors bind to double-stranded DNA and cause a single
related, there are some differences in their toxicity profiles. strand break in DNA. The camptothecin analogues topote-
Both have myelosuppression as one of the major limiting side can and irinotecan are topoisomerase I inhibitors. Topo-
effects with the nadir occurring at days 810 post-infusion. isomerase II exists as alpha and beta isoenzymes. They
A relatively rare but important side effect of paclitaxel is a undergo covalent bonding to complementary strands of
hypersensitivity reaction with dyspnoea, urticaria and hypo- DNA and cleave both strands. Topoisomerase II inhibitors
tension. Patients therefore receive prophylactic steroids and prevent the relegation of DNA cleaved by topoisomerase II
H2 inhibitors as premedication. Paclitaxel also produces a and produce protein-linked breaks in DNA. Epipodophyllo-
peripheral neuropathy characterized by sensory symptoms toxins are examples of topoisomerase II inhibitors. The
in a glove and stocking distribution. This can be permanent. anthracyclines inhibit both type I and type II topoisomerases
A newcomer to the field is abraxane, a novel nanoparticle and therefore will be discussed in this section too.
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Camptothecin was the first topoisomerase I inhibitor to be sarcomas, lung cancer, Wilms tumour, and acute myelog-
discovered. Its further development was hindered by toxicity enous leukaemia (daunorubicin).
and it was not until its analogues topotecan and irinotecan In an attempt to improve the antitumour effect of doxo-
were developed that the usefulness of this group of drugs rubicin, a liposomal preparation called doxil (CaelyxW in
became apparent. Topotecan was the first camptothecin ana- the UK) has been developed. Essentially, the doxorubicin
logue approved for clinical use and is now used in ovarian can- molecule has been formulated in a fat bubble. The bodys
cer and small cell lung cancer. It can be given intravenously or reticuloendothelial system fails to recognize the molecule
orally with the latter being far more convenient. The major side as being foreign, hence the term stealth liposome, and
effects are neutropenia and nausea and vomiting. Interestingly, therefore the drug has a longer half-life. The side effects
although the neutropenia can be profound, the nadir is very of doxil are generally less than for doxorubicin except for
short lived and therefore is seldom complicated by sepsis. the development of a hand foot syndrome called palmar
Irinotecan is a semisynthetic derivative of camptothecin. plantar erythrodysaesthesia. It is used in breast cancer
Its active metabolite SN-38 binds to the topoisomerase I and ovarian cancer.
enzyme-DNA cleaved complex and prevents religation thus
causing double strand breaks. SN-38 is mainly cleared by
the liver and the drug can only be used with caution in Miscellaneous
patients with abnormal liver function. Irinotecan has a role
in the treatment of colorectal cancer and is active in patients Platinum analogues
with 5-FU resistant disease. The major side effects are diar- The platinum drugs are widely used in a variety of
rhoea and myelosuppression. These can occur concurrently tumours such as testicular teratoma and seminoma, ovar-
with fatal outcome if the diarrhoea is not controlled cor- ian, cervical, non-small cell lung cancer and osteosar-
rectly. Irinotecan is also used in the management of upper coma. Cisplatin and carboplatin inhibit DNA synthesis
gastrointestinal malignancies. in a similar way to alkylating agents. They form cross-
Etoposide (VP16) is the most widely used epipodophyl- linkages (adducts) between a pair of their chlorine atoms
lotoxin. Like 5-FU, it is a good example of a schedule- and the guanine molecules of opposing DNA strands
dependent drug as it is more effective given over 5 days than (interstrand linkages), but differ in that they also bind
on 1 day. It can be given orally or intravenously and the to bases on the same DNA strand (intrastrand linkages).
dose-limiting toxicity is bone marrow suppression. The Both drugs are administered intravenously and are
nadir is at about 16 days. Nausea, vomiting and anorexia predominantly excreted in the urine. Cisplatin causes
are relatively minor but more marked if etoposide is given severe nausea and vomiting which can be prevented with
orally. Alopecia is also common as is mucositis. Etoposide 5-HT3 antagonists and aprepitant the NK-1 antagonist. In
is used mainly in Hodgkins disease, non-Hodgkins lym- addition, cisplatin causes renal impairment and therefore
phoma, small cell lung cancer, and testicular teratoma. it is essential that pre- and post-treatment hydration be
Daunorubicin, doxorubicin (Adriamycin) and epirubicin used. The peripheral nerves and auditory nerves are sensi-
are the principal anthracycline antibiotics. They are produced tive to cisplatin and patients may develop high frequency
from different strains of fungi (Streptomyces). The mechan- hearing loss and peripheral neuropathy. Carboplatin has
isms of their cytotoxic action are not fully understood. They the advantage of much less emesis, ototoxicity, nephro-
induce formation of topoisomerase-DNA complexes and toxicity and neurotoxicity. The dose-limiting toxicity is
prevent the enzyme from completing the religation of the to the bone marrow, particularly to platelets. Unlike the
ligationreligation reaction. In addition, they insert part of other chemotherapy agents, carboplatin is dosed depend-
their planar structure between two adjacent base pairs (inter- ing on the renal function of the patient rather than the
calation), causing single and double strand breaks. They also patients body surface area.
can undergo chemical reduction to form free radicals. Oxaliplatin is the most recent platinum analogue to be
Doxorubicin and epirubicin are given intravenously and licensed. It is a third generation platinum compound and
the main toxicity is to the bone marrow, gastrointestinal differs from the other platinum drugs by having a large
tract and the heart. The nadir of the white count is at 10 1,2 diaminocyclohexane (DACH) ligand in its structure.
days. Epirubicin causes slightly less vomiting than the other It is thought that the presence of the DACH group renders
two anthracyclines. Daunorubicin and doxorubicin and, to the molecule non-recognizable by the mismatch repair pro-
a much lesser extent, epirubicin, cause cumulative cardio- cess. This means that the DNA repair mechanisms that are
toxicity and there is a maximum recommended total dose. responsible for platinum resistance are not so effective.
Acute cardiac toxicity is manifest by arrhythmias and Oxaliplatin therefore is useful in tumours where cisplatin
abnormalities of electrical conduction. The chronic effect has failed and also in colorectal cancer, a tumour type
is a cardiomyopathy (pericarditis and congestive cardiac not classically treated by platinum agents. Oxaliplatin does
failure) and, thus, anthracyclines should be avoided if there not have the nephrotoxicity associated with carboplatin,
is previous history of cardiac failure or ischaemic heart dis- although it does have a striking neurotoxicity. Patients
ease. Their use is widespread in lymphoma, breast cancer, develop a peripheral neuropathy with cumulative drug
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Walter and Millers Textbook of Radiotherapy
exposure. They also develop an acute neuropathy that is can be dangerous (e.g. cardiovascular morbidity from
characterized by cold-induced tingling (paraesthesia) in diethylstilbestrol for prostate cancer). A careful balance
the fingertips and toes after infusion. This can also affect has to be struck between toxicity and benefit in tumour
the throat on drinking cold drinks and the patient develops control. There are five main areas that will be discussed:
a feeling of choking. Oxaliplatin is usually administered antioestrogens
with 5-FU chemotherapy, as in combination, they are aromatase inhibitors
synergistic. gonadotrophin-releasing hormone analogues
antiandrogens
Non-anthracycline antibiotics female hormones.
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Chapter | 19 | Chemotherapy and hormones
Second Fadrozole
Antiandrogens
Third Anastrazole Exemestane Flutamide is a non-steroidal antiandrogen and is a pure
Letrozole androgen antagonist used in men with prostate cancer.
One of its important metabolites, hydroxyflutamide, is
thought to be responsible for its cellular action. It blocks
the binding of dihydrotestosterone to its receptor, so inhi-
and are therefore extremely valuable drugs for post- biting the action of androgen. It is often used in combina-
menopausal women with breast cancer. In premenopausal tion with GnRH analogues. The side effects include
women, oestrogen synthesis is governed by gonadotro- gynaecomastia and/or breast tenderness, nausea and diar-
phin-releasing hormone stimulating the ovary. Aromatase rhoea and tiredness. Bicalutamide is another non-steroidal
inhibitors are therefore only useful in premenopausal antiandrogen that binds to androgen receptors and there-
women who have been oophorectomized. There are a num- fore inhibits androgen stimulation. Again, it is used in pros-
ber of first, second and third generation aromatase inhibitors tate cancer, usually in conjunction with a GnRH analogue.
available as shown in Table 19.4. Common toxicities of these Cyproterone acetate is a progestogenic antiandrogen and
drugs include nausea, headache, hot flushes and weight gain. has two actions. First, it reduces the production of testoster-
Unlike tamoxifen, aromatase inhibitors may decrease bone one in the testis by inhibiting the secretion of the pituitary
density and predispose to osteoporosis. Although clear gonadotrophins. Secondly, it competes with androgen recep-
molecular differences exist between these two types of aro- tors, from which it displaces testosterone. It is used in pros-
matase inhibitors, significant clinical differences have not tate cancer to suppress the tumour flare with initial GnRH
been forthcoming from the studies to date. There may be analogue therapy; and when GnRH analogues are contrain-
some non cross resistance between the groups as switching dicated or poorly tolerated. Side effects include liver dysfunc-
from one to another can confer a modest improvement in tion, impotence, and fluid retention. There has been much
outcome. A Cochrane analysis has found that in metastatic interest in the new hormonal agent abiaterone. CYP171A
breast cancer, aromatase inhibitors show a survival benefit is a member of the cytochrome P450 family and is responsi-
compared to other endocrine therapy although there is lim- ble for the conversion of pregnelonone and progesterone
ited data available to identify which individual aromatase to their 17a metabolites. In addition it can convert 17a-
inhibitor has the greatest efficacy. hydroxypregnelonone and 17a-hydroxyprogesterone to the
androgens androstenedione and dihydroepiandrostene-
dione. Abiraterone binds CYP17A1 irreversibly and prevents
Gonadotrophin-releasing hormone the formation of androgens in the adrenal gland and periph-
(GnRH) analogues eral tissues of castrate and noncastrate men. Studies suggest
Downregulation of the gonadotrophin-releasing hormone that the drug has activity in advanced prostate cancer follow-
(GnRH) receptors in the pituitary is achieved by the appli- ing chemotherapy and androgen deprivation failure.
cation of continuous secretion of gonadotrophin-releasing
hormone analogues. These analogues of the naturally Female hormones (oestrogens and
occurring hypothalamic luteinizing hormone-releasing
hormone (LHRH) initially cause a transient surge of gonad-
progestogens)
otrophin (LH) secretion, tumour flare. However, with Synthetic rather than naturally occurring oestrogens (these
continuous exposure to these analogues, the LHRH recep- are metabolized in the liver), such as diethylstilbestrol,
tors in the pituitary become desensitized, resulting in are sometimes used in the treatment of prostate cancer.
reduction in the secretion of gonadotrophins. They there- The side effects from these agents are significant, in
fore cause a medical oophorectomy in women and a med- particular, risk of cardiovascular disease and nausea and
ical orchidectomy in men. The advantage of this medical vomiting. With the advent of the antiandrogens, the use
suppression of gonad function with GnRH analogues is of these hormones is now declining.
that the process is reversible. Progestogens, such as medroxyprogesterone and meges-
Goserelin is the most commonly used agent and is about trol, are occasionally used in the treatment of advanced
100 times more potent than naturally occurring GnRH. breast cancer and also in endometrial cancer. Their mecha-
It is given as a subcutaneously injected capsule on either nism of action is not completely understood but probably
a monthly or 3-monthly basis for prostate cancer or the most important effect is the antiestrogenic action and
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less important the direct cytotoxic action. Side effects antibodies (cetuximab, panitumumab and trastuzumab)
include weight gain, fluid retention, increased blood clot- and oral small molecule inhibitors of the TK activity (gefi-
ting and risk of thrombosis and vaginal bleeding. tinib, erlotinib and lapatinib).
Trastuzumab (Herceptin) is a humanized anti-HER-2
(ERBB2) monoclonal antibody that has been approved
Targeted therapies for mono- or combination therapy (with paclitaxel) for
The real highlight in oncological research over the last few women with HER-2 over expressing breast cancer. Recently
years has been the incorporation of targeted therapies into it has also been licensed for HER-2 positive gastric cancer.
clinical practice. There has been a phenomenal increase in Cetuximab (Erbitux) is a chimeric IgG1 antibody and is
the understanding of the cellular and molecular events licensed for use in combination with irinotecan containing
in carcinogenesis. By focusing on the differences between chemotherapy in patients with metastatic colorectal cancer
normal and malignant tissue, we can target pathways with wild-type K-RAS mutation status. This treatment is
and receptors unique to cancer cells, thus avoiding complicated by a unique rash which is acneiform indeed
the blunderbuss, universal killing of dividing cells of con- there is a suggestion that the rash may actually be a predic-
ventional cytotoxics. Molecular events that distinguish tive biomarker of response to cetuximab. Other side effects
malignant from normal cells are activation of oncogenes include diarrhoea and infusion reactions. Panitumumab
(e.g. ras, erbB2), inactivation of tumour suppressor genes (Vectibix) is a fully human IgG2 monoclonal antibody that
(e.g. p53), and activation of immortality genes (e.g. telo- binds to the ectodomain of EGFR. It is also licensed for use
merase). At the cellular level, for a tumour cell to grow and in K-RAS wild type colorectal cancer.
divide it needs its own blood supply (angiogenesis), and Gefitinib (Iressa) is a Tyrosine Kinase Inhibitor (TKI)
the ability to migrate through local tissue (tumour inva- which blocks the binding of the adenosine triphosphate
sion and migration). to the intracellular domain of EGFR. Only patients with
Nearly all patients (90%) with chronic myeloid leukae- activating EGFR mutations respond well to the drug and
mia have a specific genetic abnormality called the Philadel- therefore gefitinib is only approved for use in metastatic
phia chromosome. This is a genetic mutation where non small cell lung cancer with activating mutations of
reciprocal translocation between chromosomes 9 and 22 the EGFR-TK. The most common side effects seen with gefi-
result in the production of the oncogene Bcr-Abl. Investiga- tinib are rash, diarrhoea and fatigue. Erlotinib (Tarceva)
tors have developed the agent imatinib mesylate (STI571) is another EGFR TKI and is licensed for use in non small
which specifically inhibits the receptor kinase of BCR-ABL. cell lung cancer and pancreas cancer. Lapatinib (Tykerb)
The results of the clinical trials are truly impressive; com- is a dual specific TKI targeting both EGFR and HER-2. It
plete haematological responses have been seen in patients is licensed for use in combination with capecitabine che-
with chronic myeloid leukaemia who failed to respond motherapy in patients with metastatic breast cancer who
to conventional agents. Moreover, not only is imatinib have progressed after trastuzumab and other chemother-
an oral drug, the patients had mild side effects, particularly apy therapy.
when compared to their previous cytotoxic-induced toxic-
ity. Results of this kind are really unprecedented in oncol-
ogy and warranted the accelerated approval of imatinib for
Signalling through RAS-RAF-ERK
clinical use. The development of imatinib therefore repre- (MAPK) and PI3K-AKT:
sents a paradigm for the development of targeted therapies. Both these pathways are major downstream signals for the
Currently there are eight kinase inhibitors which have been EGFR family members and RAS-regulated pathways inter-
approved for cancer therapy and over 100 in development. act at multiple points, including with the PI3K-AKT-mTOR
Key processes which have been targeted include pathway, and with c-MYC. The PI3K-Akt-mTOR pathway is
Epidermal Growth Factor Receptor (EGFR) signalling activated in many cancers and is not surprisingly increas-
pathway ingly being targeted by new therapies. Temsirolimus is
RAS-RAF-ERK (MAPK) and PI3 kinase pathway the first in class mTOR inhibitor licensed for use in meta-
Vascular Endothelial Growth Factor (VEGF) signalling static renal cancer.
pathway
Protease inhibitors.
Vascular Endothelial Growth Factor
(VEGF) signalling pathway
Epidermal Growth Factor Receptor
Angiogenesis is known to be pivotal in tumour progression
(EGFR) signalling pathway
and metastasis and as VEGF is the driving force behind
EGFR (ERBB1) and ERBB2 (HER2) are overexpressed angiogenesis, it is not surprising that it has been the target
or amplified in many malignancies including non-small of many approaches. Agents have been developed that tar-
cell lung, breast, head and neck, pancreas and colorectal get the VEGF ligand, blocking its interaction with the VEGF
cancers. Licensed anti-EGFR therapies include monoclonal receptors (Bevacizumab) and agents that directly block the
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receptor (tyrosine kinase inhibitors such as sunitinib). Bev- administrating therapeutic antibodies. To date there has
acizumab (Avastin) is a recombinant humanized monoclo- been greater success with the latter approach and approxi-
nal antibody to VEGF-A. It is licensed for use in metastatic mately nine monoclonal antibodies have been approved
colorectal, breast, non-small cell lung and renal cancer. The for the treatment of cancer.
side effect profile of bevacizumab includes hypertension, a Rituximab (Mabthera) is a chimeric monoclonal antibody
class effect of VEGF inhibitors, thromboembolic events targeting the CD20 antigen found on normal B cells and B
(both arterial and venous) and gastrointestinal perforation. cell lymphomas. It is licensed for use for follicular lym-
Since VEGF mediates its angiogenic effect through sev- phoma, diffuse large B cell lymphoma and chronic lympho-
eral tyrosine kinase receptors, many VEGF TKIs have been cytic leukaemia and has remarkably improved the outlook
tested. Sorafenib (Nexavar) is licensed for use in renal cell, for these patients. It can be administered either as monother-
and hepatocellular cancer and Sunitinib (Sutent) is apy or in combination with chemotherapy such as the
licensed for use in renal cell cancer and GIST. Numerous CHOP regimen. Iodine 131 tositumomab (Bexaar) and
other TKIs are in clinical studies. Some are highly selective, 90Y ibritumomab tiuxetan (Zevalin) are both radiolabelled
targeting only specific VEGF receptors whereas others are CD20 targeted antibodies. They are licensed for use in some
more promiscuous and target other kinases such as PDGF, refractory lymphomas but their costs are prohibitive.
EGFR. Despite being targeted therapies, these drugs do Alemtuzumab (previously known as CAMPATH) is a
have significant side effects including neutropenia, fatigue, humanised monoclonal antibody targeting the CD52 anti-
rashes, diarrhoea, and stomatitis. gen found on B lymphocytes. It has been licensed for use
for patients with B-cell chronic lymphocytic leukaemia
Proteasome inhibitors who are unable to receive the chemotherapy drug fludara-
bine. It is associated with significant haematological toxic-
These drugs, exemplified by Velcade (bortezomib, formerly ity especially neutropenia.
known as PS341), prevent degradation of various proteins Lenolidamide is an immunomodulating drug that is
in the proteasome. Velcade is the first selective proteasome licensed for patients with advanced multiple myeloma
inhibitor and is licensed in patients with refractory or (MM). It is a potent analogue of thalidomide and works
relapsed multiple myeloma. It is believed to be effective in a number of ways: inhibiting proliferation of certain hae-
in myeloma by interfering with normal function of the matopoietic tumour cells (including MM plasma tumour
NFkB signalling pathway, thus reducing tumour cell repli- cells and those with deletions of chromosome 5), enhanc-
cation and angiogenesis and promoting apoptosis. ing T cell- and Natural Killer (NK) cell-mediated immunity,
inhibiting angiogenesis, and inhibiting production of pro-
inflammatory cytokines (e.g., TNF-a and IL6) by monocytes.
Immunotherapy
In studies the most concerning side effects of treatment
Essentially the main premise of immunotherapy approaches were venous thromboembolic events and myelosuppres-
in cancer treatment is to stimulate the patients immune sion. Not surprising there is also a significant risk of terato-
system to attack the tumour. This can be either be achieved genicity and therefore patients or their partners must not get
by immunizing the patient with a cancer vaccine or pregnant while on treatment.
FURTHER READING
Bergh J. Quo Vadis with targeted drugs Gibson L, Lawrence D, Dawson C, Bliss J. Perry MC. The chemotherapy source
in the 21st century. J Clin Oncol Aromatase inhibitors for treatment of book. 4th ed. Philadelphia: Lippincott
2009;27(1):25. advanced breast cancer in Williams & Wilkins; 2007.
Campoli M, Ferris R, Ferrone S, Wang X. postmenopausal women (Review). Pezaro CJ, Mukherji D, De-Bono JS.
Immunotherapy of malignant disease The Cochrane Library 2009;4:1124. (2011) Abiaterone acetate: redefining
with tumor antigen-specific Grothey A, Galanis E. Targeting hormone treatment for advanced
monoclonal antibodies. Clin Cancer angiogenesis: progress with anti-VEGF prostate cancer. Drug Discov today,
Res 2010;16(1):1120. treatment with large molecules. Nat Dec 19 [Epub ahead of print].
Chanan-Khan AA, Cheson BD. Rev Clin Oncol 2009;6:50718. Quintas-Cardama A, Wierda W, OBrien S.
Lenalidomide for the treatment of Jordan VC, OMalley BWO. Selective Investigational immunotherapeutics
B-cell malignancies. J Clin Oncol estrogen-receptor modulators for B-cell malignancies. J Clin Oncol
2008;26(9):154452. and antihormonal resistance in 2010;28(5):88492.
Devita VT, Lawrence TS, Rosenberg SA, breast cancer. J Clin Oncol Stavridi F, Karapanagiotou EM,
Depinho RA, Weinberg RA. Cancer 2007;25(36):581524. Syrigos KN. Targeted therapeutic
principles and practice of oncology. Lurje G, Lenz H. EGFR signalling and approaches for hormone-refractory
9th ed. Philadelphia: Lippincott drug discovery. Oncology prostate cancer. Cancer Treat Rev
Williams & Wilkins; 2011. 2009;77:40010. 2010;36:12230.
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Chapter | 20 |
Skin and lip cancer
Charles Kelly, Trevor Roberts, Cliff Lawrence
Aetiology
Figure 20.1 Actinic keratosis with a background of sun-
The following factors can all be involved in the develop- damaged skin.
ment of keratinocyte skin tumours, but these skin
cancers are all more common in white skin. Skin pigmen-
tation protects from the development of these tumours,
so that, at one extreme, albinos have a much increased
risk of skin cancer, whereas NMSC is rare in people with
black skin.
Ultraviolet radiation
Excessive exposure to ultraviolet B from sunlight and
ultraviolet A (UVA) from sunbeds have been implicated
as an aetiological factor. In the UK, a cohort who com-
monly presented with these tumours were those World
War II soldiers who had served in the Mediterranean or
the Middle or Far East. At that time, the importance of
sun avoidance was not recognized and sun blocks were Figure 20.2 Bowens disease on a limb. Note the colour and
not available. how superficial the lesion is.
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Chapter | 20 | Skin and lip cancer
Chronic trauma
Forms of chronic ulceration (Figure 20.7), direct thermal
damage, or previous burn scars can all predispose to the
development of squamous cell carcinoma of skin.
Age
These skin cancers are essentially a disease of the elderly. As
the population ages the incidence of skin cancer is steadily
increasing.
Figure 20.4 This is a typical ultraviolet A generating machine
used in PUVA treatments. Note the tubes used to produce
the UVA.
Immunosuppression
This is most commonly seen now in patients who have had
organ transplants, and the normal ratio of SCC to BCC is
reversed, with squamous cell carcinoma becoming more Figure 20.5 This shows the very subtle palmar pitting found in
common than BCC. Gorlins syndrome.
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Chapter | 20 | Skin and lip cancer
A B
C D
E F
Figure 20.8 (A) This is a typical basal cell carcinoma, with a pearly appearance to the edge, and central ulceration. (B) Nodular basal cell
carcinoma. (CE) This is an advanced BCC. Note the local soft tissue destruction (C), the left 7th nerve palsy (D) and the bone loss due to
erosion by this tumour (E). (F, G) A typical example of a BCC at the left nasolabial fold before and 6 weeks after being treated with
radiotherapy.
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Walter and Millers Textbook of Radiotherapy
A B
Figure 20.9 (A, B) This shows an extensive squamous cell carcinoma of the back of the hand before radiotherapy and four weeks
after radiotherapy treatment.
A typical SCC before and 4 weeks after radiotherapy is areas of premalignant change. This technique allows for
shown in Figure 20.9A and B. these areas of premalignant change to be removed at the
same time and sent for histological evaluation to exclude
other areas of carcinoma in situ or frank invasive change.
Cancer of the lip With larger lesions, the tumour can be removed surgically
Cancer of the lip is predominantly a malignancy affecting using a V or W incision. Here, the amount of functional
elderly males. The lower lip is affected more frequently tissue loss may make radiotherapy more appropriate.
than the upper lip by a factor of 10. Almost all lower lip Radiotherapy is given using either an iridium implant or
cancers are squamous cell carcinomas. It is rare to find a electron beam, using wax and lead behind the lip to protect
basal cell carcinoma on the lip vermilion, but they can arise the rest of the mouth and take advantage of the back scatter
from skin immediately adjacent. Basal cell carcinoma effect. Dose/fractionation regimens used include 55 Gy in
develops most commonly on the skin close to the upper 20 fractions or 66 Gy in 33 fractions. The cosmetic result
rather than the lower lip. is usually very good, as the lip has an excellent blood supply
These malignancies are more common in fair skinned, and healing usually occurs quickly and completely. As elec-
weather-beaten outdoor workers. Sun exposure is one impor- tron treatments are highly effective, iridium implantation is
tant factor but there may be others, such as pipe smoking, as now rarely indicated.
cumulative UV exposure does not always correlate with some
of the higher risk occupational groups prone to developing Keratoacanthoma
this cancer. As with squamous carcinoma of the skin, trans-
These are benign but can be very difficult to distinguish
plant patients are at a higher risk of developing lip SCC.
from squamous cell carcinoma of the skin. They present
Clinically, premalignant changes leading to carcinoma
as a rapidly growing nodule with a central keratin plug.
of the lip may precede the development of a mass or ulcer
The central plug detaches, and the residual lesion resolves
within the lip. This then enlarges, involving more of the lip.
(Figure 20.10A, B). They are problematic in that they can-
Spread to the submental or submandibular nodes is possi-
not be differentiated from squamous cell carcinoma of skin
ble, especially with larger or more poorly differentiated
by biopsy alone and, in the growth phase, the pathologist
lesions, but spread to other neck nodes early on is uncom-
will usually call them a squamous cell carcinoma. As a
mon. Classically, 5% of lip cancers have palpable nodes at
result, although benign, they are often excised, in order
diagnosis and 5% subsequently develop nodal metastases
to avoid missing a rapidly growing squamous cell cancer.
after successful treatment of the primary.
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Chapter | 20 | Skin and lip cancer
A B
Figure 20.10 (A) Keratoacanthoma in its rapidly developing stage. The central keratin plug is obvious. This lesion has developed in a
matter of a few weeks. (B) Keratoacanthoma in its healing stage. This is the same lesion as in Figure 20.9, three months later. The
keratin plug was discharged spontaneously and complete healing rapidly ensued.
short- and long-term recurrence rate for BCC and probably Cryosurgery with liquid nitrogen
for SCC. One of the few randomized control trials in the
This is used more for BCCs than SCCs. For 23 days after
treatment of skin cancer, which was carried out in The
treatment there can be oedema, blister formation, slough-
Netherlands, has shown a lower, but not statistically sig-
ing and crust formation. It has the advantage of being able
nificant, rate of recurrence after Mohs surgery compared
to be done in the outpatient clinic and can be useful in the
to conventional excision. Operative costs were higher for
frail elderly patient, where surgery is best avoided, and
Mohs methodology.
when the patient does not wish to travel to their local radio-
Patients with these tumours should be seen in the mul-
therapy centre (Figure 20.12).
tidisciplinary skin cancer clinic where a treatment plan can
be formulated for the individual patient. Often, the deci-
sion as to which treatment is given is based not on the his-
torical evidence of the efficacy of that particular treatment,
Surgical excision
but on the size and site of the skin lesion, the age, fitness Pathological evidence of complete removal is the main
and wishes of the patient, and the local resources and dis- advantage, but for some morpheic BCCs this may give a
tances from the local hospital and cancer centre. In general, false reassurance with subsequent recurrence. For these
surgery or radiotherapy are equally effective in eradicating tumours, Mohs micrographic surgery gives a higher rate
these tumours. Radiotherapy is often avoided in younger of complete excision. The main disadvantage of surgical
patients on the basis that long-term cosmesis is usually bet- excision is that, in some sites, primary skin closure may
ter with surgery. As time passes, the surgical scar becomes be impossible and flap closure or skin grafting is required.
less obvious, whereas the hypopigmentation produced by The cosmetic results may be poor, especially in areas such
radiotherapy can become more prominent. as the tip of the nose.
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A B
C D
Figure 20.11 (A) This is an area being prepared for curettage, with local anaesthetic being given. (B) The tumour is then curetted out.
(C) Further curettage is then performed at the tumours base. (D) This shows the result at two years, following curettage.
Photodynamic therapy
A cream containing a porphyrin precursor is placed on
the skin. This is metabolized by the tumour to porphyrin.
The porphyrin is then activated by exposure to red
light and, in the process, free radicals are produced
which destroy the tumour. It is partially effective and still
being developed. It is mainly reserved for large superficial
truncal BCCs.
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Chapter | 20 | Skin and lip cancer
A B
C D
Figure 20.13 (AG) This series of clinical photographs shows Mohs micrographic surgery, with the initial incision, the further wider
excisions, and the final result.
Continued
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Walter and Millers Textbook of Radiotherapy
E F
pinna, with its underlying cartilage; the back of the hand uninvolved by cancer and is patent before radiotherapy
with its tendons lying superficially and the anterior shin begins, it is more likely than not to remain patent after
where there is a relative lack of underlying subcutaneous tis- radiotherapy.
sue. Even these sites can be treated in appropriate patients if The radiotherapy dose used for treating skin malignan-
due consideration is given to the skin condition, site of treat- cies varies from centre to centre and dose/fractionation
ment and treatment volume, total dose and fractionation. schedules have developed empirically over the years. In
In giving radiotherapy around the eye, treating the lateral general, the more fractions used the better the late cosmetic
upper eyelid may cause damage to the lacrimal gland result (Table 20.1). As well as efficacy in curing the tumour,
and ducts leading to a permanently dry eye and, in treating other factors, such as the late cosmetic effects and conve-
lesions at the medial canthus, the lacrimal drainage nience to the patient are important. Some elderly, frail
system can be occluded. However, if the lacrimal duct is patients will trade off the cosmetic outcome against
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Chapter | 20 | Skin and lip cancer
Surface
Table 20.1 Examples of superficial radiotherapy
Depth below skin surface [cm]
fractionation regimens for treating basal cell & squamous
cell carcinoma of the skin 1 2 3 4 5 6
100
% Depth dose
60
35 5 daily (if <4 cm field
size) 50
70
60 Electron beams also have the advantage of being able to use
50 the physical phenomenon of backscatter. If electrons
40 encounter lead, a proportion will be scattered back towards
30 the direction of the incident beam, and by placing wax in
20 front of the lead, some of the backscatter electrons will
10 be absorbed in the wax. By choosing the thickness of the
0 lead and the wax carefully, the degree of backscatter can
1 2 3 4 5 6 7 8 9 10
Surface
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Walter and Millers Textbook of Radiotherapy
the incident beam, and may contribute to dose outside the Superficial x-ray treatment
treatment volume and so by placing wax in front of the
lead, some of these backscattered electrons will be Most small BCCs on the face can easily be treated using x-
absorbed in the wax. Backscatter therefore has both positive ray energies of 90120 kV. A lead cut-out is placed around
and negative potential effects (Figure 20.16BF illustrate an the lesion with a margin of 5 mm if a BCC, and 10 mm if an
SCC of pinna treated by electrons). SCC (Figure 20.17A, B). If the lesion is an irregular shape,
One of the most common treatment sites for the use of then a lead cut-out may need to be specifically made,
backscatter to clinical advantage is when a cancer of the tracing the area to be treated with adequate margin onto
lower lip is treated with electrons. Wax and lead are put a piece of lead, which is then cut out. If the treated site is
behind the lip. The lead helps to protect the oral cavity from close to the eyes, then an external or internal eye-shield
the electron radiation beam. By varying the thickness of the is used to keep radiation dose to the eye to a minimum
wax for each individual patient, depending on how thick (Figure 20.18).
the lip and tumour are and, consequently, how wide the Each fraction takes only a few minutes to deliver and the
target volume needs to be, the degree of backscatter can patient should be warned that the reaction will start with
be modified, giving greater homogeneity in dose across erythema, followed by ulceration, over which a crust forms.
the tumour. Healing takes place underneath this crust, which detaches a
Figure 20.16 GL shows a wax and lead block being used few weeks after treatment. If it is detached prematurely, or
for a lower lip cancer with the area to be treated marked out is inadvertently knocked off, a second or even a third crust
in Figure 20.16I. can form.
Electron backscatter
Lead
Wax B
A
C D
Figure 20.16 (A) Here is a simplified diagrammatic representation of the electron backscatter effect. By choosing different
thicknesses of the lead and wax used, both the amount of backscatter, and how many backscatter electrons are absorbed by the wax,
can be controlled, improving the homogeneity of dose over the tumour volume. (BF) Here, use is made of the electron backscatter
effect in treating a squamous cell carcinoma on the pinna of the ear. (B) The lesion. (C) Wax and lead are then placed behind the ear, in
the thicknesses required for maximal affect. (D) A Perspex cut-out is then placed over the ear, giving the treated electron field and an
alloy cut-out is then placed over this.
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Chapter | 20 | Skin and lip cancer
E F
G H
I J
Figure 20-16, Contd (E) to tailor the electron beam to the treatment volume. (F) Finally, more wax bolus is applied to increase the
percentage depth dose, at the skin surface. (GL) The process of treating a lower lip cancer with electrons. A wax and lead insert
is first made, the treatment volume marked out with it inserted and then a Perspex mask fitted over this. An alloy cut-out is then
placed on top. In this case, it is large, not to protect the whole face, but because it is less likely to fall off during treatment. Further
wax is used to increase the surface electron dose at the lip. Finally, the treatment reaction on the last day of treatment after 55 Gy in
20 fractions is shown.
Continued
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Walter and Millers Textbook of Radiotherapy
K L
A B
Figure 20.17 (A) This is a typical example of a lead cut-out used in treating small skin tumours with a superficial x-ray machine.
(B) This shows a superficial x-ray machine being set up with a volunteer.
Moulds
Skin lesions can also be treated by the use of the an
applied mould containing a radioactive source which
the patient wears in apposition to the tumour for a set
Figure 20.18 If eye-shields are required, either an external
shield as shown covering this patients left eye, or an internal number of hours per day until the dose prescribed is deliv-
gold shield can be inserted under the eyelid after anaesthetizing ered. This method of treatment is not commonly used
the conjunctiva with local anaesthetic, as shown with the in the UK today, although there is some interest in its
right eye. reintroduction.
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Chapter | 20 | Skin and lip cancer
MELANOMA
Aetiology
Melanoma is much more common in white races and is
related to UV radiation exposure. There is evidence that epi-
Figure 20.20 Nodular melanoma.
sodes of sunburn before the age of 15 increase the risk of
developing melanoma.
Approximately 50% of melanomas arise in pre-existing
moles and 50% on otherwise normal skin. Lentigo maligna melanoma (Figure 20.21)
This makes up 515 % of melanomas. It is most commonly
found in the skin of the nose or the cheek in the elderly and
Subtypes of melanoma develops within a premalignant pigmented lesion known
As with other skin tumours, there are several types of as lentigo melanoma (Figure 20.22), which can be present
melanoma. for several years. This lesion eventually enlarges, undergoes
malignant change and may develop a central pigmented
nodule.
Superficial spreading (Figure 20.19)
Superficial spreading is the most common representing
6070%. It appears as a flat, pigmented lesion which
may be related to a naevus. As the name implies, it initially
grows outwards before invading downwards. Conse-
quently, patients may present with a better prognosis if
they seek help while the lesion is still in its horizontal or
radial growth phase, which may last for many months
or even years.
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Walter and Millers Textbook of Radiotherapy
Diagnosis
Clinically, there should be suspicion that a melanoma may
be developing. There are three cardinal features to look out
for when considering the possibility of malignant change
in an existing mole:
increase in diameter
change of colour
change in shape, i.e. becoming asymmetrical or
developing border irregularity.
This is the basis of the ABCD method: Asymmetry, Border, C
Colour, Diameter.
Moles greater than 6 mm are more likely to be
Figure 20.24 (A) This shows an amelanotic melanoma, which is
malignant. Dermatoscopic examination using an ampli-
not markedly pigmented. (B) Malignant melanoma in transit
fied illuminated image is a helpful adjunct to clinical metastases. (C) The same patient 4 months later.
examination.
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Chapter | 20 | Skin and lip cancer
N3 > 4 nodes involved or matted node mass Table 20.5 Five-year survival rates for stage groups
or satellite lesions or in-transit metastases with
nodal involvement STAGE AT PRESENTATION 5-YEAR SURVIVAL (%)
M1a Skin, subcutaneous tissue, lymph nodes beyond the I 95
regional lymph nodes
II 75
M1b Lung metastases
III 60
M1c Any other site or any metastasis with elevated lactic
dehydrogenase (LDH) IV 15
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Walter and Millers Textbook of Radiotherapy
Management of melanoma this evidence, but high-dose interferon is widely used in the
adjuvant setting in North America.
It is important to have a high level of suspicion if there is At present there is no agreed adjuvant treatment for mel-
any change in a pigmented skin lesion. Change in size or anoma, in the UK but in some centres adjuvant radiother-
shape, degree or homogeneity of pigmentation, ulceration apy is considered for the postoperative treatment of nodal
or bleeding in a pigmented lesion should lead to referral to drainage areas in the neck, axillae or groins if patients have
the local melanoma screening clinic. been shown to have had large, multiple nodes or extracap-
A suspicious mole should be excised with a margin of sular spread, to attempt to improve local control. This is
2 mm. Shaving a suspected melanoma is contraindicated based on trials performed by the Australian Trans Tasman
because this will not allow the true Breslow thickness Radiation Oncology Group (TROG). Patients at high risk of
to be measured and results in incomplete excision. The metastatic recurrence should be offered the opportunity to
pathology report should give the depth of invasion in enter clinical trials of adjuvant treatment. Several trials are
millimetres (the Breslow thickness) and state whether ongoing using immune modulators or targeted drugs such
ulceration and/or regression are present or not and as Bevacizumab, a monoclonal antibody which acts by
whether excision is complete. These are all prognostic fac- blocking angiogenesis, blocking Vascular Endothelial
tors. If regression is present then this may obscure the Growth Factor A (VEGF-A).
dermo-epidermal junction and the given Breslow depth
may be an underestimate.
If melanoma is discovered, the patient should then
Management of recurrent or
undergo a definitive wider local excision. If the tumour
was 1 mm Breslow thickness or less, another lateral exci- metastatic melanoma
sion margin of 1 cm is taken, down to the deep fascia. Any evidence of further local, regional or metastatic mela-
Tumours greater than 1.0 mm thick are normally excised noma requires that the patient be restaged to define the
with a 2 cm lateral margin down to deep fascia. extent of the recurrence. If there is only local recurrence at
Thicker, more advanced melanomas carry a higher risk of the primary site, further surgery should be considered. This
occult positive lymph nodes. Prophylactic node dissection may be appropriate even if there is other locoregional or
to identify those with occult metastases has not improved metastatic disease present in order to achieve local control.
survival and is associated with a high potential complica- If regional lymph nodes are involved, a nodal block dis-
tion rate, including wound infection and lymphoedema. section may be indicated, depending on the extent and fix-
Patients who require node dissection can be identified by ity of the nodal disease, the extent of other disease and
the sentinel biopsy technique. Trials are being performed patient factors such as performance status, frailty, co-
of the technique of sentinel node biopsy, where the first morbidities present and the potential functional loss and
node that drains the area of the primary tumour is identi- changes in quality of life (both positive and negative) that
fied by injecting both a blue dye and a radioactive marker extensive surgery may bring. In selected cases, adjuvant
close to the site of the primary tumour bed. The theory that radiotherapy may improve local control after surgery as
underlies the concept of sentinel node biopsy suggests that after nodal dissection for primary disease.
these markers are then taken up by the local lymphatics, In-transit metastasis may present in a limb (see
and identify the first or sentinel draining node. This node Figure 20.24B, C). These represent disease in cutaneous
is then sampled surgically and, if tumour free, then it is lymphatics between the primary site and local draining
thought that it is unlikely that there is tumour in further nodes. They can erupt and involve widespread areas of skin
nodes and the patient will therefore not require a nodal as small erythematous or pigmented macules and nodules.
block dissection. If the sentinel node is positive, then block In-transit metastases can be very problematic and distres-
dissection is required. No survival advantage has been sing to the patient, especially if they break down or coalesce
shown so far for sentinel node biopsy compared to remov- into larger masses. Patients who develop this condition can
ing nodes if and when they are found by clinical examina- be referred to one of a few specialized units around the
tion. Even sentinel node biopsy is associated with some country which offer isolated limb perfusion (ILP): a tech-
surgical complications. Currently, standard of care in the nique in which the circulation in a limb is isolated and che-
UK is observation of potential node bearing areas and sur- motherapy is given to the limb alone, without significant
gery if required. amounts of drug entering the general circulation. This tech-
nique can give considerable palliative benefit and, in some
patients, a complete response may be achieved with all the
Adjuvant treatment for melanoma
nodules and papules disappearing. If in-transit metastasis
At present, there is some evidence that the adjuvant use of affects the skin of the trunk, then the area cannot be
high-dose interferon may improve survival in deeper mel- isolated and systemic chemotherapy is required.
anomas (>4 mm Breslow depth) or in early node-positive Patients may develop blood-borne metastasis, most
disease at presentation. Not all authorities in Europe accept commonly in the liver, lungs, brain or bone. Radiotherapy
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Chapter | 20 | Skin and lip cancer
Primary cutaneous lymphomas are uncommon tumours. These tumours represent neuroendocrine carcinoma of
The majority are T-cell lymphomas with less than 25% the skin. They tend to affect the elderly, often presenting
being B cell. They are more common in males. At present, as a painless nodule in the head and neck or on a limb.
their aetiology is unknown, but a viral association has been They may respond well to initial treatment, but go on to
suggested. recur locally or to develop metastatic spread. They are trea-
Within the primary cutaneous T-cell lymphomas, myco- ted with wide local excision where possible, with post-
sis fungoides is the most common type and usually presents operative radiotherapy, or radiotherapy alone, if inopera-
in men over 60. There is a range of clinical presentation ble. Chemotherapy is used for advanced local or recurrent
varying from erythematous cutaneous patches, which disease, using agents similar to those used in small cell
may show very slow progression to thickened plaques or lung cancer, such as cisplatin and etoposide. Initially,
nodular tumours, over several years (Figure 20.25). tumours may respond to chemotherapy but almost inevi-
The development of lymphadenopathy or visceral tably recur. The main differential diagnosis of Merkel cell
organ involvement worsens prognosis markedly and the tumours is small cell carcinoma, which has metastasized
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Walter and Millers Textbook of Radiotherapy
A B
C D
Figure 20.26 (AE) Total skin electrons being used to treat cutaneous lymphoma.
to the skin. Cytokeratin 20 is useful in differentiating connective tissue cell precursors, including vascular
between these two possibilities histologically. nerve and muscle tissues with a wide arange of pathological
types and subtypes, often not easy to diagnose even with
adequate histological material.
SKIN SARCOMA The most important pathological diagnosis is to decide if
the tumour is benign or malignant, with the potential to
Primary sarcomas of the structures of the skin or sub- recur or metastasize. If the tumour is benign and has been
cutaneous tissues are uncommon but may present as a excised completely then no further intervention is required.
diagnostic problem. They often have no defining clinical True malignant sarcomas affecting the skin, for example
characteristics and most often present as a skin or subcuta- angiosarcoma, can carry a poor prognosis. These vascular
neous nodule. These tumours can arise from a range of malignancies (Figure 20.27A) present with an erythematous
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Chapter | 20 | Skin and lip cancer
A B
or vascular nodule, which can then ulcerate or go on to form of developing a second malignancy, often non-Hodgkins
several other nodules. They can metastasize early and wide lymphoma. Most patients are treated with relatively low
surgical excision is the treatment of choice. They are also doses of radiotherapy, such as 8 Gy in a single fraction,
associated with developing in areas of post-mastectomy lym- which may be repeated.
phoedema, either in the chest wall or arm, often a decade Epidemic KS develops in approximately 2025% of
after initial surgery. This phenomenon is known as the Stew- patients with AIDS, although there was a much higher
art Treaves syndrome. incidence in AIDS patients when the epidemic first started.
Other malignant variants of sarcoma which can develop Since the introduction of highly active antiretroviral treat-
from skin structures, include malignant fibrous histiocy- ment (HAART), the incidence of age-related Kaposis
toma, malignant peripheral nerve sheath tumours and clear sarcoma has reduced. Patients with this variant are more
cell sarcoma, which is a malignancy derived from melano- likely to develop disseminated disease. Chemotherapy
cytes. These are all uncommon and initial treatment for all is used to treat Kaposis sarcoma using agents such as
is wide surgical excision. liposomal doxorubicin or a taxane. These tumours can
As well as the skin sarcomas with true metastatic potential, be exquisitely sensitive to radiotherapy: great care must
there are also connective tissue tumours that can affect be taken in treating sites such as the oral mucosa or con-
the skin, showing local invasion and having the potential siderable morbidity can be caused. There have been a
for local recurrence if inadequately excised. Metastases are variety of dose schedules used, all giving relatively low
very rare. The most common example in this group would total doses for the management of this condition, such
be dermatofibrosarcoma protuberans (see Figure 20.27B). as a single 6 Gy fraction, using a low energy electron
These tumours can be difficult to diagnose pathologically, beam, for single or a few cutaneous lesions, or 12 Gy in
especially in their early stages, when histologically they three fractions. There is a suggestion that using slightly
may appear to be benign. They have a long natural history, higher fractionated doses, such as 2030 Gy in 1015
with local recurrences stretching over years. The can de- fractions may produce a longer lasting response for indi-
differentiate and become more aggressive clinically and his- vidual lesions.
tologically more malignant. If this occurs, there is a greater
risk of metastasis.
SKIN APPENDAGE TUMOURS
KAPOSIS SARCOMA These are also known as adnexal tumours. They arise from
skin structures including the hair follicle, sebaceous glands
This is a particular form of vascular sarcoma which is or sweat glands. There is a wide range of benign skin
derived from endothelial cells. It has become much more appendage tumours which occasionally undergo malig-
prevalent with the increased incidence of AIDS. Kaposis nant transformation. They most often appear as smooth
sarcoma (KS) has several variants including: classical KS, non-distinctive masses which are diagnosed not by their
and epidemic KS, both associated with human herpes virus clinical appearance, but on biopsy histopathology. There
type 8. There are also types associated with immunosup- are multiple pathological subtypes (Figure 20.29A, B).
pressive treatment and African KS. Sebaceous carcinoma is an example of an uncommon
Before the AIDS epidemic, classical KS was a rare disease, potentially metastatic skin appendage tumour. These classi-
affecting elderly males, usually of Italian or East European cally occur on the eyelid, diagnosed on biopsy. Surgery is the
Jewish descent, who developed the pigmented patches and treatment of choice. Sweat gland carcinoma gives a similar
nodules around the lower leg or ankle (Figure 20.28AC). indistinct clinical picture. These tumours usually present
These tumours develop slowly, but patients are at risk as an odd-looking BCC or SCC, with the diagnosis again
337
Walter and Millers Textbook of Radiotherapy
A B
A B
Figure 20.29 Skin appendage tumours. (A) A sebaceous naevus with an associated basal cell carcinoma. (B) A multiple cylindroma,
with a typically non-characteristic appearance.
338
Chapter | 20 | Skin and lip cancer
not been made until excision biopsy has been done. Surgery This condition, thought to arise from epithelial cells in
is again the treatment of choice. an apocrine duct, looks like eczema. It can give rise to pru-
Pagets disease can occur outwith the breast; extra mam- ritus and ulceration and may spread to locoregional nodes
mary Pagets disease. The most common site is the vulva. and even metastasize systemically.
FURTHER READING
Locke J, Karimpour S, Young G, et al. melanoma. N Engl J Med dacarbazine. J Clin Oncol 2009;
Radiotherapy for epithelial skin 2004;351:9981012. 27:15s (suppl; abstr 9038).
cancer. Int J Radiat Oncol Biol Phys Thompson JF, Scolyer RA, Kefford RF. Hodi FS, ODay SJ, McDermott DF, et al.
2001;51:74855. Cutaneous melanoma. Lancet Improved Survival with Ipilimumab
Petit JY, Avril MF, Margulis A, et al. 2005;365:687701. in Patients with Metastatic Melanoma.
Evaluation of cosmetic results of a Morrison WH, Garden AS, Ang KK. N Engl J Med 2010;363:711722.
randomized trial comparing surgery Radiation therapy for non melanoma Chapman PB, Hauschild A, Robert C,
and radiotherapy in the treatment skin carcinomas. Clin Plast Surg Improved Survival with Vemurafenib
of basal cell carcinoma of the face. 1997;24:71829. in Melanoma with BRAF V600E
Plast Reconstr Surg Ott MJ, Tanabe KK, Gadd MA, et al. Mutation. N Engl J Med 2011;
2000;105:254451. Multimodality treatment of Merkel 364:25072516.
Bishop JN, Bataille V, Gavin A, et al. The cell carcinoma. Arch Surg Burmeister BH, Mark Smithers B,
prevention, diagnosis, referral and 1999;134:38893. Burmeister E, et al. A prospective
management of melanoma of the Stelzer KJ, Griffin TW. A randomised phase II study of adjuvant
skin: concise guidelines. Clin Med prospective trial of radiation therapy postoperative radiation therapy
2007;7:28390. for AIDS-associated Kaposis sarcoma. following nodal surgery in malignant
Balch CM, Buzaid AC, Soong SJ, et al. Int J Radiat Oncol Biol Phys melanoma: Trans Tasman Radiation
Final version of the America Joint 1993;27:105761. Oncology Group (TROG) study
Committee on Cancer staging system Hersh E, Weber J, Powderly J, et al. 96.06. Radiother Oncol.
for cutaneous melanoma. J Clin Long-term survival of patients (pts) 2006;812:136142.
Oncol 2001;18:363548. with advanced melanoma treated
Tsao H, Atkins MB, Sober AJ. with ipilimumab with or without
Management of cutaneous
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Chapter | 21 |
Head and neck cancer general principles
Christopher D. Scrase
anatomical site, the concept of multidisciplinary team Pre-malignant conditions also exist which predispose
working is paramount in head and neck cancer and it is for the development of head and neck cancers. These
essential that the team members are involved as early as are most commonly seen in the oral cavity and include
possible to provide the best outcome in terms of tumour leukoplakia (white patches) which carry an approxi-
control, maintaining function and acceptable cosmesis. mately 5% risk of progressing to invasive malignancy
Radiotherapy, and to an increasing extent chemotherapy, and, more sinisterly, erythroplakia. Regular specialist fol-
are now widely used, either as primary therapy or post- low up is therefore essential. Lichen planus with dysplas-
operative treatments. tic features can also become malignant and requires
monitoring.
Radiation exposure is also a risk factor for developing
DEMOGRAPHICS head and neck cancers. A previous history of radiotherapy
treatment should be sought in newly diagnosed patients.
It will also have an impact on any future radiotherapy treat-
Head and neck cancers make up 45% of all new cancers.
ment options.
The incidence is higher in males than females, although the
ratio is different for specific cancers: oral cavity (2:1), larynx
(4:1), but these numbers are changing due to an increasing
incidence of smoking in women. The majority of head and PREVENTION AND EARLY DIAGNOSIS
neck cancers present beyond the fifth decade with an aver-
age age of onset of 60 years. Cancers of the head and neck When diagnosed early, head and neck cancer has quite
are more commonly found in people from the lower social good chances for cure, but at present there is no established
classes and this is multifactorial with higher incidences of screening programme. It has been shown that targeted edu-
smoking and alcoholism, late presentation, poor oral cation in the primary sector with general practitioners and
hygiene, inadequate diet etc. It is linked to delayed diagno- dentists has had some impact on early referral for oral can-
sis and worse outcome. cers. This is important as patients presenting with advanced
disease have a poorer prognosis.
Tobacco cessation is also an important factor in prevent-
AETIOLOGY ing head and neck cancers. The prevalence of cigarette smok-
ing has fallen by over 20% in men over the last 20 years
The most important risk factor in the development of head (Figure 21.1). Aggressive treatment of pre-malignant condi-
and neck cancers is tobacco. Smoking or chewing tobacco is tions is important in reducing the incidence of invasive
associated with 8590% of head and neck malignancies. cancer.
Alcohol intake has also been shown to cause an increase
in this group of cancers. There is also a synergistic effect
of combining alcohol and tobacco with regard to develop- Great Britain
ing cancers in this site. There is also a clear increase in the Percentage smoking cigarettes
incidence of second malignancy of the head and neck and
60
other sites (lung, oesophagus) in persistent smokers. Men
Other risk factors in head and neck cancers have been Women
suggested including poor oral hygiene, dental disease and 50
trauma from badly fitted dentures, though direct causation
has not been demonstrated. Viral infections have also 40
been investigated for a role in the aetiology of head and
neck cancers. There is a very strong association with 30
Epstein-Barr virus infection and nasopharyngeal cancer.
There is an increasing incidence of human papilloma virus 20
(HPV) associated oropharyngeal and oral tumours, par-
ticularly in the USA. Such tumours develop in younger 10
patients and have a distinctive pathological appearance
basaloid and predominantly poorly differentiated carci- 0
noma. Immunosuppression is known to be a risk factor
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
1998
2000
2002
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Chapter | 21 | Head and neck cancer general principles
343
Walter and Millers Textbook of Radiotherapy
is no longer required and patients have returned to suffi- voice preservation. In some sites, radiotherapy is the only
cient oral intake and proven maintained weight. option or preferred option due to the inaccessible nature
of the primary, e.g. nasopharyngeal cancer.
Poor differentiation
Stage III/IV
Multicentric primary
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Chapter | 21 | Head and neck cancer general principles
345
Walter and Millers Textbook of Radiotherapy
INDICATIONS IRRADIATION
Oral cavity
T2N0 with primary approaching midline, all T3N0 and T4N0 Levels I, II and III bilaterally
Oropharynx
Nasopharynx
Hypopharynx
Larynx
Lymph node levels are defined as follows: level 1, submandibular; level II, upper deep cervical; level III, middle deep cervical; level IV, lower deep
cervical; level V, posterior triangle
Consideration of the risk-benefit is then required depen- Debate continues on whether to irradiate the neck post-
dent in part on the irradiation technique. operatively when it is planned to irradiate the primary site
Unless there is gross residual disease or where radiother- and there is no nodal disease identified in the neck dissec-
apy is planned for the primary site following a neck dissec- tion specimen. The additional morbidity of irradiating the
tion, a GTV will not be apparent on the planning CT scan. It lower neck to intermediate prophylactic doses is relatively
is often helpful to co-register any diagnostic scans with the low compared to the rest of the neck, while recurrence in
planning CT scan in determining more precisely the pre- those not irradiated is difficult if not impossible to salvage.
operative GTVs CTV. The decision must rest with the treating clinician, but a
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Chapter | 21 | Head and neck cancer general principles
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Walter and Millers Textbook of Radiotherapy
FORWARD PLANNING
Compute DVH
Cord
No ADJUST
Plan acceptable
PLAN
Yes
Treat patient
Figure 21.6 Treating a target volume with normal tissue in the
concavity. Figure 21.9 Forward planning.
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Chapter | 21 | Head and neck cancer general principles
manual iterative process (often itself reliant on the experi- It is because IMRT achieves its goal through shifting
ence of the planner), parameters including the intended tar- dose that some structures that would not have been irra-
get volume dose to a specified volume and maximum and diated using conventional techniques need delineation.
median/mean doses allowed to normal tissues are specified For example, in the treatment of oropharyngeal tumours,
at the outset. This is a process known as inverse planning. the oral cavity will receive modest doses of radiation. By
It is evident that the process of inverse planning requires specifying a limit of dose there, it is possible to minimize
absolute clarity of target volume definition (Figure 21.10). the impact of irradiation on the oral mucosa. In addition,
This is not a minor issue as arriving at definitions, particu- it is helpful to treat the patient in such circumstances in an
larly in the head and neck area, is through a process of extended neck position to move the oral cavity out of the
integration of all planning data. This will include any pre- primary portals. Fictitious structures (dummy organs)
treatment visual inspection and imaging, operative findings, might need to be drawn to keep dose out of areas that
pathology results, postoperative and planning scans and would never normally be irradiated and/or to try to
knowledge of patterns of spread. Clearly, this approach improve conformality of target volume coverage. The end
should be applied to all radiotherapy where accurate target result is an array of volumes for the planner to utilize
volume definition is necessary, i.e. curative radiotherapy, (Figure evolve 21.11 ). This process is time-consuming but
but the ability of IMRT to achieve a high degree of conform- a prerequisite to successful IMRT. Software programs are
ality makes this crucial. International guidelines now exist under development that should speed this process through
for the definition of the nodes in the cervical chain which the use of stored templates of normal structures with built-
should lead to some uniformity between centres, but none in elasticity to morph to the individual patients anatomy
exist thus far for the primary tumour. and body profile.
The process of inverse planning requires as much clarity Before IMRT be undertaken, there is a need to carry out a
on normal tissue volume definition as that of the clinical number of pretreatment checks. This process of individual
target volume. In the head and neck region, these organs pretreatment verification seeks to ensure that the treatment
at risk (OARs) would include the spinal cord, brainstem, plan is being delivered by the linear accelerator. This is only
brain, optic pathway, cochlea and salivary tissues. Failure a check however of the output of the linear accelerator.
to delineate these accurately could mean that they are irra- On-treatment verification would include geometrical
diated unintentionally beyond conventional tolerance lim- checks of patient position, typically using orthogonal fields
its as IMRT achieves its goal of improved conformality in and verification of delivered dose (e.g. thermoluminescent
simple terms by moving dose elsewhere. Secondly, normal dosimeters (TLDs) diodes or portal dosimetry).
tissues, once delineated, require a specification of dose.
These constraints may be specified in terms of maximum
doses (e.g. spinal cord) or dose-volume constraints (e.g. The scope of IMRT in head and neck tumours
parotid glands) and will be determined on the functional The improvement in conformality in head and neck
unit arrangement (i.e. parallel versus series). tumours with IMRT has two important fundamental bene-
fits. First, it facilitates the coverage of complex and espe-
INVERSE PLANNING cially concave target volumes. Secondly, it can achieve
avoidance of dose-limiting normal tissues.
It is perhaps the avoidance function that is more useful
Define CTV and ORVs in head and neck tumours. The parallel-opposed technique
does, as the name suggests, treat everything in its path.
Mucosa and salivary glands that need not necessarily be
treated can now be spared by this approach (Figure
Define C(P)TV and (P)ORV constraints
evolve 21.12 ). The net effect is the expectation of reduced
toxicity. This has perhaps been best explored in relation to
reducing xerostomia through sparing of one or both
Define beam geometry parotid glands. In addition, however, is the improved
tolerability of some of the more intense schedules that
are emerging as superior in the management of head and
neck tumours, i.e. altered fractionation and concurrent
Optimise beam intensives chemoradiotherapy.
An improvement in conformality, however, also facili-
tates comprehensive coverage of the target volume as
TREAT defined as well as dose escalation. With conventional even
Compute delivery sequence
PATIENT 3DCRT approaches some compromise in target volume
coverage may be necessary if normal tissue tolerance has
Figure 21.10 Inverse planning. been reached. The obvious example is in the treatment of
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Walter and Millers Textbook of Radiotherapy
cervical nodes overlying the spinal cord. Typically, these PTV PTV-CTV
would be treated with electrons of a specified energy. IMRT margin
treats this concave volume to the specified dose (acknowl-
edging that there will be some inhomogeneity) with
sparing of the underlying cord without the need for elec-
tron applicators. In other sites, such as the paranasal terri- CTV Larynx CTV
tory, some of the target volume may be at risk of complete
sparing because of the complex interrelationship of normal
tissue and tumour volumes (Figures evolve 21.13 and
21.14 ). Dose escalation can be used at areas of greatest
risk of recurrence, e.g. gross residual primary tumour and Cord
nodes with extracapsular spread.
Dose escalation with IMRT needs consideration of radio-
biological principles. A single phase technique is used
throughout the whole volume (Figure evolve 21.15 ) with
different doses specified according to areas of variable risk, Figure 21.17 PTVCTV margins.
e.g. gross disease, high-risk (e.g. involved nodes post-
excision) and low-risk territories (e.g. elective nodes in conformality may have some undesirable effects. It is
contralateral neck). Not only is the total dose modified predicted that second malignancies may be increased as a
according to perceived risk but so is the dose per fraction. consequence of this. Whether these risks, arrived through
A higher than conventional dose per fraction will have a modeling, become a clinical reality remains to be seen. In
higher cell kill effect and is important in the area that is addition, it is unknown what the effects of adding chemo-
dose escalated. This approach is called the synchronous therapy will have on these zones. Since chemotherapy is
or simultaneous integrated boost technique (SIB) (Figure often utilized concurrently in head and neck cancers, this
evolve 21.16 ) and is established as an approach in IMRT issue needs clarification.
of the head and neck. Care is clearly required in the volume
of normal tissue exposed to this as higher than expected
morbidity may result because of the negating effect on nor-
IGRT
mal tissue damage. In areas to receive prophylactic irradia- There is the need to revisit IGRT introduced earlier in this
tion, the total dose may need to be modified upwards to section. Patients with head and neck tumours need a high
compensate for the longer elective treatment (e.g. 54 Gy degree of reproducibility and this is generally achieved
in 30 fractions rather than 50 Gy in 25 fractions see later through good immobilization techniques. These immobi-
section) to compensate for repopulation. lization devices cannot achieve complete immobility and it
Clearly, IMRT has real potential to improve the outcome is for that reason that a CTVPTV margin exists even in
of patients with head and neck cancer. Its implementation IMRT (Figure 21.17). IGRT seeks to reduce this margin by
requires multiprofessional engagement. daily imaging of, in the case of head and neck tumours,
bony and soft tissues, and repositioning of the isocentre.
This on-line approach of imaging and correction before
Pitfalls to intensity modulated radiotherapy the treatment itself then facilitates a reduction in that
Provided the treating clinician is confident in target volume CTVPTV margin. IMRT then seeks to achieve conformality
definition, the risks of geographical miss are small. Parallel- of the CTV, IGRT a reduction in the PTV margin required
opposed techniques work because the degree of volume (Figure 21.18).
definition is not required. Indeed, conventional head
and neck radiotherapy is still undertaken by many using
fields defined by bony landmarks. It is useful to think of DOSE AND FRACTIONATION
3DCRT and IMRT as a volume-defining initial process with
fields as part of the verification process. Thinking in terms
Definitive radiotherapy
of volumes in all head and neck cases makes the transition
to IMRT a much smoother process. The conventional schedule for radiotherapy to head and neck
Secondly, there is a need to be quite specific on normal cancer involves the delivery of 6670 Gy in 2 Gy fractions
tissue tolerance. The landmark paper of Emami, from the over 6.5 to 7 weeks treating 5 days per week. A BIR study
pre-CT planning era was published in 1991 and is still looking at a short schedule (34 weeks) compared with the
widely used. The recently published QUANTEC data has conventional schedule in larynx cancer did not show any
revised or enhanced estimates of tolerance. significant differences since this further centres have pub-
Thirdly, there remains the issue of low-moderate dose lished data suggesting that this hypofractionated accelerated
irradiation. The spreading of dose to achieve the desired schedule is useful for small volume treatments 50 Gy in
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Chapter | 21 | Head and neck cancer general principles
Figure 21.18 IGRT (in this case cone beam CT). Postoperative radiotherapy
Doses to sites of gross residual disease, i.e. the primary and
involved nodes, are treated to doses similar to the definitive
16 fractions over 3 weeks or 55 Gy in 20 fractions over setting, i.e. 6670 Gy when using 2 Gy fractions with the
4 weeks. remainder of that node station (i.e. level) treated to at least
The use of acceleration and hyperfractionation was tested 60 Gy. The remainder of the operated neck can be treated to
in a trial of CHART (continuous hyperfractionated acceler- lower doses of around 50 Gy: it has been suggested that the
ated radiotherapy) versus conventional 2 Gy per fraction operated neck requires a higher dose to sterilize micro-
per day schedule. This showed no increase in overall survival scopic residual disease than the unoperated neck. If it is
and a non-significant increase in tumour control (but intended to irradiate the contralateral neck then
reduced nodal control) for a dose of 54 Gy given in three 4650 Gy should suffice.
daily fractions over 12 days continuously. Subgroup analysis
did show improved outcome in T3/4 larynx cancers and
well-differentiated tumours. The overall feeling was that CHEMOTHERAPY IN HEAD
54 Gy was insufficient. CHART has not been adopted as a AND NECK CANCER
schedule in the UK. However, the use of moderate accelera-
tion with conventional fractionation has been shown to be
beneficial. The DAHANCA group compared six fractions per There has been much work done looking into chemother-
week with the standard five (still using 2 Gy per fraction). In apy agents in head and neck cancer. Many drugs have been
total 6668 Gy was given in either 6.5 or 5.5 weeks. They shown to have some response in squamous cell cancers of
showed improved 5-year local control in the moderately the head and neck, in particular, the platinum compounds,
accelerated group of 68% versus 56% for standard therapy. 5-fluorouracil, methotrexate, bleomycin, vinca alkaloids
The extra treatment was either given on Saturday or the and, more recently, the taxanes. There is an increasing
patients were treated twice on the Friday (with 6 hour gap). amount of data showing benefits of the addition of
Other studies have looked at increasing dose or accelera- chemotherapy.
tion but with a split in the course of treatment to allow recov-
ery of the acute toxicities. The evidence suggests that the Concurrent chemotherapy and
repopulation occurring in the gap reduces any benefit from
definitive radiotherapy
the dose escalation and the late toxicity is often increased.
A newer schedule is to use a concomitant boost to the pri- At present, the accepted standard treatment for radical non-
mary site during the conventional radiotherapy. This treats surgical therapy is concurrent cisplatin chemotherapy with
the first phase of treatment (primary disease plus involved radical radiotherapy. The evidence for this comes from
nodes and microscopic spread) in the morning and then Pignons meta-analysis (2000) which showed a small but
later the same day a second smaller boost dose is given significant survival advantage to the combined treatment
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Walter and Millers Textbook of Radiotherapy
Concurrent chemotherapy and Radiotherapy for head and neck cancer has many side
effects which must be effectively communicated to the
postoperative radiotherapy patient before embarking on treatment. A detailed explana-
A previous section has outlined the range of indications for tion is essential for informed consent but also to improve
postoperative radiotherapy. Some situations would be con- compliance with the full course of treatment to give the best
sidered particularly adverse for locoregional recurrence chance of a successful outcome. As with radiotherapy to
and, in these cases, consideration should be given to concur- any part of the body, the side effects (apart from fatigue)
rent chemoradiation postoperatively. Two recent trials and a relate to structures within the radiation field. They can be
consensus view have suggested that such patients would be divided into acute (early) or late side effects. Reactions will
those with positive primary resection margins and those with to some extent be site specific and are discussed in more
pathologically involved nodes with extracapsular spread. detail in the next chapter. However, it is useful to consider
the principles here.
Induction chemotherapy
Acute toxicity
Neoadjuvant or induction chemotherapy is used to down-
stage a primary tumour before definitive surgery or radio- Mucositis will develop in the treatment field for all patients
therapy and to decrease the incidence of distant with head and neck cancer and can be severe and disabling.
metastases. In the Pignon meta-analysis of chemotherapy It may be mild (grade 1/2), but is often severe (grade 3)
with radiotherapy in head and neck cancer, there was evi- (Figure evolve 21.19 ), especially in those receiving concur-
dence that organ preservation was increased in patients rent chemotherapy, which may lead to a break in treatment.
receiving chemotherapy followed by radical radiotherapy Grade 4 mucositis (frank ulceration) should not be allowed
compared with primary surgery for advanced but resectable to develop. Management includes analgesia using the pain
laryngeal cancer. Although the original meta-analysis did not ladder. Opiates may be required at some stage. Topical
show any real survival benefit, a more recent review on agents may be used initially and alongside systemic
updated data has shown that induction schedules may con- analgesia. Patients must have their weight monitored
vey a survival advantage of up to 23%. The majority of these and nutritional supplements considered. The majority of
studies used the previous standard induction chemotherapy patients will have a level of discomfort that requires opiate
schedule of cisplatin and 5-fluorouracil. Two recent pub- level analgesia. This can be administered in oral preparations
lished studies have shown promising activity for the triplet (solutions, syrups etc.) or delivered via feeding tube if pres-
schedule of docetaxel, cisplatin and 5-fluorouracil in terms ent. It can often become difficult for patients to tolerate oral
of survival, re-igniting the debate of induction chemotherapy medications, particularly in the latter stages of treatment, but
and its role in locally advanced head and neck cancer. the development of transdermal delivery systems for opiates
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Chapter | 21 | Head and neck cancer general principles
can be an excellent alternative in head and neck cancer possibility particularly if they have facial hair. If the area
patients where swallowing is often difficult or uncomfort- receives a dose exceeding 60 Gy then the alopecia may be
able and, in the main, these have avoided the need for sub- permanent.
cutaneous infusions of opiate, which were occasionally Xerostomia is a common late side effect of radiotherapy
required in the past for patients with severe symptoms. to the head and neck. It most commonly arises due to
Dysphagia secondary to mucositis, loss of taste, loss of radiotherapy to the parotid gland, although the subman-
appetite and thickened secretions lead to weight loss in dibular and sublingual glands can also be included. The
head and neck cancer patients. This should be predicted risk of xerostomia increases with increasing dose. The ini-
prior to treatment and a feeding tube considered in all tial symptom may become apparent from as early as the
patients with large treatment fields, especially those to be first week of therapy and irreversible damage to the gland
treated by chemoradiotherapy. If patients without a tube will arise with modest doses. It can be a most distressing
are struggling and losing weight, a tube may need to be side effect for patients and efforts to minimize the dose
inserted during treatment this will usually involve a to salivary glands should be considered during radio-
radiologically placed gastrostomy. Prophylactic tube inser- therapy planning. Once it has developed, patients should
tion is usually more satisfactory and allows early feeding to be offered artificial saliva preparations and advised to
be initiated before the patient develops difficulties. use fluoride mouthwashes regularly. Dental check-ups
Thickened secretions can be alleviated with carbocisteine are essential.
which has a systemic mode of action and acute xerostomia Osteoradionecrosis is the breakdown of bone in an area
managed symptomatically. treated with radiotherapy. It is seen in the mandible most
A skin reaction is seen in any treated area and develops as often in head and neck cancer patients and can be triggered
the treatment progresses. The skin changes from mild red- by dental extractions. It may mimic local recurrence of
ness (Figures evolve 21.20 and 21.21 ) through brisk tumour. It is difficult to manage as further surgery can exac-
erythema to desquamation initially, dry changes and erbate the problem. The best management is prevention,
peeling but progressing to moist desquamation (Figure which means dental treatment prior to radiotherapy and
evolve 21.22 ). A skin care regimen should include washing aggressive dental hygiene post-radiation treatment.
with lukewarm water and unperfumed soap, avoiding Patients must be educated about the risk of dental work
shaving until treatment is completed and applying regular after radiotherapy and seeking specialist advice for any
aqueous cream. Once skin is broken then a barrier product treatment required. It should be performed under general
should be used. The optimal regimen is unclear and is often anaesthetic and with antibiotic cover.
centre specific. Patients should be reviewed regularly post- Myelitis secondary to radiotherapy is a rare but recog-
treatment to monitor the resolution of skin and mucosal nized side effect from head and neck radiotherapy. There
reactions. is considerable debate over what constitutes a safe dose
Fatigue is seen in many patients receiving radical radio- of radiation to the spinal cord. This is complicated due
therapy. It has been shown that maintaining a level of gen- to many variables including volume treated, fraction size
tle activity is the best way to overcome the asthenia during and total dose. Different series have described different
therapy. In head and neck cancer patients, especially those maximal doses. The general consensus is that 4446 Gy
receiving chemoradiotherapy, it is usual to monitor the is a safe total dose, although many feel that up to 50 Gy
haemoglobin during radiotherapy and transfusing patients in 2 Gy per fraction is acceptable. Higher doses may be
as required to keep the level greater than 12 g/dl. There is achievable with careful planning if clinically indicated
evidence that radiotherapy is less effective in patients with but, given the catastrophic nature of permanent damage
anaemia, although no good evidence exists that correcting to the spinal cord particularly at the cervical level a con-
anaemia improves outcomes. Indeed, one randomized trial servative approach is usual. To achieve these doses in head
using erythropoietin to prevent anaemia, found a worse and neck treatments using conventional parallel-opposed
outcome in the treated group. lateral fields involves direct treatment with photon fields
up to 4446 Gy. The photon fields are then reduced to con-
tinue to treat the target and anterior neck and the posterior
Late toxicity
neck (overlying the spinal cord) has its remaining dose
Skin pigmentation/atrophy is seen in patients treated with delivered using electrons at an energy to treat nodal disease
head and neck radiotherapy due to the doses received by but to spare the underlying cord. This results in a risk of less
the skin. Skin sparing is achieved where possible due to than 1% of permanent damage owing to myelitis. Some
the use of megavoltage radiotherapy and cutting out the patients may develop Lhermittes syndrome secondary to
immobilization shell in the treatment beam. This bolus early transient myelitis. In Lhermittes syndrome, patients
effect can be used to advantage if there is evidence of skin complain of tingling or electric shocks in the legs. This
involvement in a tumour. can be provoked by flexing the neck. These symptoms
Alopecia in the treated areas can be seen in the head begin about 6 weeks following the radiotherapy and may
and neck patient. Patients should be warned of the last a few months. Progression to late damage is rare. IMRT
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Walter and Millers Textbook of Radiotherapy
can improve the coverage of nodes in this situation (as dis- to utilize the hypoxia seen in tumours and increase the
cussed earlier) though there have still been reports of Lher- benefit of the radiation. The original drugs unfortunately
mittes syndrome. had significant neural toxicity and were therefore not
adopted as standard treatments in the UK.
More recently, a monoclonal antibody to the epidermal
MOLECULAR ONCOLOGY FUTURE growth factor receptor (EGFR) has been developed which
shows a survival advantage when combined with radiother-
DEVELOPMENTS apy compared with radiation alone. Another agent with
activity against EGFR1 and HER2 (EGFR2) is currently
New therapeutic agents which exploit knowledge about the under evaluation. It is hoped that knowledge of the molec-
cell cycle and control of cancer growth are being used with ular processes will lead to more designer drugs. These may
increasing frequency in treatment of cancers. In head and eventually replace the currently used and less specific con-
neck cancer in the past, radiosensitizers were used to try ventional chemotherapy agents.
FURTHER READING
Ang KK, et al. Randomised trial of radiotherapy in head and neck cancer. modulated radiation therapy. IPEM;
addressing risk features and time Radiother Oncol 1997;44:12336. 2008.
factors of surgery plus radiotherapy in Fletcher GH. Elective irradiation of Jackson A, et al. The Lessons of
advanced head-and-neck cancer. Int J subclinical disease in cancers of the QUANTEC: Recommendations for
Radiat Oncol Biol Phys head and neck. Cancer Reporting and gathering data on
2001;51:5718. 1972;29:14504. Dose-Volume Dependencies of
Bernier J, et al. Postoperative irradiation Fu KK, et al. A radiation therapy oncology Treatment Outcome. Int J Radiat
with or without concomitant group (RTOG) phase III randomized Oncol Biol Phys 2010; 76 Issue 3
chemotherapy for locally advanced study to compare hyperfractionation Supplement.
head and neck cancer. N Engl J Med and two variants of accelerated Lengele B, et al. Anatomical bases for the
2004;350:194552. fractionation to standard radiological delineation of lymph
Bernier J, et al. Defining risk levels in fractionation for head and neck node areas. Major collecting trunks,
locally advance head and neck squamous cell carcinomas: First report head and neck. Radiother Oncol
cancers: a comparative analysis of of RTOG 9003. Int J Radiat Oncol Biol 2007;85:14655.
concurrent postoperative radiation Phys 2000;48:716. Moharti BK, et al. Short course palliative
plus chemotherapy trials of the Gregoire V, et al. Selection and delineation radiotherapy of 20Gy in 5 fractions for
EORTC (#22931) and RTOG (#9501). of lymph node target volumes in head advanced and incurable head and
Head Neck 2005;27:84350. and neck conformal radiotherapy. neck cancer: AIIMS study. Radiother
Bonner JA, et al. Radiotherapy plus Proposal for standardizing Oncol 2004;71:27580.
cetuximab for squamous-cell terminology and procedure based on Nutting CM, et al. Parotid-sparing
carcinoma of the head and neck. surgical experience. Radiother Oncol intensity modulated versus
N Engl J Med 2006;23:112535. 2000;56:13550. conventional radiotherapy in head
Bourhis J, et al. Hyperfractionated or Gregoire V, et al. CT-based delineation of and neck cancer (PARSPORT): a phase
accelerated radiotherapy in head and lymph node levels and related CTVs in 3 multicentre randomized controlled
neck cancer: a meta-analysis. Lancet the node-negative neck: DAHANCA, trial. The Lancet Oncology
2006;368:84454. EORTC, GORTEC, NCIC, RTOG 2011;12:12736.
Budach W, et al. A meta-analysis of consensus guidelines. Radiother Overgaard J, et al. Five compared with six
hyperfractionated and accelerated Oncol 2003;69:22736. fractions per week of conventional
radiotherapy and combined Gregoire V, et al. Proposal for the radiotherapy of squamous-cell
chemotherapy and radiotherapy delineation of the nodal CTV in the carcinoma of head and neck:
regimens in unresectable locally node-positive and the post-operative DAHANCA 6&7 randomised controlled
advanced squamous cell carcinoma of neck. Radiother Oncol trial. Lancet 2003;362:93340.
the head and neck. BMC Cancer 2006;79:1520. Peters LJ, et al. Evaluation of the dose
2006;6:28. Gupta NK, et al. A randomised clinical for postoperative radiation therapy
Cooper J, et al. Postoperative concurrent trial to contrast radiotherapy with of head and neck cancer: first report
radiotherapy and chemotherapy for radiotherapy and methotrexate given of a prospective randomized trial.
high-risk squamous-cell carcinoma of synchronously in head and neck Int J Radiat Oncol Biol Phys
the head and neck. N Engl J Med cancer. Clin Radiol 1987;38:57581. 1993;26:311.
2004;350:193744. Institute of Physics and Engineering in Pignon JP, et al. Chemotherapy added to
Dische S, et al. A randomised multicentre Medicine. Report 96 Guidance for the locoregional treatment for head and
trial of CHART versus conventional clinical implementation of intensity neck squamous-cell-carcinoma: Three
354
Chapter | 21 | Head and neck cancer general principles
meta-analyses of updated individual with docetaxel in head and neck Wiernik G, et al. Final report of the
data. Lancet 2000;355:94950. cancer. N Engl J Med general clinical results of the British
Pignon JP, et al. Meta-analyses of 2007;357:170515. Institute of Radiology fractionation
chemotherapy in head and neck Vermorken JB, et al. (EORTC 24971/TAX study of 3F/wk versus 5F/wk in
cancer (MACH-NC): an update. 323) Study. Cisplatin, fluorouracil, radiotherapy of carcinoma of the
Int J Radiat Oncol Biol Phys 2007;69 and docetaxel in unresectable head laryngo-pharynx. Br J Radiol
(Suppl. 2):S1124. and neck cancer. N Engl J Med 1990;63:16980.
Posner MR, et al. (TAX324 Study Group). 2007;357:1695704.
Cisplatin and fluorouracil alone or
Figure evolve 21.5 Conformal including sparing the one Figure evolve 21.19 Acute side effects of
radiotherapy treatment remaining eye. . . radiotherapy acute mucositis
Figure evolve 21.7 Step and shoot Figure evolve 21.14 . . .achievable with Figure evolve 21.20 Marked erythema in
technique IMRT a patient treated for nasopharynx
Figure evolve 21.8 Sliding window Figure evolve 21.15 The scope of cancer (neck)
technique IMRT in sparing the parotid Figure evolve 21.21 Marked erythema in
Figure evolve 21.11 The array of and delivering dose according to risk a patient treated for nasopharynx
volumes for the planner to work with of disease cancer (face)
Figure evolve 21.12 The scope of IMRT Figure evolve 21.16 The scope of IMRT Figure evolve 21.22 Acute side effects of
in sparing the parotid and mucosa in treating high risk areas with the radiotherapy skin erythema with
Figure evolve 21.13 Challenges synchronous boost technique associated dry desquamation
in paranasal sinus tumours
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Chapter | 22 |
Sino-Nasal, Oral, Larynx and Pharynx Cancers
Christopher D. Scrase, Paul Symonds
Treatment 364
CHAPTER CONTENTS
Radiotherapy technique 364
Nasopharynx 358 Complications 364
Anatomy 358 Results 364
Anterior wall 358 Paranasal sinus tumours 364
Posterior wall 358 Anatomy 364
Lateral walls 358 Maxillary sinuses 364
Superior wall 358 Frontal sinus 365
Inferior wall 358 Ethmoid sinus 365
Incidence of nasopharyngeal tumours 358 Sphenoid sinus 365
Staging system for nasopharyngeal tumours 359 Incidence of paranasal sinus tumours 365
Aetiology, pathology and lymphatic spread 360 Staging system for paranasal sinus tumours 365
Signs and symptoms 360 Aetiology, pathology and lymphatic
Diagnosis and staging 360 spread 365
Treatment 361 Signs and symptoms 366
Radiation technique 361 Diagnosis and staging 366
Complications 361 Treatment 366
Results 362 Radiotherapy technique 367
Nose and nasal cavity 362 Complications 367
Anatomy 362 Results 367
Superior wall 363 Lip and oral cavity carcinoma 367
Inferior wall 363 Anatomy 367
Anterior wall 363 Incidence of oral cavity carcinoma 367
Posterior wall 363 Staging system for oral cavity lip carcinoma 367
Lateral wall 363 Aetiology, pathology and lymphatic spread 368
Incidence 363 Signs and symptoms 368
Staging system 363 Diagnosis and staging 369
Aetiology, pathology and lymphatic spread 363 Treatment Lip cancers 369
Signs and symptoms 363 Radiotherapy technique 369
Diagnosis and staging 363 Cancers of oral cavity 370
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
Inferior nasal
meatus
Pharyngeal orifice
of auditory tube
External
nares
Hard Uvula
palate NASOPHARYNX
OROPHARYNX
Vallecula
Tongue Epiglottis
LARYNGOPHARYNX
Vestibular fold
Ventricle of larynx
Vocal fold
Hyoid
Thyroid
cartilage
Oesophagus
Cricoid
cartilage Trachea
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
disease and if basic screening tools are in any way suspi- the whole cervical lymphatic chain should be outlined and
cious. A positron emission tomography (PET)-CT may treated as routine, though doses prescribed will be deter-
be useful in that regard. mined by whether they are overtly involved and proximal
to the primary site or more distal and clinically uninvolved.
In other words, even in early cases, at least prophylactic
Treatment doses of radiation should be given to the nodes.
The relative inaccessible nature of the primary tumour and A full head and neck immobilization device is manda-
frequent involvement of Rouvieres node dictates that radi- tory with the shoulders kept well down. A tongue depressor
ation therapy is the main modality for treatment. In addi- is frequently utilized but a drop in jaw position might
tion and unlike other head and neck squamous cell negate the perceived benefits of this technique in sparing
carcinomas, the presence of substantial neck nodes should the oral cavity. A single shell is preferred throughout the
not lead to initial surgical excision as they generally treatment with the degree of neck extension optimized at
respond well to radiation therapy. Any nodes that have the outset.
failed to respond adequately or at recurrence can, provided Except in the case of intensity modulated radiotherapy
the primary disease is controlled, then be managed by an techniques, a multiple phase technique will be utilized
appropriate neck dissection. to treat the primary disease and involved nodes using
Prior to radiation therapy, a thorough dental assessment is parallel-opposed fields. The lower cervical nodes will be
mandatory with essential treatment performed as necessary. treated by an anterior (or anterior-posterior (AP) depend-
Small tumours of the nasopharynx can be adequately trea- ing on the location of nodes in the AP plane) field matched
ted with radiation alone. However, the majority should, on preferably by the mono-isocentric technique. As a
co-morbidity permitting, be managed with concurrent general rule, matching of fields should not occur at sites
chemoradiation. The nasopharynx is the one head and neck of gross disease but this may not be practical in nasopha-
site where concurrent chemoradiation has been more readily ryngeal cancers.
adopted internationally due in part to the intergroup 0099 Where the primary tumour is relatively small (T1, T2), it
study. This study compared concurrent chemoradiation might be practical to irradiate it as a final phase with a
and adjuvant chemotherapy with radiotherapy alone and three-field technique thereby sparing some of the laterally
showed a significant advantage in survival with the combined placed normal structures from the maximum intended
modality approach. The control arm was particularly inferior, dose. Alternatively, and according to available expertise,
however, when compared with other studies. Further studies intracavity, stereotactic radiosurgery or intensity modu-
and a recent meta-analysis specifically of nasopharyngeal lated radiotherapy (IMRT) may facilitate dose escalation
cancers have, however, supported the concurrent chemora- at the site of gross disease with improved local control.
diation approach. Neoadjuvant chemotherapy may result
in useful reduction of the primary and/or nodal disease. Complications
A major problem in delivering adjuvant chemotherapy is
the poor compliance following definitive therapy. Research The significant volumes of normal tissue ordinarily irra-
from Taiwan suggests that adjuvant treatment after concomi- diated can give rise to a range of long-term sequelae.
tant chemoradiotherapy may only be necessary for patients Irradiation of major aspects of the salivary tissue will lead
with a high chance of developing metastatic disease. This to chronic xerostomia. The technique of IMRT may facili-
includes patients with a single lymph node >6 cm, multiple tate less of an impact here, though care will need to be
nodes over >4 cm or supraclavicular nodes. The most fre- taken in underdosing any adjacent diseased lymph nodes.
quently used regimen is cisplatin (100 mg/m2 or 20 mg/m2 In practice, it may be prudent to spare only the superficial
for 5 days) plus 5-fluorouracil (400100 mg/m2 daily parotid glands bilaterally even using IMRT.
by infusion for up to 4 days). This is repeated at 34 weekly High doses of radiation may be delivered to a substantial
intervals during radiotherapy. component of the mandible, particularly when using the
parallel-opposed technique and where there are involved
nodes. As a consequence, treatment risks osteoradionecro-
Radiation technique (Figures evolve 22.3 sis (ORN) and preventive measures beyond meticulous
radiation technique should be adopted. Moreover, the
22.8 for NPC section)
proximity of the pterygoid muscles to the primary target
The technique of Ho forms the basis of the 2-dimensional volume will give rise to trismus and jaw exercises should
approach to treating nasopharyngeal carcinoma. Treatment be encouraged to minimize this.
fields are precisely defined according to local staging. Deter- Endocrine failure due to irradiation of the pituitary and
mination of the primary clinical target volume is now very thyroid glands, though relatively easy to treat, is a not
much individualized based on all clinical information uncommon outcome in long-term survivors and should
available allowing for a more conformal 3-dimensional be actively sought through routine testing in the follow
approach. The pattern of spread outlined earlier dictates that up of these patients.
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Walter and Millers Textbook of Radiotherapy
Advanced tumours with extension into the skull base ranging from 0 to 20%, often succumbing to distal failure.
introduce additional tissues exposed to the high doses of Late recurrences are recognized suggesting that follow up
radiation that will be necessary to achieve local control. beyond 5 years might be prudent and/or advising patients
Aspects of the temporal lobes, optic nerves and chiasm, and primary care practitioners of this so that they can re-
middle and inner ear will be irradiated and, as a conse- referred without delay. Recurrent disease may, on occasions,
quence, are at risk of late neurological damage. The addi- be amenable to re-irradiation as long as volumes to be trea-
tion of chemotherapy may add to this toxicity. In all ted are relatively small and the patient is prepared to accept
cases, the brainstem and spinal cord are organs of risk the additional risks associated with such an approach.
and prescribed doses should not exceed an agreed tolerance
dose. The complex interrelationship with such a range of
normal tissues mandates a meticulous radiation technique NOSE AND NASAL CAVITY
to minimize these complications. The technique of IMRT
lends itself to such a site but does not obviate the need
for precise target volume delineation. Results using IMRT Anatomy
demonstrate superior coverage of advanced tumours and The external nose is like the tip of an iceberg with a complex
an improvement in disease control. array of passageways and air cavities within it that form
The undifferentiated type of nasopharyngeal cancer is the nasal cavity and paranasal sinuses. The hair-bearing
rather more radiosensitive and, as such, slightly lower entrance that forms the vestibule and the mucociliary esca-
doses may be delivered with a consequent lessening effect lator provides an important initial defence against the inha-
on late sequelae. lation of germs (Figure 22.9).
The nasal vestibule lies within the aperture of the nostril.
It is bounded laterally by cartilage that forms the nasal ala,
Results
medially by cartilage that forms the columella and inferi-
Small tumours of the nasopharynx are successfully treated orly by the most anterior portion of the floor of the nose.
in about 8090% cases. More advanced tumours, when Importantly, this area is lined by squamous epithelium as
treated optimally, will result in 5-year survival rates of an extension from the outside skin.
the order of 5070%. Those patients with extensive nodes The nasal cavity or nasal fossa proper lies between the max-
and/or involvement of the skull base with cranial nerve illary sinus inferiorly and the eyes and ethmoidal sinus supe-
palsies fare particularly badly with 5-year survival rates riorly. It is divided into two by a midline cartilaginous septum.
Sphenoethmoidal recess
Opening of spenoidal sinus
Frontal sinus
Choana
Tongue
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Walter and Millers Textbook of Radiotherapy
Complications
Superficial tumours will inevitably manifest acute skin Nasal Maxillary
reactions that usually heal promptly. In the longer term, vestibule sinus
atrophy of the nasal cartilage may result in some loss of
the original nasal profile. Figure 22.16 Paranasal sinus anatomy.
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
sinus (fenestration) as obstruction is invariably associated Late sequelae following surgery relate to fibrosis within
with infection. This alone should be performed if the the operated bed potentially exacerbated by radiotherapy
tumour is inoperable prior to radiotherapy with/without and issues related to any prosthesis used.
chemotherapy. Radiotherapy with or without surgery will invariably
Where radiotherapy comprises definitive therapy, it may result in some xerostomia due to the irradiation of the ipsi-
be given concurrently with chemotherapy and/or following lateral parotid gland with its usual sequlae. It is for that
neoadjuvant chemotherapy. On occasions, surgery may reason that any teeth remaining following resection should
follow such therapy. be in healthy condition. Trismus may result and should be
Radiotherapy when given postoperatively is delivered to actively managed with appropriate jaw exercises. Unless
the operative bed comprising the original location of the the orbit is frankly involved, the globe is spared but the lens
tumour and known and potential areas of spread. In the and retina are at risk of damage and the exiting anterior
definitive setting, the volume irradiated will be determined beam gives a significant dose to the optic chiasm and brain-
by all staging information available to the clinician. When stem. Binocular blindness is a rare but catastrophic compli-
neoadjuvant chemotherapy has been used, the pretreat- cation of maxillary sinus irradiation. Pituitary failure may
ment volume will typically be used where it is safe to emerge in long-term survivors.
include it. In practice, routine coverage of the whole ipsilat- Given the complex relationship of tumour and normal
eral paranasal complex is indicated. tissues, particularly the optic chiasm, it is anticipated that
the technique of intensity modulated radiotherapy will
Radiotherapy technique (Figures facilitate a reduction of such late sequelae by improved
conformality and preliminary data support this view.
evolve 22.2022.23 )
An immobilization device should be used. Care should be
taken in achieving the optimal head position. In practice, Results
it is often best for the plane of the floor of the orbit to be Overall, paranasal sinus tumours lead to a 2530% 5-year
perpendicular to the treatment couch. A tongue depressor survival. Tumours within the infrastructure and where
facilitates movement of the tongue inferiorly away from there is good clearance by surgery give rise to more favour-
the treatment volume. A full head and neck shell over able outcomes of the order of 50% 5-year survival.
the shoulders, even if the intention is not to irradiate the
neck nodes, should give rise to smaller set-up errors and
is preferred. LIP AND ORAL CAVITY CARCINOMA
The volume definition has been outlined above.
Volumes should be delineated on a contrast-enhanced
planning CT scan. Rarely is it necessary to include the neck Anatomy
nodes as a clinical target volume but the retropharyngeal Cancers of the lip arise from the vermilion (external) border.
nodes should be included as routine. Co-registration of The anatomical sites conventionally regarded as consti-
images is invaluable in the process of volume delineation. tuting the oral cavity are buccal mucosa, upper and lower
A typical conformal technique will comprise 6 MV photons alveolus, retromolar trigone, hard palate, tongue (anterior
using a two- or three-field arrangement. The contralateral two thirds: anterior to the circumvallate papillae) and the
beam supplements any fall off in dose at the posteromedial floor of mouth.
margin. Beam weighting will vary according to the target
volume shape and body profile but, typically, will derive
predominantly from the anterior beam. As such, there is
Incidence of oral cavity carcinoma
a significant exiting dose. Beam arrangements for ethmoi- The oral tongue and then the floor of mouth are the com-
dal and sphenoidal sinus tumours are best derived follow- monest subsites. Overall, they are still a rare group of can-
ing careful volume delineation. cers making up less than 1% of cancer deaths. The UK
The doses used will be determined by treatment intent. incidence of lip and oral cavity cancers in 2004 was just
Gross disease postoperatively and when used in the defini- under 5000, or six cases per 100 000 population. The inci-
tive setting will demand a higher dose (see elsewhere) with dence remains higher in men than women, although the
consideration to irradiation of critical normal tissues. ratio has fallen from 5:1 to just over 2:1 with increasing
prevalence of alcohol and tobacco use in women.
Complications
Staging system for oral cavity and
The biggest risk with treatment of these tumours is lack of
lip carcinoma
local control given the generally advanced nature at presenta-
tion. On the other hand, those patients who do survive long T1 Tumour <2 cm
term or are cured are at risk of treatment-related sequelae. T2 Tumour 24 cm
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Walter and Millers Textbook of Radiotherapy
T3 Tumour >4 cm
T4a Tumour invades through cortical bone, inferior
alveolar nerve, floor of mouth, or skin of chin or
nose (lip) and cortical bone, into deep/extrinsic
muscle of tongue, maxillary sinus, or skin of face
(oral cavity)
T4b Tumour invades masticator space, pterygoid plates,
or skull base, or encases internal carotid artery
N1 Single ipselateral node 3 cm diameter
N2A Single ipselateral node >3 cm 6 cm
N2B Multiple ipselateral nodes 6 cm
N2C Bilateral or contralateral nodes 6 cm
N3 Any node >6 cm
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
Radiotherapy technique
The technique will be similar to that used for skin tumours.
A margin of at least 1 cm is required around the disease
as assessed by inspection and palpation to arrive at a suit-
able CTV.
An individualized lead cut-out, and an internal gum
shield will usually be used. This arrangement facilitates
appropriate sparing of the adjacent tissues including the
unaffected (usually upper) lip and the deeper tissues of
the oral cavity. These lesions are usually exophytic, so elec-
Figure 22.29 Carcinoma of buccal mucosa. trons will often be preferred to low energy x-rays and,
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Walter and Millers Textbook of Radiotherapy
because the energy chosen is likely to be less than 12 MeV, a surgery with modern reconstructive techniques offered a rel-
few millimetres of wax should be placed over the lesion to atively non-mutilating approach, and one that achieved
ensure maximum dose at the tumour surface. The gum excellent local control (often not achieved with primary
shield will require wax on its anterior surface to absorb radiotherapy). Over the next decade, this approach became
any backscatter electrons that could potentially enhance almost universal around the UK (as in other parts of the
the dose to the treated volume. An alternative is to use world), and this seems the likeliest explanation for the
orthovoltage photons (250 kV) which may be more prac- improved survival figures that have been achieved.
tical to administer in an elderly patient. Care will need to The surgery for oral cavity cancers depends on the extent
be exercised in the degree of underlying bone irradiated of the primary. Small T1 and T2 lesions may be suitable for
that cannot be shielded by the gum shield (Figures simple excision which may be left to heal or closed with a
evolve 22.3322.35 ). split-skin graft or free flap. Larger lesions or those with more
Dose schedules for squamous cell carcinomas of the extensive invasion may require hemi-mandibulectomy with
lip are similar to those for skin cancers and the reader is or without removal of part of the mandible and reconstruc-
referred elsewhere. Longer fractionation schedules give bet- tion with myocutaneous flaps (e.g. pectoralis major flap).
ter long-term cosmesis than a few large fractions and are pre- Radiotherapy remains an integral part of many patients
ferred. Usual treatment regimens for these tumours range treatments, as postoperative adjuvant treatment has been
from 50 to 55 Gy in 1520 fractions, treating daily. established as an important part of the overall management
of many of these tumours. In recent years, evidence has
accumulated of the value of adding chemotherapy to radio-
Cancers of oral cavity therapy schedules in high-risk patients.
Whereas at many other head and neck sites primary radio- Selection criteria for giving postoperative radiotherapy or
therapy (or, increasingly, chemoradiotherapy) is becoming chemoradiotherapy are widely agreed, even if the evidence
more usual as first-line treatment, this is not so for oral cav- level for some of these indications is not high. The reader is
ity tumours, where primary surgery retains its place. High- referred to the earlier chapter on these criteria.
level evidence to support the use of surgery here is scant, Radiotherapy as definitive treatment is still an option for
but other evidence does support this approach. patients with early T1 or T2 tumours of the floor of mouth
In general, survival after treatment for head and neck can- or lateral part of the mobile (anterior two-thirds) tongue.
cer in the UK has shown very little change over past decades. The results of surgery and radiotherapy for such tumours
Oral cavity tumours are an exception. Recent data from the are very similar and much depends on local expertise.
Scottish Cancer Registry show that 5-year survival for oral The tumours that respond best to radiotherapy tend to be
cancers has improved by about 50% since 1980. In the superficial and exophytic. Ulcerated tumours do less well
late 1970s/early 1980s, primary radiotherapy was widely and perhaps should be considered more carefully for surgi-
employed in the UK for oral cancer. At about that time, cal resection.
the Canniesburn plastic surgeons began to persuade the rest Brachytherapy for T1/T2 tongue tumours is still widely
of the head and neck oncology community that primary practised in continental Europe but expertise is lacking
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
in many parts of the UK and only some centres offer this rates of 1030% at best, but these outcomes may be
form of radiotherapy. Suitable lesions are less than 1 cm enhanced with concurrent chemotherapy.
thick and no more than 2.5 cm in length situated on the Tumours of the buccal mucosa are usually well differen-
lateral edge of the mobile part of the tongue (Figure tiated and may originate from areas of leukoplakia. Small
evolve 22.36 ). Such lesions can be implanted with T1 verrucous tumours may be readily treated by surgical exci-
three or four iridium hairpins spaced 12 mm apart to cover sion, but the functional and cosmetic results are better when
the lesion plus a margin of 1 cm. A typical dosage is 65 Gy larger T1 or T2 tumours are treated with radiotherapy: the
in 67 days. In France, brachytherapy treatment is often control rates are similar for surgery or radiation treatment.
accompanied by a supra-hyoid neck dissection.
Significant involvement of the alveolar ridge by even a
Radiotherapy technique
small floor of mouth tumour is a contraindication to radio-
therapy. Involvement of the mandibular bone occurs early An immobilization device is used and should include fixa-
when tumour originates or spreads to the gingival mucosa. tion of the shoulders even if it is not intended to irradiate
Tumour can spread rapidly through the marrow cavity. the neck nodes comprehensively. An intra-oral device is fre-
Involvement of the mandible is an indication for surgery quently used. For tongue tumours, it has as its purpose to
followed by radiotherapy. move the tongue into the treatment volume and, as a con-
T3 or T4 tumours of the tongue or the oral cavity sequence, achieve sparing of some of the palate. There is
(Figures 22.37 and 22.38) are difficult to cure with then sparing of some of the minor salivary tissue. For buc-
radiation alone. Radiotherapy alone in patients with co- cal tumours, its intention is different: here, it is helpful to
morbidity felt to be truly unsuitable for surgery gives cure move the tongue away from the irradiated mucosa and
thereby lessen the toxicity.
Volumes should be defined on a planning CT scan.
A fundamental decision is whether to treat the neck bilat-
erally. This decision should be based on the anticipated risk
of contralateral spread and will vary according to tumour
site within the oral cavity. For well-lateralized tumours,
an ipsilateral approach will often suffice and has as its
advantage sparing of the contralateral parotid gland. As a
result, permanent xerostomia is reduced. Relapse in the
contralateral neck can potentially be salvaged later.
Postoperatively, the surgical tumour bed and nodes are
included even if node negative, though this is an area of
debate (see earlier). For most oral cancers seen in UK prac-
tice, there is a low risk of involvement of the retropharyn-
geal nodes so they can be excluded from the CTV unless
there is extensive node involvement pathologically. This
has the benefit of sparing the temporomandibular joint
and part of the parotid tissue. For large buccal mucosal
Figure 22.37 CT showing carcinoma of left lateral tongue. or hard palate tumours, a different view might be consid-
ered. For anteriorly placed oral cavity tumours where the
patient is node negative, it is reasonable to exclude level
5 (and 2B) making the delivery of radiotherapy simpler
when using conventional techniques. Where there is
involvement of the mandible, the whole of that hemi-
mandible should be included in the initial CTV.
In the definitive setting, the primary site is treated with a
23 cm margin to give the primary CTV. The nodes treated
will vary according to the primary site and the level of risk
of involvement can be used to dictate an appropriate dose.
A typical field arrangement is to treat the upper neck, i.e.
the oral cavity and level 1 and 2 nodes, with a parallel-
opposed pair and the lower neck with an anterior field
matched at approximately the level of the bottom of the
hyoid bone using the mono-isocentric technique. There is
midline shielding for the spinal cord and upper oesophagus
Figure 22.38 CT showing carcinoma of base of tongue. in the lower neck field. The cord is spared in the lateral fields
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
almost 900 new cases diagnosed in 2004 according to the Histologically, almost all oropharyngeal carcinomas are
CRUK database. These cancers mainly occur in the fifth to the squamous cell cancers prevalent in the head and neck
seventh decades and are approximately three to four times region. One variant of the SCC of the oropharynx is the
more common in men than women. lymphoepithelioma. Histologically, it is lymphocyte pre-
Of oropharyngeal cancers, the most common are tonsil- dominant and may mimic lymphoma. It may arise in the
lar (60%) followed by 25% in the base of tongue and base of tongue, tonsils or nasopharynx. It is a very radio-
10% in the soft palate. sensitive variant of squamous cell cancer. Other cancers
in this area include minor salivary gland carcinomas and
lymphoma. Mention has already been made of Waldeyers
Staging system of oropharyngeal ring. It is a site of extra-nodal non-Hodgkins lymphoma.
tumours Approximately one-quarter of tonsillar tumours are such
Tx Primary tumour cannot be assessed lymphomas.
T0 No evidence of primary tumour The oropharynx has a rich lymphatic supply; 60% of
Tis Carcinoma in situ oropharyngeal cancers have nodal involvement at presen-
T1 Tumour 2 cm in greatest dimension tation. In tonsillar tumours, this is predominantly unilat-
T2 Tumour >2 cm but 4 cm or smaller in greatest eral spread unless the primary crosses the midline and is
dimension important when determining volumes to irradiate. Tonsil-
T3 Tumour >4 cm in greatest dimension lar cancers drain to the adjacent jugulodigastric or subdigas-
T4a Tumour invades the larynx, deep/extrinsic muscle tric node (the so-called tonsillar node) and then the
of tongue, medial pterygoid, hard palate or remainder of the deep cervical nodes of level 2 and 3. The
mandible remainder of oropharyngeal cancers are midline structures
T4b Tumour invades lateral pterygoid muscle, and therefore can drain to bilateral nodes. Tumours of the
pterygoid plates, lateral nasopharynx, or skull base soft palate and posterior pharyngeal wall drain to the retro-
or encases the carotid artery pharyngeal nodes and upper deep cervical lymph nodes,
Nx Regional lymph nodes cannot be assessed i.e. level 2. Base of tongue tumours commonly spread to
N0 No regional lymph node metastasis the mid and upper cervical nodes, i.e. levels 2 and 3.
N1 Metastasis in a single ipsilateral lymph node, 3 cm
or smaller in greatest dimension Signs and symptoms
N2a Metastasis in a single ipsilateral lymph node larger
than 3 cm but 6 cm or smaller in greatest Cancers in this region commonly present with sore throat
dimension or painful swallowing. Tumours in the tonsillar region or
N2b Metastasis in multiple ipsilateral lymph nodes, posterior oropharynx may present with earache due to
6 cm or smaller in greatest dimension extension into the parapharyngeal space or the sensation
N2c Metastasis in bilateral or contralateral lymph of a lump in the throat. Tumour or ulceration in the oro-
nodes, 6 cm or smaller in greatest dimension pharynx can usually be visualized in the clinic via direct
N3 Metastasis in a lymph node larger than 6 cm in inspection or nasendoscopy. A fine needle aspiration
greatest dimension (FNA) or biopsy can often be taken at the time.
As with many head and neck cancers, the presentation
may be via a neck mass from secondary lymph nodes. In
Aetiology, pathology and this case, the primary may be identified from tonsillectomy
or blind biopsies of the tongue base at examination under
lymphatic spread
anaesthesia (EUA) or endoscopy.
As with other head and neck cancers, tobacco and alcohol
consumption are the most significant risk factors for devel-
Diagnosis and staging
oping cancers in this region. There are no specific genetic
risk factors for this type of tumour. There appears to be a Patients with a history of persistent sore throat should be
specific group of oropharyngeal carcinomas in younger referred urgently to the ENT clinic. Patients may also be
(often non-smoker) patients which are found to be asso- referred urgently for persistent tonsillar swelling or neck
ciated with the human papilloma virus (HPV). Here, there lymphadenopathy.
appears to be distinct histopathological appearances with A full history should be undertaken. The importance of
less differentiation and basaloid type cells. Review of the co-morbidities may affect whether patients are operable or
outcome of these specific tumours compared with the typi- can be treated with chemotherapy and/or radiotherapy.
cal squamous cell carcinomas suggests an improved prog- This is particularly the case in patients who are heavy smo-
nosis. It may also direct future treatment strategies given kers or have a history of alcohol intake.
the recent developments of vaccines directed at cervical A full ENT examination is performed in the clinic.
cancer prevention. This allows delineation of the primary. It should include
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Walter and Millers Textbook of Radiotherapy
indirect laryngoscopy or fibreoptic examination to look for hypopharynx and, if no obvious primary site has been iden-
synchronous tumours. The neck should be clinically exam- tified clinically, an ipsilateral tonsillectomy.
ined for palpable lymph nodes. A neck dissection with biopsy of the suspected primary
Patients should have an examination under anaesthesia site (biopsy can mean tonsillectomy here) is a reasonable
and biopsy to confirm the tissue diagnosis (Figure first therapeutic gesture. The pathological detail can inform
evolve 22.39 ). later radiotherapy planning especially with regards to
Radiological assessment of the primary is essential to dose. However, the increasing availability of PET-CT means
complete the staging. This is usually a CT or MRI scan that we can consider delaying neck surgery for use only in
(Figure 22.40). This may also reveal pathological lymphan- lesions that seem resistant to chemoradiation. Excellent
denopathy not identified clinically. Imaging of the chest is regression of even large neck masses is not unusual after
also essential for exclusion of metastatic spread or synchro- chemoradiation, but sometimes this clinical improvement
nous primary tumours of the lung. is illusory, and then neck recurrence can be a harbinger of
disaster.
Patients not treated with neck dissection initially should
Treatment be examined closely during and after radiotherapeutic treat-
Currently, management of primary tumours of the oro- ment. If there is residual nodal disease post-radiotherapy
pharynx is largely non-surgical. Chemoradiation is the then the patient requires a neck dissection. There may
standard-of-care for the younger and healthier patients, be no remaining active disease but FNA or biopsy are
radiotherapy alone for the less robust, typically using not reliable and surgery is essential. There is increasing
an altered fractionation schedule. Management of neck evidence that a PET-CT may be useful in node-positive
disease is more complex, and the integration of surgical patients who appear to have had a complete clinical
interventions with chemoradiation is subtle. response to chemoradiotherapy. The PET-CT should be
Control of even large primary cancers can now often be done 1012 weeks post-treatment to allow inflamma-
achieved without surgery, but significant nodal disease is tory changes to resolve. If the scan is negative then
still widely considered to be a more intractable problem, the patient can be followed up as per the usual proto-
and neck dissection retains an important place, especially col. If positive then a neck dissection should be consid-
for more extensive neck disease. This meaning any N stage ered. This is still an area requiring ongoing research.
above N1, i.e. multiple nodes or nodes >3 cm. Clinical N1
disease is usually well controlled by radiation, with or with- Radiation technique
out chemotherapy.
(Figures evolve 22.4122.48 )
Many patients with oropharyngeal cancer present with
cervical lymphadenopathy and an asymptomatic primary Patients are treated in an immobilization device that
tumour. A complex interaction between clinical oncologists includes the head and shoulders. The patient is treated
and other members of the team must be initiated early, even supine. The neck will typically be in a neutral position,
before the suspected primary site has been confirmed. A pos- unless the patient is treated with IMRT, when a more
itive cytological diagnosis from the node should be followed extended position is preferred as part of the oral cavity
by examination under anaesthesia, biopsy of any suspicious can then be excluded from the primary beam. A tongue
areas, random biopsies of oropharynx, nasopharynx and depressor is not usually used.
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
A planning CT scan co-registered with diagnostic scans wherever possible, be moved inferiorly so that overt disease
facilitates precise volume definition. The primary CTV must lies above that point. In patients with tongue base tumours,
include reasonable margins to account for microscopic the match point is typically slightly more inferior too at the
spread. This means inclusion of the parapharyngeal space level of the thyroid notch to encompass the primary CTV.
that surrounds the oropharynx, in the case of tonsillar Alternatively an IMRT approach can be used.
tumours, a component of the soft palate and tongue base Fractionation schedules used in this situation are very
even if not overtly involved and some of the oral tongue much along the lines of that discussed in the previous chap-
for tongue base tumours. The selection of lymph nodes is ter. Concurrent chemotherapy, certainly in younger fitter
based on known pattern of spread of these tumours. patients, forms an important component of this treatment.
A well-lateralized early tumour of the tonsil rarely spreads Indeed, the strongest evidence for concurrent chemora-
to the contralateral lymph nodes and, as such, affords diotherapy originates from oropharyngeal tumours.
useful sparing of the contralateral salivary tissues. Where
a neck dissection has been carried out, this additional
information allows for appropriate doses to be specified Complications
according to the risk of disease, i.e. nodes with extracapsu- Acute reactions in the oropharynx are predictable. Mucosi-
lar spread would be irradiated to a high dose. tis will compromise nutrition and should be managed
aggressively. In practice, this often means that these
Tonsillar tumours patients have feeding tubes sited prior to therapy and opi-
Small ipsilateral primary tumours with a node-negative ate analgesia. Acute xerostomia and the often copious
neck can be treated with a small volume treatment that mucous production should be managed symptomatically.
includes the primary site and level 1B and 2A cervical Skin reactions and reversible alopecia will occur in the irra-
lymph nodes. In practice, the CTV will extend superiorly diation portals.
to the level of the hard palate and inferiorly to at least Chronic xerostomia is a common side effect of wide-field
the level of the hyoid bone. The medial margin, as dis- radiotherapy as used here. There is now level one evidence
cussed earlier, should include part of the soft palate and that sparing of at least one parotid gland with IMRT tech-
tongue base and, as such, extends to the midline. Ante- niques (either the contralateral gland or bilateral superficial
riorly, the volume extends beyond palatoglossus to the glands) results in an improvement in the quality of life of
middle of the tongue and, posteriorly, just anterior to the these patients. Trismus may result from high dose radio-
spinal cord to include level 2A (but not 2B) nodes. therapy to the pterygoid muscles. Active stretching exercises
The above treatment field can be treated with a wedged can help to alleviate this.
pair arrangement which allows coverage of the volume but
has the advantage of sparing the contralateral parotid gland Results
and thus avoiding permanent xerostomia.
The relatively small volumes of irradiation mean that For node-negative tumours, the 5-year survival for oropha-
shorter fractionation schedules, such as 55 Gy in 20 daily ryngeal tumours is 75%, but this almost halves for
fractions, are reasonable. patients with involved nodes. Local control ranges from
75 to 95% for T1 tumours falling through the stages
Large tonsillar tumours and other (80% for T2, 60% for T3) to approximately 1035% for
T4 disease. Five-year survival for the same groups is 60
oropharyngeal tumours
80% for T1 but less than 30% for T4 disease.
Larger tumours of the tonsil which approach or cross the
midline, that have spread locally to the base of tongue or
which are node positive should be treated with a volume
which encompasses the primary and bilateral upper cervi- LARYNX
cal neck nodes.
Other oropharyngeal tumours, i.e. base of tongue, post-
Anatomy
pharyngeal wall and soft palate, usually require a similar
bilateral approach due to the high risk of contralateral The larynx is a cartilaginous frame held in position by
lymph node involvement. intrinsic muscles and ligaments. The anterior and lateral
A typical field arrangement to achieve coverage of these part of this box is formed by the thyroid cartilage. The cri-
volumes, i.e. the primary and node levels 1 and 2, is with coid cartilage is below the thyroid cartilage forming a com-
a pair of parallel-opposed lateral fields. The lower neck, i.e. plete ring around the larynx just below the vocal cords.
node level 3 and 4, is treated with a matched anterior field The larynx is divided into three areas. The supraglottis,
with shielding for the central structures. Typically, the match glottis and subglottis (Figure 22.49). The structures of
point for these patients is at the level of the hyoid bone. If the supraglottis are the epiglottis, the ariepiglottic folds,
there is bulky lymphadenopathy, the match point should, the aretinoids, the ventricular bands (often called the false
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Walter and Millers Textbook of Radiotherapy
Epiglottis
Hyoid bone
Cricoid
Anterior Cartilage
commissure
A B
Figure 22.49 Landmarks of the normal larynx and pharynx from A the posterior and B the lateral aspect.
(Redrawn from Robinson, Surgery, Longmans)
cords) and the ventricular cavities. The true glottis is the has a poor lymphatic supply and tumours arising from
area by the vocal cords. The subglottic area is the area the true vocal cord are relatively slow to metastasize to
beneath the vocal cords, and above the trachea. regional lymph nodes. This is even true of T3 glottic can-
cers. But supraglottic carcinoma of larynx spreads far more
readily to the lymph nodes within the neck. The incidence
Incidence of laryngeal cancer of lymph node spread from even T1 and T2 lesions ranges
In the UK in 2000, there were 2407 cases of laryngeal can- between 27 and 40% and for T3/T4 lesions the rate of
cer (4.1 per 100 000 per annum) which makes the larynx lymph node metastasis is 5565%.
the most common site for head and neck cancer in the UK. Initially, lymphatic spread is upwards to the jugulodigas-
In some parts of France, Spain and Italy, the incidence of tric lymph nodes immediately beneath the angle of the jaw.
laryngeal cancer can be up to six times more common. Tumours also commonly spread to the mid-jugular lymph
Unlike the UK, where true glottis is the most common site, nodes. Over 95% of laryngeal tumours are invasive squa-
the supraglottic area is the most common site for laryngeal mous carcinoma. Usually well differentiated but some
tumours in southern Europe. In the West Midlands region tumours, especially of the supraglottic region, can be
of England, 6070% of tumours begin in the glottis, 25% poorly differentiated and more likely to spread to lymph
of cases are supraglottic, 2% only are true subglottic cancer nodes. A common variant of well-differentiated squamous
and the remainder are transglottic tumours, where the pre- cancer is a verrucous carcinoma. This tumour contains a
cise site of origin cannot be determined. large amount of keratin and has a heaped-up warty appear-
ance. Sometimes, invasive cancer can be preceded by carci-
noma in situ of the epithelium of the vocal cords. However,
Staging system for laryngeal cancer this usually transforms into invasive cancer within 1
2 years of detection.
See Table 22.1.
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Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
T PRIMARY TUMOUR
Supraglottis
T1 Tumour limited to one subsite of supraglottis with normal vocal cord mobility
T2 Tumour invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis
(e.g. mucosa of base of tongue, vallecula, medial wall of piriform sinus) without fixation of the larynx
T3 Tumour limited to larynx with vocal cord fixation and/or invades any of the following: post-cricoid area, pre-epiglottic
tissues, deep base of tongue
T4 Tumour invades through thyroid cartilage and/or extends into soft tissues of the neck, thyroid and/or oesophagus
Glottis
T1 Tumour limited to vocal cord(s) (may involve anterior or posterior commissure) with normal mobility
T2 Tumour extends to supraglottis and/or subglottis and/or with impaired vocal cord mobility
T4 Tumour invades through thyroid cartilage and/or extends to other tissues beyond the larynx, e.g. trachea, soft tissues of
neck, thyroid, pharynx
Subglottis
T4 Tumour invades through cricoid or thyroid cartilage and/or extends into other tissues beyond the larynx, e.g. trachea, soft
tissues of neck, thyroid, oesophagus
N2 Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension or in multiple
ipsilateral lymph nodes none more than 6 cm in greatest dimension or in bilateral or contralateral lymph nodes none more
than 6 cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes none more than 6 cm in greatest dimesnion
N2c Metastasis in bilateral or contralateral lymph nodes none more than 6 cm in greatest dimension
377
Walter and Millers Textbook of Radiotherapy
378
Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
apple). The position of the vocal cords can be confirmed by Patients with persisting oedema should be carefully exam-
screening the patient on a simulator during quiet respira- ined for persisting recurrent tumour. Laryngeal necrosis is
tion. Parallel opposed is the most commonly used field rare with an incidence of <1%.
configuration. Anterior oblique fields are often useful in
patients with short necks and offer a theoretical advantage Advanced (T3 and T4) carcinoma of larynx
of a lower dose to the carotid arteries and less subsequent
radiation-induced vascular disease. The anterior commis-
(Figures evolve 22.5822.64 )
sure of the larynx may be close to the skin and in the mega- The management of T3 tumours is controversial (Figure
voltage build up area. If this area is involved by tumour, a evolve 22.65 ). Some ENT surgeons would say that all
1 cm thick wax block has to be placed over the skin above T3 cancers should be treated by laryngectomy. Many oncol-
the tumour to ensure the anterior part of the larynx receives ogists would reject this point of view as being too rigid.
a full dose. Dosage schemes in use nationally and interna- Patients who are likely to do well with a fixed vocal cord
tionally range from 50 Gy in 16 fractions to 66 Gy in 33 are those with a relatively small bulk of tumour, especially
fractions. The British Institute of Radiology short versus exophytic lesions. Tumours forming deep ulcers, especially
long trial compared a 3-week schedule against a 6-week bulky transglottic cancers, are best treated by surgery if the
schedule and showed that, if anything, the complication patient is fit for laryngectomy. However, some patients with
rate was higher among patients treated over 6 weeks. tumours best treated by surgery are unfit for this radical treat-
T2 glottic cancer is treated in a similar way to T1 tumours ment. The most common contraindication to surgery is
but often slightly larger fields are used (7 cm in length). chronic obstructive airways disease caused by smoking.
Many centres give a slightly higher dose for T2 tumours Total laryngectomy leads to loss of voice and a perma-
(52.5 Gy in 16 fractions for T1, 55 Gy for T2 in 20 fractions nent tracheostomy. Patients views with regard to survival
or 60 Gy in 30 fractions for T1 carcinomas and 60 Gy in 25 and voice preservation differ. Some patients may prefer a
fractions for T2 tumours). trial of radiotherapy then a salvage laryngectomy if radio-
therapy fails rather than proceeding to immediate surgery.
The only randomized trial in which patients with T3 can-
Supraglottic carcinoma of larynx
cers were randomized to immediate total laryngectomy
Owing to the fact that supraglottic larynx tumours are more or radiotherapy followed by surgery yielded a similar 5-year
likely to spread to lymph nodes in the neck, some centres survival of 60% in both arms and two-thirds of irradiated
advocate prophylactic irradiation of the jugular chain even patients retained their larynx.
if there are no palpable lymph nodes or lymph nodes detect- Unlike patients with T3 lesions, those with large T4 can-
able on MRI scanning. Many oncologists incorporate at least cers are less likely to be suitable for salvage laryngectomy if
the jugulodigastric lymph node within the irradiated volume radiotherapy fails. Surgery is the treatment of choice for
for part or all of the treatment. This lymph node partially such patients. Again, a minority of T4 patients may have
overlies the upper part of the supraglottis (the epiglottis) to be treated with radiotherapy or chemoradiotherapy if
and it is comparatively easy to include this node within they are unfit for surgery. Patients with T3 true glottic can-
the treatment volume by increasing the length of the treat- cers may be treated with relatively small fields. However,
ment field by 2 cm or so. Typical treatment volume for an patients with more extensive tumours are often treated in
early supraglottic larynx cancer would stretch from 1 cm two phases. Phase one incorporates known disease plus
beneath the vocal cords to 1 cm above the tip of the epiglot- possible areas of lymph node spread and phase two con-
tis. Somewhat higher doses are often given to treat supraglot- centrates on known disease with a small margin (see
tic compared to glottic cancer. In the USA, doses of 70 Gy in 7 Figures evolve 22.5922.65 ). Patients are often treated
weeks are frequently prescribed. In the UK, schedules vary to doses of 6670 Gy in 6.57 weeks, often with concomi-
between 50 Gy in 16 fractions to 66 Gy in 33 fractions. tant chemotherapy (see below).
379
Walter and Millers Textbook of Radiotherapy
than 3 cm. Techniques vary, the aim would be to include if required. The results of radiotherapy alone can be substan-
nodal drainage areas normally anterior to the spinal cord. tially improved by the administration of concomitant cis-
If there is extensive lymph node involvement, occasionally platin chemotherapy.
the posterior triangle nodes need to be included within
the treatment volume.
The tracheostomy opening is a potential site for recur- HYPOPHARYNGEAL CARCINOMA
rence, especially if the patient has had an emergency trache-
ostomy or if there is subglottic tumour. The tracheal stoma
should be included in all or part of treatment. The radiation Anatomy (Figure 22.66)
reaction though can be brisk around the tracheostomy with The hypopharynx extends posterolaterally in relation to the
soreness, desquamation and occasionally bleeding after larynx, at the level of the hyoid bone to about the lower
doses as low as 40 Gy in 20 fractions. Patients are usually level of the cricoid cartilage. The hypopharynx comprises
treated with lateral parallel-opposed fields plus a single the piriform fossa, the post-cricoid region and the posterior
anterior field to take in the tracheostomy and the lower cer- pharyngeal wall and, therefore, cancers of these three
vical lymph nodes or anterior and posterior fields. If ante- regions comprise the hypopharyngeal carcinomas. The
rior and posterior fields are used, the neck should be piriform fossae (or sinuses) are pear-shaped channels that
extended to take the parotid glands and oral cavity outwith run alongside the larynx and are adjacent to the inner
the treated volume. Differential weightings, such as treating aspect of the thyroid cartilage. The post-cricoid region is
largely from an anterior field (4:1) weighting, are popular in behind the larynx and runs from the arytenoids to the infe-
the USA. rior border of the cricoid cartilage. The posterior pharyn-
geal wall links the floor of the vallecula to the cricoid
Chemotherapy cartilage (Figure evolve 22.67 ).
Results of treatment
Early laryngeal cancers
Some centres report a 5-year survival greater than 90% for
patients treated with T1 glottic cancers. Approximately 5% Tip of Faucial
epiglottis tonsil
of patients require salvage laryngectomy, even among
those with T1 lesions. The need for salvage laryngectomy Larangeal
Base of
increases to 1015% for those with T2 lesions. The overall vestibule
tongue
local control rate is in the order of 80% with 8085% Aryteno-
5-year survival. Results tend to be slightly inferior for supra- epiglottic Posterior
glottic lesions. Local control and 5-year survival tends to be fold pharangeal
510% less than those reported for true glottic cancers. wall (open)
Arytenoid
Piriform
sinus
Advanced laryngeal cancers
Posterior
It is possible to get 65% 5-year survival with radiotherapy cricoid
alone in selected T3 glottic cancers. In the past, more
advanced transglottic T3 lesions had between a 4050% sur-
Oesophagus
vival if treated by radiotherapy alone rising to about 65%
if treated by laryngectomy with postoperative radiotherapy Figure 22.66 Hypopharyngeal carcinoma anatomy.
380
Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
381
Walter and Millers Textbook of Radiotherapy
Piriform fossa
For small, node-negative T1/T2 tumours of the piriform
fossa then the radiotherapy treatment involves treatment
of the primary site with upper cervical nodes in an
arrangement similar to that for supraglottic tumours, i.e.
two lateral fields only. For all other piriform fossae
tumours, the classical three-field technique (two parallel-
opposed fields to the pharynx and upper neck, with a single
anterior field for the lower neck) is widely used.
When using the three-field technique, whereas for many
other tumours of the head and neck region, the lower ante-
rior field will conventionally use midline shielding to pro-
tect the larynx, hypopharynx, upper oesophagus and spinal
cord, the situation is different here. The first three aforemen-
tioned are likely to be part of the CTV or to be unavoidable.
Figure 22.69 Carcinoma of piriform fossa. The propensity of hypopharynx cancer to spread submuco-
sally means that central shielding of the midline in the lower
neck could lead to tumour sparing, so the midline shielding
Treatment must be omitted. Care must now be taken with evaluating
Surgery is considered the optimal initial treatment for bulky dose to the spinal cord. A widely-used convention is that dose
or T4 tumours in this region and usually involves pharyngo- from this field is prescribed at a depth of 3 cm. The spinal cord
laryngectomy. In other instances, the aim of organ preserva- is not many centimetres beyond this, so caution is advised.
tion via treatment with radiotherapy or concurrent Unless there is gross disease in the lower neck, it may be pref-
chemoradiotherapy should be considered. Tumours of the erable to limit the dose from this field to 46 Gy at the 3 cm
piriform fossa have two very sinister aspects: they have a reference point. There is yet another consideration for cord
great propensity for extensive submucosal spread, and for dose. When no midline shielding is used, the junction of
lymphatic dissemination, and the latter can be bilateral. the upper edge of the lower neck anterior field with the lower
Postoperative or definitive radiotherapy therefore needs to edge of the laterals can potentially lead to an area of overlap if
be extensive and would ordinarily include the retropharyn- there is even minor imprecision in set-up. This could lead to a
geal nodes as these are not part of the standard neck dissec- part of the spinal cord receiving far more than 50 Gy,
tion and the lower central structures routinely spared with with consequent risk of radiation myelopathy. To prevent
conventional techniques. Patients with nodes managed this, a small shielding block (or one leaf of a multileaf
without initial surgery should be monitored very closely fol- collimator (MLC)) on the lower posterior corner of the lateral
lowing completion of treatment along the lines discussed for fields is frequently used unless there is gross disease there.
oropharyngeal tumours. This, of course, results in a small area of underdosing, but
in a very low-risk area, even in node-positive patients.
Radiotherapy technique
Posterior pharyngeal wall tumours
Patients are treated in supine position and immobilized in
the usual fashion. The shell must extend over the shoulders. The location of these tumours means that surgery is
The shoulders should be held well down as the primary tar- unlikely to result in complete clearance and is either
get volume sits relatively low in the neck and would be completely avoided or is conducted in combination with
clipped by standard lateral fields. radiotherapy. The volumes irradiated will be similar to piri-
A planning CT scan facilitates delineation of the form fossa tumours, though level 5 can be avoided if node
primary tumour and nodes. The intimate relationship negative simplifying to some extent the delivery technique.
between areas of the hypopharynx means that primary
CTVs are generally quite large themselves. The choice of
nodes to include in the irradiation volume, i.e. the nodal
Post-cricoid tumours
CTV is based on the previous discussion though, in prac- In node-negative cancers, treatment is given with radiother-
tice, all the nodes in the neck are irradiated. The exception apy to the primary tumour and adjacent nodal areas (levels
would be small tumours of the piriform fossa, i.e. T1 and 3, 4 and 6). The classical set-up is similar to that for subglot-
low volume T2 with no clinical or radiological evidence of tic tumours, i.e. two lateral double-wedged fields are used
node involvement. In this case, the primary site and which are angled inferiorly to increase the dose to the lower
immediate draining nodes, i.e. levels 2A and 3 alone, neck and upper mediastinum. In node-positive patients,
can be irradiated. the target volumes do not lend themselves to optimal
382
Chapter | 22 | Sino-Nasal, Oral, Larynx and Pharynx Cancers
FURTHER READING
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clinically negative neck in supraglottic 1990;12:197203. carcinoma of the hypopharynx:
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2004;10:3358. treatment based on definitive with radiation alone to the
Agulnik M, et al. State-of-the-art radiotherapy: who is suitable for primary disease. Head Neck
management of nasopharyngeal laryngeal preservation? J Laryngol 1996;18:31722.
carcinoma: current and future Otol Oct 2007;12:17. Jackson SM, et al. Cancer of the tonsil:
directions. Br J Cancer Claus F, et al. An implementation results of ipsilateral radiation
2005;92:799806. strategy for IMRT of ethmoid sinus treatment. Radiother Oncol
Al-Sarraf M, et al. Chemoradiotherapy cancer with bilateral sparing of the 1999;51:1238.
versus radiotherapy in patients optic pathways. Int J Radiat Oncol Jones AS, et al. The treatment of early
with advanced nasopharyngeal Biol Phys 2001;51:31831. laryngeal cancers (T1T2N0): Surgery
cancer: phase III randomized Duthoy W, et al. Postoperative or irradiation? Head Neck
Intergroup study 0099. J Clin intensity-modulated radiotherapy in 2004;26:12735.
Oncol 1998;16:13107. sinonasal carcinoma. Cancer Lee MS, et al. Treatment results and
Baujat B, et al. Chemotherapy as an 2005;104:7182. prognostic factors in locally advanced
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Otolaryngol Head Neck Surg Induction chemotherapy plus Kam M, et al. Treatment of
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Byers RM, et al. Selective neck dissections radiation in patients with advanced intensity-modulated radiotherapy: the
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1990;19:136976. Scola B, et al. Management of cancer of cancers: importance of the proportion
OSullivan B, et al. The benefits and the supraglottis. Otolaryngol Head therapy delivered with interstitial
pitfalls of ipsilateral radiotherapy in Neck Surg 2001;124:1958. therapy. Int J Radiat Oncol Biol Phys
carcinoma of the tonsillar region. Int J 1990;18:152930.
Figure evolve 22.3 Volume delineation: Figure evolve 22.23 The inevitable (and Figure evolve 22.52 Landmarks for early
primary and nodes potentially clinically significant) dose laryngeal cancer on a DRR
Figure evolve 22.4 Primary site and inhomogeneity with a conventional Figure evolve 22.53 Volume on a
proximity to normal tissues field arrangement single axial slice and as seen in sagittal
Figure evolve 22.5 Upper neck fields Figure evolve 22.26 Small cell DRR
Figure evolve 22.6 Lower neck fields carcinoma of lip Figure evolve 22.54 Field arrangement.
Figure evolve 22.7 Primary boost field Figure evolve 22.27 Extensive carcinoma Note that, in this case, the two fields are
Figure evolve 22.8 Dose distributions of dorsum of tongue non-coplanar so that they exit above
Figure evolve 22.10 Gross tumour Figure evolve 22.28 Tumour on left the shoulders
volume in the case of a low nasal cavity lateral edge of tongue Figure evolve 22.55 Beams-eye view of
tumour superimposed upon a digitally Figure evolve 22.33 Extensive lip fields
reconstructed radiograph carcinoma Figure evolve 22.56 Dose distribution
Figure evolve 22.11 Clinical target Figure evolve 22.34 Lead cut-out and using two anterior oblique fields with
volume with gross target volume gum shield for 300 kV treatment thick end of wedge anteriorly
defined on axial CT slice. Note bolus Figure evolve 22.35 300 kV treatment Figure evolve 22.57 Early (T1)
material for lip cancer carcinoma of vocal cord
Figure evolve 22.12 Resulting dose Figure evolve 22.36 Lateral radiograph Figure evolve 22.58 Volume definition
distribution in the axial plane showing three iridium hairpin Figure evolve 22.59 GTVs superimposed
Figure evolve 22.13 Resulting dose insertion in an early tongue tumour upon sagittal DRRs
distribution in the sagittal plane shown Figure evolve 22.39 Advanced tonsillar Figure evolve 22.60 CTVs superimposed
at midline cancer involving soft palate upon DRRs
Figure evolve 22.14 Dose cloud and Figure evolve 22.41 Volume definitions Figure evolve 22.61 Fields for phase 1
surface dose in the same patient for a postoperative tonsillar case Figure evolve 22.62 Fields for phase
Figure evolve 22.15 Anterior wedged Figure evolve 22.42 Primary and 23
pair arrangement. Note GTV, CTV and involved node CTVs superimposed Figure evolve 22.63 Field margin for
PTV are all defined upon digitally reconstructed phase 3
Figure evolve 22.18 Extensive tumour of radiographs (DRRs) Figure evolve 22.64 Dose distribution in
the left paranasal sinus territory with Figure evolve 22.43 Low-risk CTV mid-plane
extension into subcutaneous tissues Figure evolve 22.44 Initial PTVs Figure evolve 22.65 T3 carcinoma of
and infratemporal fossa superimposed on DRRs larynx with a fixed cord
Figure evolve 22.20 Typical paranasal Figure evolve 22.45 Field for phase 1 Figure evolve 22.67 Carcinoma of the
sinus volume viewed anteriorly Figure evolve 22.46 Field for phase 2 hypopharynx (right pyriform fossa).
Figure evolve 22.21 Typical paranasal Figure evolve 22.47 Field for lower (Reproduced with permission from
sinus field viewed anteriorly neck Macfarlane, Textbook of Surgery,
Figure evolve 22.22 Typical field Figure evolve 22.48 Potential dose Churchill Livingstone)
arrangement viewed from above. Note distribution in a coronal plane
the third field on the right
384
Chapter | 23 |
Thyroid cancer
Ujjal Mallick, Joyce Wilkinson, Charles Kelly
CHAPTER CONTENTS
INTRODUCTION AND EPIDEMIOLOGY
Introduction and epidemiology 385
Anatomy 385 Thyroid cancer is a spectrum of tumours characterized by
Aetiological factors 386 different biology and clinical behaviour. The presence of
a micropapillary carcinoma of thyroid may have little
Presentation, diagnosis and patient
impact on life expectancy, whereas anaplastic thyroid can-
pathway 386
cer is often lethal. While this disease is uncommon, repre-
Differentiated thyroid cancer 387 senting only about 1% of all cancers, thyroid cancer is the
Management of differentiated most frequently occurring endocrine malignancy and inci-
thyroid cancer 388 dence of Papillary thyroid cancer is increasing. It is the fast-
Surgery 388 est rising cancer in men and women in the United states. In
Radio-iodine ablation 389 excess of 2100 new cases each year in the UK and over
48,000 in the United States. The incidence is increasing
Thyroglobulin 390 worldwide (213,000 new cases in 2008) including a 2.6-
Management of hypocalcemia 390 fold increase in the USA 19732006.
Management of Loco regional recurrence 390 Differentiated thyroid cancer is highly curable (about
Metastatic disease 390 95% or more five year survival) and can also affect children,
young adults. Thyroid cancer should be treated by a multi-
Medullary thyroid cancer (MTC) 390
disciplinary team of experts.
Anaplastic thyroid cancer 391
Thyroid lymphoma 391
Thyroid sarcoma 391 ANATOMY
Hurthle cell carcinoma 391
External beam radiotherapy for thyroid The thyroid gland is situated in the anterior part of the neck
cancer 392 just above the clavicle and sternum (Figure 23.1). The
Palliative high dose 392 gland consists of a right and left lobe joined by an isthmus
which crosses the trachea at the second and third cartilagi-
Low dose palliation 392
nous rings. The average weight of the thyroid gland is 20 g.
Radiotherapy for thyroid lymphoma 393 The parathyroid glands lie on the posterior surface of both
Follow-up policy for thyroid cancer thyroid lobes and the recurrent laryngeal nerves are in a
patients 393 cleft between the trachea and the oesophagus. Lymphatic
Further reading 394 drainage from the thyroid can be to nodes superior to
Thyroid cartilage
Omohyoid
Ext. jugular v.
Cricoid cartilage
C6
Isthmus of thyroid
C6
Carotid sheath
T2/3 Prevertebral (cont. comm. carotid
fascia a., int. jugular v. and
vagus n.) with
sympathetic chain
Suprasternal
B behind
notch
A
Figure 23.1 (A) Structures palpable on the anterior aspect of the neck, together with corresponding vertebral levels. (Redrawn from
Ellis, Clinical Anatomy, 5th edn, Blackwells, 1975). (B) Transverse section of the neck through C6 showing the relations of the thyroid
gland. (Reproduced with permission from Ellis, Clinical Anatomy, 5th edn, Blackwells, 1975).
the thyroid gland, lateral to the gland and to the paratra- radiation induced), PAX8/PPARg (Follicular); abnormal
cheal region. miRNAs (microRNA) with gene methylation problems
also play its part. All these are now being detected on Fine
needle aspiration cytology. This will avoid diagnostic
ETIOLOGICAL FACTORS lobectomies for indeterminate and benign nodules in the
future protecting patients from unnecessary surgery as well
Thyroid cancer shows two age-related peaks of incidence, as allowing one-stage total thyroidectomy for cancer
one before the age of 40 and one after 60. The condition patients (instead of lobectomy followed by total thyroidec-
is approximately three times as common in women than tomy in Thy3 cases) and saving costs. P53 mutations are
men. Exposure to ionizing radiation in childhood, either thought to be a late event in progression from differen-
therapeutic, such as radiotherapy for Hodgkins disease, tiated to Anaplstic thyroid cancer in a high proportion
or associated with environmental exposure, increases the of cases.
risk of developing thyroid cancer. There is, however, no
proven relationship between the development of thyroid
cancer and administration of iodine-131 for the treatment PRESENTATION, DIAGNOSIS AND
of hyperthyroidism.
Other medical conditions which affect the thyroid PATIENT PATHWAY
have also been linked with an increased risk in develop-
ing thyroid cancer, namely, endemic goiter, which occurs The most common presenting feature is a painless, lower
in areas where there is low natural iodine, Hashimotos neck lump in the thyroid area which may or may not
thyroiditis, a past history of thyroid adenoma or a family have been noted to have increased in size. In more
history of thyroid adenoma or cancer. Some genetic con- advanced cases, patients may complain of a lump on
ditions which increase the risk of thyroid cancer include the side of the neck due to spread to lymph nodes, hoarse-
Gardener syndrome, Cowdens syndrome, familial ade- ness or change in voice suggesting recurrent laryngeal
nomatous polyposis and the multiple endocrine neopla- nerve involvement, stridor or, rarely, dysphagia. A rapid
sia syndromes. enlargement of the mass or a rapid development of symp-
Thyroid cancer initiation and progression is supposed to toms, suggesting compression of other structures, may be
be through accumulation of genetic and epigenetic events. due to a more rapidly growing anaplasic carcinoma or
It point mutations of BRAF (Predominantly Papillary) and Lymphoma.
RAS (N,H,K-Ras Predominantly Follicular) genes and Chro- In the first instance, the patient should be referred to an
mosomal rearrangements-RET/PTC-(Papillary particularly ENT or general surgeon with a particular interest and
386
Chapter | 23 | Thyroid cancer
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Walter and Millers Textbook of Radiotherapy
388
Chapter | 23 | Thyroid cancer
If there is lateral cervical neck node involvement, then replacement is twofold. The first is to replace the natural
a selective radical neck dissection should be considered. hormone produced by the gland and the second is to sup-
Removal of single nodes is inadequate treatment. Central press the patients thyroid stimulating hormone (TSH).
neck node removal (level VI nodes), can be considered with This is produced in the pituitary gland, and can stimulate
or near total thyroidectomy in appropriate cases. well differentiated tumours as well as any thyroid remnant.
The target TSH level for suppression is <0.1 mU/L.
The patient has a further radio-iodine diagnostic scan,
Radio-iodine ablation
46 months after ablation and, if any residual thyroid tis-
This is recommended following surgery in many as it helps sue still remains, the patient may require further treatment
monitoring by measuring thyroglobulin, and might reduce doses. If the 6-month challenge scan shows no evidence of
recurrence and improve survival in high and intermediate any remnant of thyroid tissue, the patient does not require
risk cases patients with differentiated thyroid cancer by further radio iodine diagnostic (RAIS) scans and can be
destroying any remaining microscopic foci of thyroid carci- monitored clinically and by thyroglobulin level. Regular
noma cells. It destroys any remaining normal thyroid tissue RAIS are being replaced in low risk cancers by thyroglobu-
and any rise in serum thyroglobulin following ablation lin assessment only after recombinant human TSH injec-
should only suggest tumour recurrence, thereby helping tions and neck ultrasound (/ FNAC).
earlier detection and treatment of recurrent disease. If there If radio-iodine uptake scans are required, the patient
is a large thyroid remnant remaining, further surgery may must discontinue thyroxine 4 weeks prior to the scan. T3
be appropriate. can then be substituted for 2 weeks and discontinued
In some centres, the patient undergoes a postoperative 2 weeks before the scan. Many patients understandably
radio-iodine uptake scan using iodine-123 to show any complain of lethargy and other symptoms of severe hypo-
thyroid-derived tissue remaining. Iodine-131 is generally thyroidism during this period when their replacement thy-
avoided so as not to interfere with the later ablation roid hormone is removed. These symptoms can be
dose. This is followed by radio-iodine remnant ablation countered by the use of Thyrogen (recombinant human
where the patient is usually given a dose of 3700 MBq TSH), which does not interfere with the challenge scan
of 131I in the first instance. Thyroxin (T4) or usually and allows the patient to continue with T4 treatment.
131
triiodothyronine (T3) are withdrawn before radio-iodine I therapy can cause some discomfort and swelling in
to ensure TSH levels are >30 mu/l to enhance the the neck. This can be treated by a short course of steroids.
uptake of 131I. Sialoadenitis, (inflammation of the salivary glands) can
Patients are discharged home when total body radio- occur because of the preferential iodine uptake by these
activity has fallen below the permitted levels. The dose rate glands. Radiation cystitis from excretion of radio-iodine
from the patient in mSeiverts is measured at 1 meter on is also possible but both these are uncommon. Replace-
each day of their hospital stay following administration ment thyroxine is restarted 2 days after any radio-iodine
of radio-iodine, these points are plotted on a graph, and diagnostic (if no further treatment is planned), remnant
future levels over the next few days are extrapolated. ablation or treatment scan. Before any radioactive iodine
Typical permissible doses are as follows: patients are is given, pregnancy should be excluded and patients
allowed home using private transport when the dose rate advised to avoid pregnancy for one year after 131I ablation
from the patient has fallen to 40 mSieverts/hour. Use of or treatment. The usual dose for ablation is 3.7 GBq.
public transport is only permitted when the dose emitted There is a small dose-related risk of developing leukae-
by the patient has fallen to 20 mSieverts. Patients are mia following treatment with radio-iodine. This risk
advised to avoid public gatherings such as going to the increases with cumulative doses greater than 18.5 GBq
cinema or church, close contact with family members or and if the patient also has external beam radiotherapy to
journeys on public transport lasting longer than an hour the neck. Patients who receive cumulative injections of
131
until a level of 7.5 mSieverts per hour has been reached. I do have a higher risk of developing second malignan-
Patients should not have close contact with children, preg- cies, for example bladder and salivary gland, as a conse-
nant women or go to work until the extrapolated level is quence of the treatment. The total dose should be kept
1.5 mSieverts/hour. to <40 GBq in any individual patient and, as with any radi-
All patients require thyroid hormone replacement ation, the total cumulative dose should be kept as low as
and can recommence thyroid hormone replacement with possible.
either thyroxine (T4). Thyroxine (T4) has the advantage Thyroid ablation is considered for many patients with
of being given as a once daily tablet and gives more optimal tumours greater than 1 cm. There is a minority school of
suppression of TSH. The initial dose of T4 is usually 200 mg thought, particularly in the USA, that argues that radio-
daily, which is altered depending on TSH measurements. iodine ablation is only advised in high-risk patients and
As the half-life of T3 is shorter than T4 (thyroxine), it is eas- that in the low-risk group, optimal surgery with full TSH
ier to stop and then restart while the patient is undergoing suppression should be sufficient. In this context, high-risk
scanning or radio-iodine treatment. The aim of thyroid patients would be defined as having a primary tumour
389
Walter and Millers Textbook of Radiotherapy
greater than 5 cm or with extra thyroid spread, extensive inoperable, or salvage surgery has been incomplete and
nodal or presence of distant metastasis. Trials are being the recurrent tumour does not take up radio-iodine, then
designed to address this. external beam radiotherapy is an option.
390
Chapter | 23 | Thyroid cancer
form give a positive family history as the condition can prognosis than differentiated thyroid cancer. Anaplastic
skip generations. These familial syndromes can be broadly carcinoma develops from the follicular cells. This rare
divided into three. tumour occurs in older patients who present with a rapidly
Familial medullary thyroid cancer can occur by itself growing mass in the neck. The trachea and oesophagus are
and is inherited in an autosomal dominant pattern and frequently involved at an early stage leading to dysphagia,
is associated with a mutation in the RET proto-oncogene. dysponea and, later, stridor. The voice may be hoarse because
If this mutation is present, then almost 100% of patients of infiltration of the laryngeal nerves and subsequent vocal
will develop medullary thyroid cancer. If it occurs by itself cord palsies. Neck node involvement and metastatic spread,
without other endocrine neoplasia, the thyroid cancer may usually to the lung, are relatively common. Diagnosis is done
behave in a more indolent manner than when it appears as with FNAC, core biopsy or very rarely open biopsy.
a part of the multiple endocrine neoplasia syndromes Patients usually have advanced disease at presentation
(MEN). It is also a component of the familial syndromes, and tend to be older and more frail than other thyroid
MEN 2A, (also known as Sipple syndrome) and MEN 2B. cancer patients. In a small minority, surgery with total thy-
Patients may develop pheochromocytoma in both 2A roidectomy and radical neck dissection may be possible. In
and 2B, hyperparathyroidism in MEN 2A, and ganglioneur- the majority, surgery is either impossible or inappropriate
omatosis in MEN 2B. Medullary thyroid cancer may occur and management is with external beam radiotherapy with
relatively early in MEN 2B and be more aggressive. or without concurrent chemotherapy. Anaplastic thyroid
Patients with any of these syndromes should be offered cancers, however, can show a variable radio-sensitivity with
prophylactic thyroidectomy while still young, before med- some tumours continuing to enlarge, even while under-
ullary thyroid cancer develops. As this condition is poten- going radiotherapy.
tially inheritable, patients and family members should Palliative chemotherapy with Adriamycin with or with-
be offered genetic testing with the local clinical genetics out cisplatin is also used. Median survival for this condition
service after appropriate counselling, detailing the implica- is usually between 6 and 9 months from diagnosis.
tions of positive or negative test results, for them and their
relatives.
Diagnosis in this type of thyroid cancer can be made THYROID LYMPHOMA
with FNA cytology. An elevated serum calcitonin helps
confirm the diagnosis. Patients presenting with these These are non-Hodgkins B-cell lymphomas of varying grade
tumours require screening for the other potential com- and can be associated with Hashimotos thyroiditis. They
ponents of these familial syndromes, with CT and/or usually present as an enlarging thyroid mass. Core biopsy
MRI of the neck, chest and abdomen. These cases should is often required in addition to FNA cytology to determine
be treated by specialist teams including a surgeon, endo- the grade and type of lymphoma. Majority are high grade
crinologist, geneticist, oncologist etc. in cancer centres diffuse large B-cell lymphomas although low grade tumours
for their rarity. do occur. Once a diagnosis of lymphoma has been made,
In those patients who present with this thyroid cancer, the staging is as for other extra nodal sites for lymphoma, with
majority will have positive neck nodes at presentation and CT scan covering all the potential nodal and extra-nodal
so require total thyroidectomy with selective radical neck lymphoma sites, and marrow examination. Treatment is
dissection. Adjuvant radiotherapy is rarely indicated. Serum usually postoperative chemotherapy and radiotherapy or
calcitonin levels are used postoperatively for monitoring radiotherapy only to the neck with excellent long term
potential recurrence. Monitoring can be improved by using survival.
a pentagastrin-stimulated calcitonin evaluation. Radioactive
iodine has no effect in these tumours.
If recurrent medullary cancer presents, then further sur- THYROID SARCOMA
gery should be used, if possible. If surgery is not possible,
high dose external beam radiotherapy may be considered
in selected cases. In recent years targeted therapy with These tumours are uncommon, but can be difficult to dis-
Vandetanib and Sorafenib are showing some benefit in tinguish from anaplastic thyroid cancer or sarcomatoid var-
progression free survival. Palliative chemotherapy, using iants of differentiated thyroid cancers. As they are radio-
a variety of agents in combination, has also been tried iodine insensitive, treatment is with surgery and external
but not very effective. beam radiotherapy.
Anaplastic tumours are less common making up less than These tumours consist of eosinophilic Hurthle cells and
5% of thyroid malignancy but carry a much worse have been thought to be variant of follicular carcinoma
391
Walter and Millers Textbook of Radiotherapy
and stage for stage behave as such; however, some believe it for phase I of radical/adjuvant treatment, or in palliative treat-
is more aggressive than the other differentiated forms, with ments, the fields may be defined on a conventional simulator
a higher incidence of recurrence and metastatic spread and or virtual simulator (Figure evolve 23.2 ).
a reduced 5-year survival because it does not usually take up The anatomical boundaries for the planning treatment
radio-iodine (10% of cases). volume are:
tip of the mastoid process, superiorly
the carina, inferiorly
EXTERNAL BEAM RADIOTHERAPY laterally to include the supraclavicular fossae (Figures
FOR THYROID CANCER evolve 23.3 and 23.4 ).
This volume includes the thyroid bed and adjacent relevant
External beam radiotherapy (EBRT), although not used fre- lymph node drainage areas. The length of cervical and
quently, does have a role in all histological types of thyroid upper thoracic spinal cord should be noted as an organ
cancer. Its main role is in Differentiated Thyroid cancer at risk. This technique is appropriate for many ATC with
(DTC), Anaplastic thyroid cancer and lymphoma. In medul- poor prognosis in frail patients with a typical dose of
lary thyroid cancer it has a limited but defined role. In DTC 30 Gy/10 fractions.
according to UK BTA (2007) Guidelines the indications are: For radical or adjuvant treatment, specially for DTC and
As adjuvant treatment: MTC conformal 3D CT-based planning to cover the thyroid
i gross evidence of local tumour invasion at surgery, bed and level II to level VII nodes are usually required for
presumed to have significant macro or microscopic phase 1. Subsequently a phase II planning target volume
residual disease, particularly if the residual tumour fails (PTV) is defined, encompassing the thyroid bed and imme-
to concentrate sufficient amounts of radioiodine diate lymph nodes, as well as areas of residual disease
ii extensive pT4 disease in patients over 60 years of age which should be included in the high dose volume with
with extensive extranodal spread after optimal surgery, usually about a 2 cm margin. In appropriate cases, the
even in the absence of evident residual disease. superior margin could be at the hyoid bone and the inferior
High-dose external beam radiotherapy as part of primary margin at the suprasternal notch to reduce side effects
treatment: (Figures evolve 23.5 and 23.6 ).
3-D conformal treatment fields are used in this situa-
i unresectable tumours that do not concentrate
tion, with the PTV extending posteriorly, on both sides
radioactive iodine
of the cord, encompassing the whole of the thyroid bed
ii unresectable bulky tumours in addition to radioactive
and lymph nodes (Figure evolve 23.7 ). CT-based locali-
iodine treatment.
zation and planning allow summation of both phases,
showing overall dose to the PTV and the organs at risk,
Palliative high dose in this case the spinal cord.
The maximum acceptable spinal cord dose should not
High-dose palliative external beam radiotherapy for recur- exceed 46 Gy in 23 fractions if more than 20 cm of spinal
rent neck disease uncontrolled by surgery and 131I therapy. cord is included in the treatment field. Lung and mandible
shielding is also used, with either customized blocks or
Low dose palliation multileaf collimators.
The dose given for phase I, using a photon beam of
Spinal cord compression adequate megavoltage energy, is 4044 gy in 2022 frac-
Stridor tions, treated daily 5 fractions per week.
Superior vena caval obstruction For phase II, the dose is 2022 Gy in 1011 fractions,
Cerebral metastases with or without surgery treated daily 5 fractions per week.
Solitary or limited number of bone metastases along with In all treatments, dose is prescribed at the isocentre
surgery etc if appropriate (ICRU reference point).
Dysphagia If the PTV extends into the upper mediastinum, then
Bleeding tumour etc. oblique fields can be tilted caudally by use of couch rota-
If palliative high dose treatment is to be given, a polyfoam or tion, so that the field enters superiorly to the shoulder
orfit head support, or similar, can be made for patient immo- region (Figure evolve 23.8 ).
bilization, but if radical or adjuvant radiotherapy is required, If both the neck and superior mediastinum are treated,
a customized beam directional shell (BDS) is preferable. then the patient contour can change significantly in the
Localization and treatment plan generation are done with a longitudinal plane, and may require compensation in the
planning CT scan, with the patient planned and treated in a caudal-cephalic axis.
supine position, with the cervical spine as straight as possible. Problems in planning occur when the PTV extends poste-
For large anterior and posterior parallel-opposed fields, used riorly to include the thyroid bed and nodes producing a
392
Chapter | 23 | Thyroid cancer
393
Walter and Millers Textbook of Radiotherapy
metabolism problems. They are also followed up because function tests, thyroglobulin and Thyroglobulin antibody
they have a small risk of developing second malignancies and a calcium screen if appropriate. Arrangements can
related to Radioiodine treatment. At each visit, patients be made for ultrasound, other imaging and radioiodine
are examined clinically, blood samples taken for thyroid uptake scans.
FURTHER READING
Cooper DS, Doherty GM, Haugen BR, Powell C, Newbold K, Harrington KJ, Clin Oncology 22(6) August 2010
et al. Revised American Thyroid Bhide SA, Nutting CM. External Beam Special Issue- Thyroid Cancer.
Association management guidelines Radiotherapy for Differentiated Hay ID, Bergstralh EJ, Goellner JR, et al.
for patients with thyroid nodules and Thyroid Cancer. Special Issue Thyroid Predicting outcome in papillary
differentiated thyroid cancer. Thyroid Cancer Clin Oncol 2010;22:456463. thyroid carcinoma: Development
2009;19:1167214. Tala H, Tuttle RM. Contemporary post of a reliable prognostic score in a
British Thyroid Association. Royal surgical management of differentiated cohort of 1779 patients treated
College of Physicians. Guidelines for thyroid carcinoma. Special Issue surgically at one institution during
the management of thyroid cancer. Thyroid Cancer Clin Oncol 1940 through 1989. Surgery
Second edition. 2007. 2010;22:419429. 1993;114:10508.
Figure evolve 23.2 Anterior field defined Figure evolve 23.7 Concave PTV Figure evolve 23.12 Lateral isodose
on virtual simulator, shielding defined Figure evolve 23.8 Couch rotation to maps showing dose distribution of
with MLCs avoid field entry through shoulders IMRT boost to nodal disease. Red
Figure evolve 23.3 Anterior view of PTV Figure evolve 23.9 Four-field technique, 100%, orange 50%, blue 20%
Figure evolve 23.4 Lateral view of PTV cord dose 78% Figure evolve 23.13 Anterior dose
Figure evolve 23.5 Phase II anterior view Figure evolve 23.10 IMRT five-field distribution of IMRT boost to nodal
of PTV inverse plan disease
Figure evolve 23.6 Phase II lateral view Figure evolve 23.11 IMRT boost to
of PTV nodal disease
394
Chapter | 24 |
Gastrointestinal cancer
Ramesh Bulusu
Epidemiology 401
CHAPTER CONTENTS
Aetiology 401
Cancer of the oesophagus 396 Pathology 401
Epidemiology 396 Clinical features 401
Aetiology and pathology 396 Staging 401
Risk factors for squamous cell carcinomas 396 Management 402
Risk factors for adenocarcinoma 397 Surgery 402
Gastrooesophageal reflux disease (GORD or GERD) 397 Perioperative (neoadjuvant and adjuvant)
Obesity 397 chemotherapy 403
Alcohol and tobacco 397 Adjuvant chemoradiation 403
Anatomy 397 Radiation techniques 403
Clinical manifestations 398 Palliative treatments in advanced/metastatic
gastric cancer 403
Diagnostic evaluation 398
Palliative chemotherapy 400
Therapy 399
Palliative radiotherapy 403
Surgery 399
Summary 403
Radiotherapy 399
Hepatocellular carcinoma 404
Definitive chemoradiation 399
Cholangiocarcinoma and Gallbladder
Adjuvant radiation or chemoradiation 400 cancer 404
Radiation therapy techniques 400 Pancreas 404
External beam radiation 400 Anatomy 404
Brachytherapy 400 Incidence and epidemiology 405
Chemotherapy 400 Pathology 405
Neoadjuvant chemotherapy 400 TNM staging 405
Palliative chemotherapy 400 Clinical features 405
Other treatments 400 Diagnostic evaluation and imaging 406
Esophagogastric junctional tumours 401 Therapy 406
Summary 401 Surgery 406
Chemoradiotherapy in locally advanced pancreatic
Stomach 401
cancer 406
Anatomy 401
External beam radiation techniques 406 common in China, Iran, Russia, South Africa, France and
Adjuvant therapy 407 Switzerland. In the UK, in excess of 7000 new cases area
diagnosed per year with an annual death rate of around
Palliative chemotherapy 407
6900. Three to four decades ago, most esophageal cancers
Supportive care for symptom palliation 407 were squamous carcinomas. Over the last two decades, an
Colon and rectum 407 increasing incidence of adenocarcinomas of the oesopha-
Epidemiology 407 gus and cardia has been observed. Within Europe there
Aetiology 407 are significant differences in the incidence of esophageal
Histopathology and clinical features 408 cancer, the highest rates being in the UK with 4.28.9/
100 000 cases and Holland with 4.2/100 000, the lowest
Staging systems 408 being 0.7/100 000 in Poland and 0.5/100 000 in the Czech
Colon cancer treatment principles 408 Republic.
Surgery 408 Worldwide, males are more commonly affected than
Adjuvant chemotherapy 408 females. The male to female ratio in the USA ranges from
2.1:1 to 3.7:1. Both squamous and adenocarcinomas are
Chemotherapy for advanced disease 409
rare before the age of 40 years and steadily increase with
Newer targeted therapies 410 each decade of life. Racial and ethnic differences have
Radiotherapy and colon cancer 410 been reported in high incidence areas and also in the
Follow up 410 USA. The black populations of North America and South
Africa appear to be at increased risk of squamous cell car-
Rectal cancer treatment principles 410
cinomas (rates in excess of 15 cases/100 000 person
Radiotherapy technique 411 years).
Chemotherapy 412
Follow up 412
Anal cancer 412 Aetiology and pathology
Epidemiology and aetiology 412 The most common histological subtypes are squamous cell
Anatomy 412 carcinoma and adenocarcinoma, accounting for more than
90% of tumours.
Histopathology 413
Clinical features 413
Staging 413 Risk factors for squamous cell
Diagnostic work up and staging 413 carcinomas
Treatment 414 Alcohol and tobacco make up the largest risk factors
Surgery 414 for oesophageal squamous cell carcinoma in the western
Definitive chemoradiation 414 world. The relative risk is reported as 6.2 for smokers
who do not consume alcohol. Smokers who have sig-
Radiotherapy treatment principles 414
nificant intakes of alcohol have a 1025 fold increa-
Treatment-related toxicity 415 sed risk of squamous cell cancer. Equally, chewing
Follow up 415 tobacco and betel leaves as practised in southern Asia,
Salvage treatment 415 contributes to the excess risk seen in these regions.
Nitrosamines, N-nitroso compounds, aromatic amines,
Palliative treatment 415
polycyclic hydrocarbons found in alcohol and tobacco,
Prognosis 415 alone or in combination contribute to the carcinogenic
Gastrointestinal Stromal Tumours (GISTS) 415 effect.
Further reading 415 Patients with iron deficiency anaemia and diet low
in riboflavin Plummer-Vinson/Paterson-Kelly Brown
syndrome are at a higher risk of upper digestive tract
squamous cell carcinomas. Tylosis, a hereditary condi-
CANCER OF THE OESOPHAGUS tion characterized by hyperkeratosis of the palms and
soles and papilloma of the oesophagus, is associated
with a one in three chance of developing oesophageal
Epidemiology
cancer below the age of 50 years. Long-standing achala-
Oesophageal cancer is among the top ten commonly occur- sia cardia is associated with 5% risk of oesophageal squa-
ring cancers and has a distinctive epidemiologic pattern mous carcinoma. Patients with a history of previous
characterized by marked geographic variation. It is more cancer of the aerodigestive tract have a 24% incidence
396
Chapter | 24 | Gastrointestinal cancer
Stomach
Coeliac and
perigastric nodes
397
Walter and Millers Textbook of Radiotherapy
398
Chapter | 24 | Gastrointestinal cancer
Tis, N0, M0 T1,N0,M0 IIA T2/T3,N0,M0 T3,N1,M0 IVA Any T, any N, M1a
HISTOPATHOLOGICAL GRADING
G1 Well differentiated
G3 Poorly differentiated
G4 Undifferentiated
Radiotherapy
stage following preoperative chemoradiation because it External beam radiation alone or as part of combined
may not be able to differentiate between residual tumour modality treatment has been evaluated in both squamous
and post-radiation inflammation/fibrosis. cell and adenocarcinoma of the oesophagus. Primary radi-
In patients with hoarseness of voices or hemoptysis/ ation treatment alone for treatment of clinically localized
unexplained cough, bronchoscopy is recommended to rule esophageal cancer is not recommended in the curative
out recurrent laryngeal nerve involvement or tracheobron- setting. Both local and distant failure rates remain too
chial fistula. high despite higher doses of radiation. Five-year survival
The role of 2-fluorodeoxy-D-glucose positron emission is reported to be less than 5%. Preoperative radiation
tomography (FDG PET-CT) in the initial staging of poten- (i.e. without chemotherapy) has not shown any signifi-
tially operable esophageal cancer has been the subject of cant survival advantage. These two approaches are not
numerous studies. In a recent systematic review, the pooled recommended for patients fit for a potentially curative
sensitivity and specificity of FDG PET for distant nodal and approach.
hematogenous metastases was 67% and 97%, respectively.
The change in patient management as a result of FDG PET
Definitive chemoradiation
ranged from 3 to 20%. Preliminary data suggest that early
FDG PET following neoadjuvant chemotherapy may pre- Chemoradiation protocols typically use cisplatin and
dict pathologic response and overall survival and thus 5-fluorouracil (5FU) (recent studies have explored addi-
may define a subset of patients who are more likely to tional agents such as paclitaxel) with fractionated external
benefit from surgery. beam radiation to a dose of 4560 Gy. In two phase III
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Chapter | 24 | Gastrointestinal cancer
Palliative treatment options are tailored to the individual has increased. The incidence of stomach cancer has been
patient and are best discussed in a multidisciplinary setting declining in the UK since 1930. CRUK (2004) reported
along with the palliative care team. Esophageal stenting 9660 cases in the UK with an incidence of 16.5 per
provides palliation of dysphagia. Endoscopic laser treat- 100 000 making this the sixth most common cancer in
ment may be suitable for bulky endoluminal squamous Britain.
tumours. Palliative radiation (external beam or brachyther-
apy) and chemotherapy are other alternative options for
symptomatic benefit. Aetiology
Environmental and genetic factors play a role in the patho-
Esophagogastric junctional tumours genesis of gastric cancer. Carcinogens implicated in the
aetiology include nitrates and nitrites in food, smoking
Adenocarcinomas of the esophagogastric junction have and industrial dust exposure. The role of alcohol remains
been divided into three subtypes as proposed by Siewert uncertain. Increased risk has been reported with a specific
and Stein. Typ. 1 junctional tumours primarily arise from strain of Helicobacter pylori (CAGve) especially in non-car-
the distal oesophagus and involve the junction, typ. 2 junc- dia lesions. Pernicious anaemia and previous subtotal gas-
tional tumours straddle the junction and typ. 3 tumours are trectomy for benign conditions, and villous adenomas are
predominantly in the cardia of the stomach involving the thought to be associated with increased risk of gastric
junction. Typ. 1 junctional adenocarcinoma is treated cancer after a long period of latency.
using oesophagus protocols. Typ. 3 junctional tumours Genetic factors include mutations in specific genes,
are thought to behave like gastric adenocarcinoma, there- CDH1 and p53. CDH1 encodes for E-cadherin and
fore, are treated using gastric protocols. mutations in this gene are associated with hereditary
diffuse gastric cancer. Another familial gastric cancer
syndrome is associated with p53 mutations. Gastric
Summary cancer is also a component of Li-Fraumeni syndrome,
Management of esophageal cancer has evolved over the hereditary non-polyposis colorectal cancer (HNPCC),
past three decades. Treatment decisions should be made Peutz-Jegher polyposis, BRCA-2 mutations and juvenile
within a multidisciplinary team setting. Careful staging polyposis.
and selection of patients for curative treatments is vital
and surgery should be performed in high volume special-
ist centres for best outcome. Combined modality treat- Pathology
ments remain the standard of care in curative setting for Adenocarcinoma constitutes 95% of the gastric cancers.
all patients with oesophageal cancer except the very early They are classified into intestinal and diffuse types
tumours. (Laurens classification system). The intestinal type is more
common in older patients, high-risk groups and men. The
diffuse type is more commonly seen in women and youn-
STOMACH ger patients and carries a poorer prognosis. Other histolog-
ical types of gastric malignancies include carcinoids,
lymphomas and gastrointestinal stromal tumours (GISTS).
Anatomy GISTS are the most common mesenchymal tumours of the
gastrointestinal tract.
The stomach begins at the esophagogastric junction and
ends at the pylorus. It is divided into three parts: cardia
(fundus), body and pyloric antrum. The blood supply Clinical features
of the stomach is derived from the branches of the coeliac
axis. The regional lymphatics drain into the coeliac axis The most common presenting symptoms are anaemia, weight
nodes, splenic hilar, porta hepatis, gastroduodenal and loss, anorexia, haematemesis, melena, upper abdominal
suprapancreatic nodal groups. Venous drainage is primar- pain/discomfort/mass, nausea/vomiting. Occult bleeding is
ily through the portal venous system into the liver. more common than overt haematemesis. Possible clinical
findings include anaemia, abdominal mass, left supraclavicu-
lar lymphadenopathy, and ascites.
Epidemiology
There is a considerable variation in the worldwide inci-
Staging (Tables 24.4 and 24.5)
dence of gastric cancer. The highest incidence is seen in
Japan, South America and eastern Europe. The incidence The initial investigations often include a barium meal/
in western Europe is in decline. However, the incidence swallow and endoscopy. Gastroscopy and biopsy will con-
of tumours of the cardia and esophagogastric junction firm the diagnosis in the majority of patients. Multiple
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Walter and Millers Textbook of Radiotherapy
Table 24.4 Stomach cancer TNM clinical classification Table 24.5 Stomach cancer stage grouping
Stage 0 Tis N0 M0
T: Primary tumour
Stage IA T1 N0 M0
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour Stage IB T1 N1 M0
Tis Carcinoma in situ: intraepithelial tumour without T2 N0 M0
invasion of the lamina propria
T1 Tumour invades lamina propria or submucosa Stage II T1 N2 M0
T2 Tumour invades muscularis propria or subserosa T2 N1 M0
T3 Tumour penetrates serosa (visceral peritoneum) T3 N0 M0
without invasion of adjacent structures T4 N0 M0
T4 Tumour invades adjacent structures
Stage IIIB T3 N2 M0
Notes:
Stage IV T4 N1,N2,N3 M0
1. A tumour may penetrate muscularis propria with
Any T Any N M1
extension into the gastro-perforation of the visceral
peritoneum covering these structures. In this case,
the tumour is classified as T2. If there is perforation
of the visceral peritoneum covering the gastric
ligaments or omentum, the tumour is classified as T3. Management
2. The adjacent structures of the stomach are the spleen,
The optimal management of gastric cancer should take
transverse colon, liver, diaphragm, pancreas, abdominal
wall, adrenal gland, kidney, small intestine and place within a multidisciplinary setting. The treatment
retroperitoneum. options are surgery, neoadjuvant and adjuvant chemother-
3. Intramural extension to the duodenum or oesophagus is apy, adjuvant chemoradiation, palliative chemotherapy
classified by the depth of greatest invasion in any of and radiation.
. these sites including stomach
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Chapter | 24 | Gastrointestinal cancer
Perioperative (neoadjuvant and adjuvant) adequately cover the volume but more complex techniques
chemotherapy including oblique/lateral portals with 3D CT planning may
help to optimize the dose and minimize the normal tissue
The relapse rate is high for patients who have had gastrec- dose. The standard dose fractionation is 45 Gy in 25 fractions
tomy for stages T2 and beyond. This is thought to be over 5 weeks with concomitant intravenous 5-fluorouracil
mainly due to the locoregional failure and micrometa- (425 mg/m2, folinic acid 20 mg/m2 for 5 days repeated
static disease present at diagnosis. Various adjuvant treat- every 4 weeks during radiotherapy and for two cycles after
ments have been explored to improve the survival. radiotherapy). The patient needs to be monitored carefully
Perioperative chemotherapy with epirubicin/cisplatin/5- with weekly full blood counts, biochemistry, dietetic assess-
fluorouracil has been shown to improve the disease-free ment including weight and adequate measures for gastroin-
and overall survival in patients with resectable gastric cancer. testinal toxicity (nausea, vomiting, and diarrhoea).
The MRC UK MAGIC trial randomized over 500 patients to
either surgery alone or three cycles of preoperative ECF (epir-
ubicin 50 mg/m2, cisplatin 60 mg/m2 day 1 and infused Palliative treatments in advanced/
5-fluorouracil 200 mg/m2 for 21 days) followed by surgery metastatic gastric cancer
and then three more cycles of postoperative ECF. Both pro-
gression-free and overall survival were superior in the com- Palliative chemotherapy
bined modality arm. Five-year survival rates were 23% in the Platinum- and fluoropyrimidine-based regimens are now
surgery alone arm and 36% in the perioperative chemother- considered to be the standard option for systemic chemo-
apy arm. In the UK, following the publication of this trial, therapy for patients with advanced/metastatic gastric
perioperative chemotherapy has become the standard of adenocarcinoma. CF, ECF and DCF are regimens with
care for patients with curable and resectable gastric cancers. response rates of 3545% and a median overall survival
Future directions explore the addition of targeted therapy around 9 months. The REAL-2 study comparing cisplatin
(anti-VEGF bevacizumab or anti-EGFR cetuximab) to versus oxaliplatin and IV 5FU versus oral capecitabine
chemotherapy. In the current UK led international trial showed that the four regimens are of similar efficacy.
of perioperative chemotherapy (NCRI ST03), patients will Docetaxel-based regimen, DCF (docetaxel, cisplatin and
be randomized to ECX (epirubicin, cisplatin and capecita- 5-fluorouracil) and irinotecan with cisplatin produce
bine) or the same plus the antivascular endothelial growth similar median survival figures of around 9 months.
factor (VEGF) monoclonal antibody bevacizumab. A recent meta-analysis based on aggregate data on the
benefits of palliative chemotherapy confirmed the bene-
fits of chemotherapy.
Adjuvant chemoradiation Recently, in the subpopulation of patients with HER-2
In North America, adjuvant chemoradiation is offered for ve gastric cancer, addition of Trastuzumab to cispaltin
patients with resected gastric cancer based on the updated fluoropyrimidine chemotherapy has been shown to
results of the Intergroup 0116 randomized trial comparing improve both overall and progression free survival. In the
surgery alone to surgery followed by postoperative chemora- ToGA trial, the subgroup patients with HER-2 ve (FISH
diation with 5-FU and folinic acid. The adjuvant chemoradia- ve or IHC 3ve) gastric cancers had a 4.2 months improve-
tion improved the median progression-free survival (19 ment in overall survival with the addition of trastuzumab
versus 30 months P<0.001) and overall survival (26 versus to chemotherapy (16 months vs 11.8 months, HR 0.65
35 months P<0.006). It is felt that a significant proportion 95% CI 0.51-0.83). This is considered as the new standard
of patients may have had suboptimal lymph node dissection of care in HER-2 ve metastatic gastric cancer.
and the postoperative chemoradiation may have compen-
sated for the inadequate surgery. However, based on this
pivotal study, adjuvant chemoradiation has become the
Palliative radiotherapy
new standard of care in North America. In selected patients, palliative radiotherapy (810 Gy in
a single fraction or 20 Gy in five fractions) may help to
palliate pain, bleeding, and obstructive symptoms.
Radiation techniques
The postoperative radiation target volumes are generated
Summary
based on the tumour site in the stomach, known pattern
of locoregional failure and need to be tailored to the Management of gastric cancer has improved over the last
individual patients T stage and type of surgery. The clinical decade. Most patients with resectable gastric adenocarci-
target volume includes the gastric/tumour bed, gastric rem- noma are likely to need a combined modality approach
nant, nodal stations along the lesser and greater curvature for best results. Future directions in systemic therapy
of the stomach, coeliac axis, suprapancreatic, porta hepatis include integrating the newer targeted molecules into exist-
and splenic groups. Parallel pair anterior/posterior may ing protocols.
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Walter and Millers Textbook of Radiotherapy
a paraneoplastic feature. The liver may be enlarged and there Chemoradiotherapy in locally advanced
may be epigastric fullness/mass on palpation. pancreatic cancer
Combined modality treatment with chemoradiation using
fluoropyrimidines (5FU or capecitabine) is considered a
Diagnostic evaluation and imaging standard approach for locally advanced pancreatic cancer
A full blood count may reveal anaemia and biochemical in North America. 3-D conformal radiotherapy and inten-
tests confirm obstructive jaundice. CA19.9, a serum sity modulated radiotherapy (IMRT) techniques may opti-
tumour marker, is raised in between 60 and 90% of mize the tumour dose and minimize the radiation dose to
patients with pancreatic cancer. the normal tissue. Dose escalation to 60 Gy or above has
Endoscopic retrograde cholangiopancreatography (ERCP) not shown to improve the survival in locally advanced pan-
is an extremely useful investigation for evaluating the creatic cancer. Median overall survival in these studies
ampulla, obtaining cytological specimens and also for ranged between 7 and 12 months for the chemoradiation
biliary drainage. Multislice CT with 3D reconstruction is group. The structures around the pancreas, i.e. duodenum,
extremely useful to define the relationship of the tumour kidneys, spinal cord, stomach etc., limit the radiation dose.
to the vessels and surrounding structures. Endoscopic ultra- Intraoperative radiotherapy (IORT) and stereotactic
sound by an experienced endoscopist will help in detecting radiotherapy remain investigational. IORT with electrons
small lesions, any nodal involvement and, more impor- has been used to boost the dose to the primary tumour fol-
tantly, venous involvement. Endoscopic ultrasound- lowing external beam radiation or in patients who have
guided fine needle aspiration (EUS FNA) may increase had resection of their primary tumour. A dose of 15
the diagnostic sensitivity to near 100% and has been shown 30 Gy has been recommended. Local tumour control
to be reliable for presurgical work up. Laparoscopy is help- seems to have improved but with no major impact on
ful in detecting unsuspected peritoneal disease since up to the overall survival.
30% of patients with locally advanced pancreatic cancer Preoperative chemoradiation in potentially resectable
have occult microscopic peritoneal disease. FDG-PET is cancers may provide better local control and some survival
an additional imaging modality with varying degrees of benefit has been demonstrated in single institute retrospec-
specificity and sensitivity in detecting pancreatic cancer. tive series on par with adjuvant therapy. However, it is
A recent meta-analysis showed a sensitivity of 73100% difficult to compare these studies because of small num-
and specificity of 53100% for the detection of pancreatic bers and inconsistent criteria for patient selection and
cancer. In selected patients, magnetic resonance imaging resectability. Down staging an initially unresectable
(MRI) may offer a better definition of vascular anatomy tumour to enable resection with a neoadjuvant approach
prior to surgery. is rare. These approaches should be part of well-designed
randomized clinical trials.
Therapy
External beam radiation techniques
Surgery In patients with locally advanced pancreatic cancer, the tar-
Less than 20% of patients have potentially surgically get volumes are defined using the information from the
resectable lesions. Standard surgical treatment is pancrea- imaging studies (EUS, CT). Multiple field (four to six) frac-
tico-duodenectomy pioneered by Whipple and his team tionated high energy photon beam techniques are used to
in 1935. Distal body and tail of the pancreas tumours deliver 4550 Gy in 1.8 Gy fractions. The clinical target vol-
may require en bloc resection of the spleen along with ume (CTV) includes the primary tumour, adjacent nodal
the pancreas. The overall 5-year survival following surgical groups (suprapancreatic, coeliac axis, and pancreaticodu-
resection is 520%. For best results, surgery should be per- doenal) and the duodenal wall for head of pancreas
formed in high volume centres with specialist experience. lesions. The superior extent of CTV should cover the coeliac
In the absence of distant metastases, the features which axis with 1.52 cm margin and inferiorly the volume
make a tumour potentially unresectable are significant extends to include the superior mesenteric lymph nodes.
involvement/encasement of the superior mesenteric vein, The posterior margin of the CTV is crucial and should
portal vein or superior mesenteric artery by the tumour or extend to at least 1.5 cm beyond the anterior margin of
invasion of adjacent organs (kidney, adrenal, and colon). the vertebral body. This is to ensure that the splanchnic
Patterns of failure after surgical resection without any nerves and plexus are included in the CTV (note the risk
adjuvant therapy are well described; 5085% of patients of perineural spread). The anterior margin extends up to
have local relapse, 2535% have peritoneal recurrences 1.52 cm from the GTV. All the organs at risk, i.e. stomach,
and 2590% have liver metastases. Tumour stage, grade duodenum, liver, both kidneys, spinal cord and surround-
and resection margin status are the best predictors for sur- ing small bowel should be outlined. One has to remember
vival after potentially curative surgery. that pancreas, despite being a retroperitoneal organ, moves
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Chapter | 24 | Gastrointestinal cancer
vertically up to 1.52 cm with respiration. This has to be Gemcitabine capecitabine and gemcitabine erlotinib
taken into account in defining the CTV!planning target have shown a modest increase in the survival.
volume (PTV) margin in the vertical plane.
CT-based treatment planning and 3D-conformal radia- Supportive care for symptom palliation
tion or IMRT techniques permit the generation of treatment
plans that optimize the radiation dose to the PTV but min- Endoscopic biliary stenting of a resectable pancreatic tumour
imize the dose to the critical organs at risk. Dose volume for the release of jaundice is as good as surgical bypass to
histograms for each of the organs at risk should be critically relieve jaundice. The duodenal obstruction can be relieved
evaluated before accepting the final plan, in particular, the by expandable stents. Pain relief is important for the pallia-
dose to the kidneys should be kept to a minimum. Some tion of pancreatic cancer. Severe pain can be caused by infil-
radiation centres recommend assessment of individual kid- tration of the coeliac plexus and this can be relieved by
ney function prior to starting radiation treatment. Postop- destruction of the plexus by an injection of alcohol which
erative adjuvant radiation fields are designed on the basis can be carried out either under x-ray control or CT guidance.
of the preoperative CT data on primary tumour site and Future directions in pancreatic cancer research hope for a
extent, known nodal spread and operative clip placement. better understanding of the molecular events, in particular,
Future strategies in combining radiation and systemic K-Ras and the downstream signaling pathways which may
agents are likely to explore novel chemotherapeutic agents, represent attractive therapeutic targets.
targeted therapy with trastuzumab (HER-2neu antibody),
cetuximab (EGFR antibody), erlotinib, sunitinib (tyrosine
kinase inhibitors) etc. COLON AND RECTUM
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Walter and Millers Textbook of Radiotherapy
This is borne out clinically as early dysplastic polyps that Staging systems
are not excised have a risk of malignant transformation
of about 510% at 10 years. Larger polyps, and multiple The simplest staging of large bowel cancer is the Dukes
polyps increase the risk of malignant transformation. staging scheme in which tumours are staged A to C. Stage
Patients with a family history of bowel malignancy, or A is tumour involving the mucosa or penetration into the
who have themselves had a previous bowel malignancy, submucosa, Stage B is penetration through the muscularis
are at increased risk of developing colorectal cancer. Two propria but no lymphatic spread and Stage C is spread to
specific cancer syndromes, namely familial adenomatous lymph nodes. This staging scheme has been modified
polyposis (FAP) and hereditary non-polyposis colon cancer over the years and the modified Astler-Coller scheme is
(HNPCC: Table 24.8), have generated much interest. Both widely used in the USA. The staging schemes are listed in
are autosomal dominant mutations with high penetrance. Table 24.9.
The genetic mutations associated with these cancer predispo- Use of the UICC TNM should be encouraged where pos-
sition syndromes have been isolated, and genetic screening sible as it offers more accurate information on primary
can now be offered to families thought to be at risk. HNPCC tumour and nodal status and, in the Royal College of
is the most common hereditary syndrome accounting for Pathologists minimum data set for the reporting of colorec-
27% of the total. The diagnosis is based on strict clinical tal cancer, use of the TNM classification is mandatory.
and molecular criteria. FAP accounts for 1% of all colorectal
cancers. In this syndrome, multiple adenomas progress to Colon cancer treatment principles
invasive cancers in nearly 100% of patients by 4050 years
of age. Prophylactic surgery is recommended at age 1621. Surgery
Surgery is still the main treatment modality. The aim of sur-
Histopathology and clinical features gery is excision of the primary tumour with wide excision
margins. The tumour spreads to the lymph nodes located
The vast majority of colorectal cancers are adenocarcino- in the mesentery close to the vascular supply for that por-
mas. Macroscopically, they present as exophytic masses. tion of colon. This portion of node-bearing mesentery
They typically show glandular differentiation, mucin for- is excised along with the bowel. Continuity of the bowel
mation, and stain positively for carcinoembryonic antigen is usually re-established by a direct anastomosis, either
(CEA). Small cell carcinomas, lymphomas, melanomas between excised segments of colon or the colon and the
and adenosquamous carcinomas have been reported. terminal ileum.
Usually, patients will present with symptoms of rectal
bleeding, altered bowel habit, or weight loss. The diagnosis
is usually made by characteristic filling defects on barium Adjuvant chemotherapy
enema (apple core lesions) or at colonoscopy. Bulky Adjuvant chemotherapy is of proven benefit for patients
lesions may present with overt bowel obstruction. with node positive (Dukes C) colon cancer. Six months
Occasionally, patients will present with liver metastases of 5-fluorouracil and folinic acid chemotherapy given to
and no obvious primary tumour on barium enema or colo- such patients is estimated to reduce the risk of death by
noscopy. In such cases, morphological features on light 30% which translates into a 1013 % absolute improve-
microscopy, CEA staining, and differential staining cyto- ment in survival. Two randomized controlled trials have
keratins CK 7 and CK 20, can be helpful in confirming confirmed that the addition of oxaliplatin to 5-fluoroura-
the tissue of origin. Tumours of the lower gastrointestinal cil and folinic acid improves 3-year survival by an addi-
tract are typically CK 7 negative and CK 20 positive. tional 7%. Patients with Dukes B tumours have derived
less benefit from adjuvant chemotherapy. Trials, such as
the British QUASAR trial, have shown only a 3.6%
Table 24.8 Revised Amsterdam criteria for suspected increase in 5-year survival in this group of patients. How-
hereditary non-polyposis colon cancer (HNPCC) ever, Dukes B is a heterogeneous group of patients and
multivariate analysis of patterns of relapse has shown that
3 relatives with an HNPCC-related cancer, one of whom patients with T4 tumours, tumour perforation, lympho-
should be a first degree relative of the other two vascular invasion and poor differentiation are most likely
to derive benefit from chemotherapy. The X-ACT trial has
2 generations should be involved
shown that oral capecitabine is at least as effective as 5-
1 case diagnosed under age 50 fluorouracil and folinic acid. Orally administered capeci-
tabine is an alternative treatment for patients who may
Familial adenomatous polyposis must be excluded not be able to tolerate oxaliplatin-based regimens. Cur-
HNPCC cancers include colon and rectum, endometrium, rently, irinotecan-based regimens have not been shown to
small bowel, ureter and renal pelvis give an advantage in an adjuvant setting therefore are not
currently recommended.
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Chapter | 24 | Gastrointestinal cancer
STAGE GROUPING
TNM DUKES
Stage 0 Tis N0 M0
Stage 1 T1 N0 M0 A
T2 N0 M0 A
Stage II T3 N0 M0 B
T4 N0 M0 B
Any T N2 M0 C
Chemotherapy for advanced disease folinic acid, yields a significantly higher response rate of
For nearly 40 years, 5-fluorouracil has been the mainstay of 39%, with a survival benefit of 15.9 months. The novel
treatment for advanced colorectal cancer. It is typically platinum-based compound oxaliplatin shows similar
given with folinic acid to increase efficacy as an inhibitor response rates of 51%, when used in combination with
of thymidilate synthetase. The response rate for 5FU and 5FU and folinic acid. Both agents have activity in disease
folinic acid based regimens is of the order of 20%. A num- that has become resistant to 5FU, albeit with lower res-
ber of regimens exist for administering 5FU, as outlined in ponse rates than seen when used in first line therapy. Oxa-
Table 24.10. Many centres favor the Lokich regimen of con- liplatin and irinotecan regimens are listed in Table 24.11.
tinous venous infusion, due to the favorable toxicity pro- The development of oral fluoropyrimidines, such as
file, and ease of administration. capecitabine, provides another option for treatment, espe-
In the last decade, novel agents have become available cially in elderly patients. Capecitabine is a pro-drug, which
with activity in colorectal cancer. The DNA topoisomerase is selectively activated by thymidine phosphorylase to fluo-
1 inhibitor irinotecan, used in combination with 5FU and rouracil. Thymidine phosphorylase is expressed in much
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Walter and Millers Textbook of Radiotherapy
Table 24.10 Typical 5FU regimens Table 24.12 Prognosis of colon cancer by modified
Dukes staging
Lokich regimen: 5FU 300 mg/m2 per 24 hours as continuous
venous infusion STAGE EXTENT OF TUMOUR 5-YEAR SURVIVAL
2
Weekly regimen: 5FU 370 mg/m iv bolus & folinic acid
A No deeper than >90%
20 mg/m2 iv bolus weekly
submucosa
Modified de Gramont regimen: Folinic acid 175 mg iv
B1 Not through bowel wall 8085%
infusion, 5FU 400 mg/m2 bolus, followed by 5FU 2800 mg/
m2 as 46-hour ambulatory infusion B2 Through bowel wall 7075%
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Chapter | 24 | Gastrointestinal cancer
produced a reduction in local recurrence rates, but at the or intractable pelvic pain. A short course of treatment (20
cost of a fourfold increase in perioperative mortality. 30 Gy in 510 fractions) is often used for such patients.
However, more recent studies using a short course of
preoperative radiotherapy have produced better results.
A dose of 25 Gy in five fractions, using smaller pelvic Radiotherapy technique
fields, yielded a reduction in local recurrence rates from Technique
21% to 10%. A 10% improvement in overall survival
was also observed, with no significant increase in periop- The patient is immobilized in the prone position using
erative mortality. stocks to immobilize the legs. Ideally, the bladder should
Specialist colorectal surgeons have been trained in the be comfortably full at the time of simulation. For conven-
technique of total mesorectal excision (TME). This tech- tional simulation, barium contrast is introduced into the
nique involves removal of the entire rectum and associated rectum, and the lowest extent of disease is marked with a
mesorectal fat, and reduces the risk of local recurrence at 5 wire, together with an anal marker. AP and lateral simulator
years from 20% to 6%. It has also been shown that the sin- films are taken for volume definition. For CT planning, the
gle most important factor for predicting disease recurrence patient is scanned from mid-femur to the umbilicus. Typi-
is the circumferential resection margin. The circumferential cally, the patient is treated with a three-field technique
resection margin is said to be clear if there is no evidence of (8 MV or higher energies, using posterior and two lateral
tumour from either the primary site, or in an associated fields) or a four-field brick for 6 MV machines.
lymph node, that extends to within 1 mm of the inked
resection margin around the circumference of the excision Target volume
specimen. Patients at high risk of local recurrence are typi- For primary radiotherapy treatment, the target volume
cally offered long course postoperative radiotherapy, typi- includes the rectum and surrounding mesorectal fat,
cally a dose of 45 Gy in 25 fractions over 5 weeks. including the entire presacral space, together with local
As TME surgery is now the gold standard for surgical exci- lymphatics. This includes the perirectal, obturator, and
sion, and recurrence rates have fallen to 56%, the role of internal iliac nodes.
preoperative radiotherapy has been brought into question. For conventional planning on orthogonal films, the vol-
A recent Dutch study reported after a median follow up ume is defined as follows:
of just over 2 years, that the local recurrence rate was Superior: L5/S1 interspace to encompass nodes in the true
2.4% for patients who received preoperative radiotherapy pelvis
prior to TME surgery, compared to an 8.2% recurrence rate Inferior: 3 cm below the lowest extent of the tumour,
in patients receiving no preoperative radiotherapy. The sparing the sphincter complex if at all possible
MRC CR07 study was a large prospective study in which Lateral: 1 cm lateral to the pelvic sidewall, to cover the
patients with operable rectal cancers are randomized to internal iliac nodes
either receive short course preoperative radiotherapy, or Anterior: a margin should be allowed from the most
primary surgery followed by long course postoperative anterior part of the rectum. A sagittal MRI image can be very
radiotherapy if the circumferential resection margin is pos- helpful in determining this distance. Typically, the volume
itive. Local recurrence after short course radiotherapy was extends to the middle of the femoral heads
4.4% at 3-years compared to 10.6% (p<0.0001) for post- Posterior: the volume extends to the back of the sacrum, to
operative chemoradiotherapy. encompass the entire presacral space.
Advances in pelvic imaging, specifically endoscopic
Very extensive tumours with involvement of the bladder, or
ultrasound and magnetic resonance imaging of the pelvis,
tumours that are being treated with palliative intent, are
can provide excellent soft tissue definition in perirectal tis-
often treated with an anterior and posterior parallel-
sues, and visualize tumour penetration through the mesor-
opposed pair of fields.
ectal fascia. Such patients may then be suitable for long
course preoperative radiotherapy, to downstage the
tumour prior to surgery. Radiotherapy planning using CT planning
Patients who are offered long course radiotherapy receive technique
concomitant chemotherapy with either infusional 5FU at Rectal tumours are ideal for CT planned conformal
200 mg/m2/day continuous schedule OR oral capecitabine radiotherapy, as even small reductions in target volume
825 mg/m2 bid for the duration of radiotherapy. In more can significantly reduce the volume of irradiated small
locally advanced tumours, neoadjuvant chemotherapy with bowel.
oxaliplatin and capecitabine for 12 weeks, concomitant che- Patient set up: prone if patient can tolerate otherwise
moradiation with oral capecitabine and another 12 weeks of supine. Oral contrast to outline small bowel. Intravenous
adjuvant oxaliplatin and oral capecitabine is recommended. contrast to highlight vessels is strongly recommended.
Palliative radiotherapy can be very helpful in patients Scan from L5 to 4 cm below the anal marker, recom-
with advanced rectal tumours, with symptoms of bleeding mended slice thickness is 3 mm.
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Walter and Millers Textbook of Radiotherapy
The target volume definitions are given below: propensity for nodal metastases and spread to the liver.
GTV: primary tumour, extramural spread, nodes and any Patients are offered adjuvant chemotherapy for high-risk
intervening normal rectal wall. Outlined on each CT slice. Dukes B tumours and Dukes C tumours. The same chemo-
CTVA: GTV with 1 cm margin in all directions. therapy regimens used in advanced colonic cancer are used
CTVB: includes the mesorectal nodes within the in advanced rectal cancer.
mesorectum, presacral and internal iliac nodes.
CTVF (Final CTV): combination of CTVA and CTVB, Follow up
modified at the clinicians discretion. Patients with rectal cancer require regular endoscopic fol-
PTV: CTVF 1 cm margin in all directions. low up to look for local recurrence, and the development
The anatomical boundaries for the CTVB are as follows: of new tumours. In most protocols, the liver is imaged
Superior limit: S interspace for mid and lower third rectal by CT or ultrasound scanning.
cancers. There should be a 2 cm margin above the most
superior limit of the GTV. CTVB margin may have to extend
above S to achieve this 2 cm margin from the GTV
ANAL CANCER
Inferior limit: CTVB inferior limit is 1 cm inferior to CTVA or
the puborectalis muscle if there is no involvement of Epidemiology and aetiology
puborectalis (whichever is inferior). If there is involvement
of puborectalis or sphincter or levator ani, then the lower Anal cancer constitutes 1% of all malignancies of the
limit for CTVB would be the ischiorectal fossa. bowel, with 250300 new cases being diagnosed each year
Lateral limit: No internal iliac node involvementmedial in the UK. In most patients, no obvious predisposing fac-
aspect of the obturator internus Internal iliac node tor can be found, though the incidence is higher in homo-
involvement presentlimit is bony pelvic sidewall sexual men, due to the association with human papilloma
Anterior limit: 1 cm anterior to the anterior mesorectal fascia virus type 16 (HPV16) infections. HPV16 DNA is found in
or 7 mm anterior to the internal iliac artery (whichever is the tumour cell genome in 8090% of tumours, in both
anterior). men and women. The detection of HPV in the tumour
Posterior limit: anterior margin of the sacrum. is not a prognostic factor. Tumours are more common
in immunosuppressed patients (HIV infection or systemic
Dose and energy immunosuppression). Other infectious agents linked
include herpes simplex virus, gonorrhea and chlamydia.
Short course preoperative radiotherapy: 25 Gy in 5 fractions Smoking has been shown to increase the risk of anal
over 1 week (68 MV photons) cancer. Tumours in the anal canal are more common
Long course preoperative radiotherapy: 45 Gy in 25 frac- in women, while anal margin tumours occur more
tions over 5 weeks (68 MV photons) with concurrent intra- commonly in men. Anal intraepithelial neoplasia (AIN)
venous infusional 5FU or oral capecitabine chemotherapy is associated with HPV infections and is thought to be a
Long course postoperative radiotherapy: 45 Gy in 25 frac- precursor for invasive carcinomas, though the natural his-
tions over 5 weeks (68 MV photons) with concurrent intra- tory is not as clearly defined as in cervical intraepithelial
venous infusional 5FU or oral capecitabine chemotherapy neoplasia.
Palliative radiotherapy: 2030 Gy in 510 fractions
(68 MV photons)
Anatomy
Treatment toxicity
During treatment, patients may experience cystitis, proctitis The anus is defined as extending from the rectum to the
and lethargy. The dose-limiting structure for long-term tox- skin of the perianal region. The superior margin is the pal-
icity is the small bowel, with the associated risk of fibrosis, pable upper border of anal sphincter and puborectalis mus-
stricturing and obstruction. The risk of small bowel toxicity cle. Inferiorly, it extends to skin within a 5 cm radius of the
is directly related to the volume of irradiated small bowel. anal verge (Figure 24.2).
With careful planning, the risk of significant small bowel There is a transition in the histological type of epithelium
toxicity is reduced to around 5%. Other long-term toxicities lining the anus. Perianal skin is squamous epithelium,
that need to be considered are impotence in male patients which turns to a transitional type epithelium at the dentate
and the increased risk of femoral neck fractures when lat- line, and then into the glandular mucosal lining of the
eral fields are used. rectum.
The anus has a dense lymphatic supply via three main
routes. The upper canal drains to perirectal and superior
Chemotherapy hemorrhoidal nodes. The area round the dentate line
The experience of chemotherapy treatment for colon cancer drains to hypogastric and obturator nodes. The anal verge
has been applied to rectal cancers, as both have a and perianal skin drains to superficial inguinal nodes.
412
Chapter | 24 | Gastrointestinal cancer
Clinical features
Rectal mucosa
LM The symptoms often are non-specific and common symp-
toms include anal pain and bleeding, pruritus, a mass in
PR the anal region, or discharge. Occasionally, tumours may
Anorectal ring
affect the sphincter mechanism and cause incontinence.
DES On examination, patients may present with ulcerated or
IS exophytic lesions, and inguinal lymphadenopathy may
Transitional zone
SES be present. Associated features, such as anal warts or leuko-
Squamous mucosa plakia, may be present. Inguinal lymph node metastases are
noted in 15% of patients and surgical series show that pel-
True skin vic nodal spread is present in about 30% of patients at pre-
sentation. Systemic metastatic spread is observed in less
Figure 24.2 Anatomy of the anal canal. LM longitudinal than 5% of patients at the time of initial diagnosis. Increas-
muscle, PR puborectalis, DES deep part of the external ing tumour size and depth of penetration into the anal wall
sphincter, IS internal sphincter, SES Superficial part of the increase the risk of nodal metastases.
anal sphincter.
(Reproduced with permission from Scott, An Aid to Clinical Surgery,
1977, Churchill Livingstone, Elsevier Ltd) Staging
The UICC TNM 2002 classification is most commonly
used. The staging classification differs for tumours of the
Histopathology anal canal and anal margin (Tables 24.13 and 24.14).
Approximately 80% of anal tumours are squamous cell car-
cinomas (Figure 24.3). The recognized subtypes are kerati- Diagnostic work up and staging
nizing large cell, non-keratinizing (transitional cell) and
basaloid. Adenocarcinomas occur in 10% of cases, and Full history and physical examination including risk factor
tend to arise from the glandular mucosa of the upper anal assessment is followed by an examination under anesthetic
canal. Other tumour types include lymphomas, melano- to assess the extent of the tumour and to obtain a biopsy for
mas, small cell carcinomas and sarcomas. histological confirmation of the diagnosis. One-third of
patients present with enlarged inguinal lymph nodes. These
should always be biopsied, as 50% of enlarged lymph
nodes are reactive, usually due to infection associated with
the primary tumour. The patient should also have a chest
radiograph, and CT scan of the abdomen and pelvis to
Table 24.13
T1 Primary tumour 2 cm
T2 Primary tumour 25 cm
M0 No distant metastasis
Figure 24.3 Exophytic squamous cell carcinoma of the anal M1 Distant metastasis
margin.
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Walter and Millers Textbook of Radiotherapy
complete staging. MRI of the pelvis provides improved soft Set-up conventional planning
tissue definition of the primary tumour, and pelvic lymph
The patient is immobilized prone, with the bladder com-
nodes. It may also be appropriate to perform HIV testing on
fortably full to displace small bowel from the treatment
patients, as patients with undiagnosed HIV and low CD4
field. A marker is placed at the anal verge and barium is
counts tend to tolerate chemoradiation poorly.
instilled to opacify the rectum. Any enlarged inguinal
nodes are marked with wire. The volume is treated with
Treatment an anterior and posterior parallel pair arrangement. The
field is defined as follows:
Surgery
Superior: 2 cm above bottom of sacroiliac joints
In the past, abdomino-perineal excision was the treatment
Inferior: 3 cm below the anal marker, or 3 cm below the
of choice for anal cancers, except for small lesions below
lowest extent of disease
the dentate line that could be treated with an implant. Sur-
Lateral: 1 cm lateral to the pelvic sidewall. If inguinal nodes
gery was typically associated with 5070% 5-year survival
are involved, the field needs to be extended laterally to
rates, but with significant morbidity and the necessity for
include the affected inguinal nodes.
a permanent colostomy. Locoregional failure rates were
around 2535%. Patients with inguinal nodal disease at The first phase is treated to a dose of 45 Gy in 25 fractions
presentation have a poor outcome with surgery alone with over 5 weeks, with concomitant 5-fluorouracil and
only a 1020% 5-year survival rate. Several trials reported mitomycin-C given during weeks 1 and 5 of external beam
favorable results with chemoradiation, producing long-term radiotherapy. After a 6-week gap, the patient is then treated
disease control, and preservation of normal sphincter func- with an interstitial implant to a dose of 25 Gy, or a 15 Gy
tion. Surgery can then be used to salvage patients with resid- boost to the primary tumour.
ual or recurrent disease after radiotherapy.
Set-up ACT II protocol
Definitive chemoradiation Again, patients are immobilized prone with a full bladder
and a marker at the anal verge. Any enlarged nodes are
Nigro et al, in 1974, first reported the benefits of concurrent
marked with wire.
chemoradiation for squamous cell carcinoma of the anal
Phase 1 is treated using a parallel pair technique. The
canal. Three major randomized clinical trials compared radia-
field is defined as follows:
tion alone to chemoradiation (chemotherapy consists of 5FU
and mitomycin-C). Locoregional control, disease-specific and Superior: 2 cm above bottom of sacroiliac joints
overall survivals were superior in the chemoradiation arm. Inferior: 3 cm below lowest extent of disease
The UKCCCR ACT trial of chemoradiation with 5- Lateral: Medial border of greater trochanter.
fluorouracil and mitomycin-C showed that local control The phase 2 volume depends on the nodal status of the disease.
rates improved from 39% at 3 years with radiotherapy alone, For node-negative disease, a CT planned volume is used, with a
to 61% with chemoradiation. Overall survival was also 3 cm margin from GTV to PTV. For node-positive disease,
improved with chemotherapy, but failed to reach statistical treatment is continued with a parallel pair, using a 3 cm mar-
significance. The treatment regimen from the ACT study gin round the primary tumour and any enlarged nodes.
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Chapter | 24 | Gastrointestinal cancer
Phase 1 is treated to a dose of 30.6 Gy in 17 fractions, ter outcome compared to the anal canal tumours. The over-
and phase 2 to a dose of 19.8 Gy in 11 fractions. Chemo- all survival at 5 years for anal canal tumours is 6080% for
therapy is given during weeks 1 and 5 of radiotherapy chemoradiation patients and for anal margin tumours
and, in the maintenance chemotherapy arm, again at 5-year survival rates vary from 65 to 100%. Locoregional
weeks 10 and 14. recurrence is associated with poor prognosis. Salvage sur-
gery may prolong survival in a selected small proportion
Treatment-related toxicity of patients.
FURTHER READING
Esophagus Kelsen DP, Ginsberg R, Pajak TF, Allum WH. Medical Research
Herskovic A, Martz K, Al-Sarraf M, et al. et al. Chemotherapy followed Council Oesophageal Cancer
Combined chemotherapy and by surgery compared with Working Party: Surgical resection with
radiotherapy compared with surgery alone for localized or without preoperative
radiotherapy alone in patients with esophageal cancer. N Engl J Med chemotherapy in oesophageal cancer:
cancer of the esophagus. N Engl J Med 1998;339:197984. a randomised controlled
1992;326:15938. trial. Lancet 2002;359:172733.
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Walter and Millers Textbook of Radiotherapy
416
Chapter | 25 |
Tumours of the thorax
Alison Armour
Diagnosis
Non-small cell lung cancer (NSCLC)
Patients presenting with the above symptoms require
a chest x-ray. A lateral view may be helpful. A computed Staging
tomography (CT) scan of the chest and upper abdomen is The NSCLC Staging system (Table 25.2) is based on the
recommended before bronchoscopy as peripheral tumours TNM (tumour, node, metastases) method of staging and
will not be reached by bronchoscopy and, in these cases, a divides patients into prognostic groups for treatment.
CT-guided biopsy is required for histological diagnosis. The staging and survival of NSCLC (Table 25.3) illustrates
Magnetic resonance imaging (MRI) can be used to deter- the prognostic importance of the current staging system.
mine if there are direct invasion structures contraindicating
surgery but is not superior to CT in the detection of
mediastinal disease (Table 25.1). The management of NSCLC
Surgery
PET scanning Surgery offers the best chance of cure. Patients must be care-
Positron emission tomography (PET scanning) is not cur- fully selected, as incomplete excision is of no benefit.
rently widely used in the diagnosis and follow up of Patients must undergo extensive staging and, in practice,
418
Chapter | 25 | Tumours of the thorax
419
Walter and Millers Textbook of Radiotherapy
0 Ca in situ
IV Any M1 1 Palliative
OPERABLE CONTRAINDICATIONS
A mean lung dose of 1821 Gy is thought to give a low INDICATION SUGGESTED DOSE REGIMENS
risk of development of pneumonitis, whereas 2426 Gy
patients are more likely to develop acute pneumonitis. Radical postoperative 50 Gy 2023 fractions given in
V20, the volume of both lungs receiving more than dose 45 weeks
20 Gy, is probably the most reliable predictor at present
Radical radiotherapy 55 Gy 20 fractions given in
and it is suggested that this value be less than 32% to avoid
4 weeks
grade 3 or more pneumonitis. 60 Gy 30 fractions given in
The spinal cord should receive no more than 4044 Gy 6 weeks
depending on fraction size. Twelve centimeters of
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Chapter | 25 | Tumours of the thorax
Acute reactions
General fatigue and oesophagitis are common. Oeophagi-
tis should respond to simple analgesics and antacids and
should settle within 4 weeks of treatment.
Late reactions
Acute pneumonitis occurs in 10% of cases and is the most
common and serious complication of radical treatment.
Patients present with dry cough, fever and shortness of
breath. A chest x-ray may show a hazy appearance, usually
in the treated area. Therapy should be oxygen, antibiotics
and high dose steroids (prednisolone 60 mg per day).
Occasionally Lhermittes sign (an electric shock sensation
when flexing the neck) is seen. Pulmonary fibrosis, esoph-
ageal stricture and pericardial effusion are seen in the lon- Figure 25.8 Palliative radiotherapy.
ger term.
Brain metastases
Palliative radiotherapy Patients aged less than 60, with good performance status
The volume of a treatment field is determined by the site of and controlled extracranial disease should receive whole
the tumour and disease extent but the dose for palliative brain radiotherapy, 20 Gy in five fractions.
treatment was established by a series of MRC trials pub- Patients with isolated, accessible, single brain metas-
lished between 1991 and 1996. tases and controlled extracranial disease should be
Table 25.7 demonstrates the effectiveness of palliative considered for surgical resection or radiosurgery on an
radiotherapy for the common symptoms of lung cancer. individual patient basis. This is usually followed by whole
Palliative treatments should be simple and effective. The brain radiotherapy (30 Gy in 10 fractions) (Figure 25.9).
treatment field should include the gross tumour volume
and drainage nodal groups. Contralateral paratracheal
Chest retreatment
nodal involvement has been found in 2545% of tumours.
Treatment is a parallel pair (average size 10 12 cm) Retreatment of patients having had palliative radiotherapy
(Figure 25.8). can be considered on an individual patient basis if the
Good performance status patients not suitable for patient has had a previous response to radiotherapy and
neoadjuvant chemotherapy may benefit from 39 Gy in it is more than 6 months from the initial treatment
13 fractions. This dose exceeds cord tolerance so many cen- (Table 25.8).
tres apply cord shielding to the posterior field once cord
tolerance is reached.
Bone metastases
Bone pain and pathological fracture are common
complications of lung cancer. Pain can be controlled
by an 8 Gy single fraction delivered in a parallel pair or
direct field.
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Walter and Millers Textbook of Radiotherapy
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Chapter | 25 | Tumours of the thorax
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Walter and Millers Textbook of Radiotherapy
Limited 80 60 14 20
Extensive 60 23 8 <5
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Chapter | 25 | Tumours of the thorax
the temporal lobes and cribiform plate are included in the retrospective studies suggest that these patients may do well
treated volume. Both fields are irradiated daily. The dose is if standard chemotherapy and radiotherapy follow treat-
prescribed to the midpoint intersection of both beams ment. There is no evidence that patients with more
(ICRU 50). advanced disease, T3 or N2 benefit from surgical treatment.
Dose
Mesothelioma
The optimum dose of PCI is not known. Evidence suggests
that a doseresponse relationship probably does exist. The Mesothelioma is a malignant tumour of the pleura and the
UK/EORTC trial compared three arms, no PCI versus 24 Gy majority of cases are caused by exposure to asbestos.
versus 36 Gy. Three hundred and fourteen patients were There are two main types of asbestos fibres: serpentiles
recruited from 1987 t0 1995. No difference in local control (white asbestos) and amphiboles (blue asbestos). White asbes-
rates was found between those patients that received tos fibres are pliable, curly and easily broken down in the lung
no PCI or only 24 Gy. There was, however, a difference releasing magnesium, iron and silica. About 90% of industry
between the no treatment group and those that received used this type and, fortunately, it is rarely associated with meso-
36 Gy; 24 Gy in 2 Gy fractions is probably insufficient thelioma. Blue asbestos fibres, however, are rigid and non-
but 24 Gy given in 3 Gy fractions is more effective. It is pos- pliable. Lung phagocytes repeatedly attempt to breakdown
sible that higher doses per fraction produce better local these fibres and eliminate them. It is thought that this chronic
control. However, retrospective studies suggest that CNS inflammatory response leads to eventual mesothelial cell pro-
damage will occur with doses greater than 30 Gy given in liferation, mutation and malignancy. This may explain the
fractions of 3 Gy or greater. Therefore, doses greater than long latency period of 2040 years from first exposure to asbes-
30 Gy should be given in fractions less than 3 Gy. tos and development of this tumour. It may also explain why
even a short period of exposure can result in mesothelioma.
Toxicity Asbestos was commonly used for insulation in buildings
Common acute side effects are headache, tiredness, nausea, and homes, building ships, and car parts. It is estimated
and reversible alopecia. These can be treated with steroids that the risk of development of this disease is greatest in
or other antiemetics. About 810 weeks post-irradiation, men born around 194550, of whom, it is anticipated that
somnolence is common and anorexia, sleepiness and leth- 1 in 150 will die of mesothelioma.
argy are common complaints. These are self-limiting, how- In Turkey, there is a high incidence of mesothelioma. At
ever, and do not predict late neurotoxicity. Patients with first this was thought to be due to asbestos like mineral fibres
SCLC have a limited life span so the true incidence of late in the soil. However, these non-asbestos related tumours are
neurological damage is not known. hereditary in nature and have been found to be associated
with carriage of an autosomal dominant gene.
Timing of PCI
The optimum timing of PCI is unknown. Radiotherapy may
cause disruption of the bloodbrain barrier and can poten- Natural history
tiate the neurotoxic effects of chemotherapy drugs. Most Clinically, it is a very heterogeneous disease, but the major-
clinicians now administer this after chemotherapy. PCI must ity of patients will progress rapidly and succumb to their
be completed within 6 months of diagnosis to be of benefit. illness within 8 months but others may remain stable for
some time without any clinical intervention.
Safety Patients initially present with a pleural effusion but, in the
Small retrospective studies led to concern about the inci- later stages of the illness, the tumour encases, constricts and
dence of neuropsychological sequelae in patients treated focally invades the underlying lung causing increasing pain
with both chemotherapy and PCI. and dysponea (Figure 25.10). Despite this, symptoms of
However, two large trials incorporated an assessment of superior vena cava obstruction and dysphagia are uncom-
neurological function as part of follow up and found no mon. Similarly, metastases are common at post-mortem
difference between those patients who received PCI and but rarely clinically relevant unless surgery or a prolonged
those that did not. natural history alters the natural history of the disease.
These studies have shown no loss of neurocognitive Prognostic groups are based on the following factors:
function or neurological deficit following PCI. However, patient age, sex, weight loss and performance status,
40% of patients had some degree of cognitive impairment tumour histology and clinical stage, values of haemoglo-
after chemotherapy but this was not worsened by PCI. bin, leukocyte (>8.3 109/L) and platelet count (>400
109/L) at presentation.
The role of surgery Computed tomography with magnetic resonance imag-
Less than 10% of patients have stage one (T1, T2) disease ing in selected cases often allows a fair approximation of
and, occasionally, these patients have surgical resection clinical stage and PET scanning may prove to be of addi-
to remove an undiagnosed pulmonary nodule. Small tional value.
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Walter and Millers Textbook of Radiotherapy
Palliative radiotherapy
Radiation therapy is also performed to control pain. Irradi-
ation is effective when pain is caused by a direct extension
of the tumour into the chest wall and ribs. Conversely, it is
Figure 25.10 Mesothelioma on CT. not effective and may even be harmful if pain originates
from compression of the intercostal nerve as a result of
Several different staging systems exist with no general retraction of the chest wall. Post-radiation fibrosis can
consensus on use. The Butchart staging system is the sim- aggravate pain in these cases.
plest (Table 25.14). The IMIG staging system is more
detailed, based on TNM (Table 25.15). The disadvantage Postoperative adjuvant radiotherapy
of these systems is that they are surgically based requiring At present, this treatment should not be considered out-
information about surgical resection margins and lymph with the context of a clinical trial. The challenges are mul-
node involvement when the majority of patients are tiple. The clinical target volume involves the entire
technically irresectable (Table 25.16). hemithorax and mediastinum. It includes the full thickness
of the chest wall at the incision sites. This area is sur-
Radiotherapy rounded by radiosensitive critical normal structures, e.g.
the remaining contralateral lung, spinal cord, liver, spleen,
Indications for the role of radiotherapy in mesothelioma
kidney and intestine. The challenges of delivering a radical
are:
dose around an empty air-filled cavity and the need for cor-
prophylaxis drain site recurrence rection factors should also be considered.
palliation of pain and shrinkage of chest wall masses Usually, a mixture of photon beams and electrons is used
postoperative in combined modality. to deliver a dose of 5055 Gy to the resected area plus a mar-
Mesothelioma has the ability to track out from the chest wall gin to include other areas that may include tumour. Occa-
resulting in painful subcutaneous nodules. If radiotherapy is sionally, small sites are boosted to 60 Gy. This treatment is
applied to the drain site area within 4 weeks, it alters the still experimental, intensity modulated radiotherapy (IMRT)
capillaries and stroma in this area making an unfavorable techniques are being developed and each plan should be
environment for tumour cells to embed and proliferate. carefully tailored to the individual clinical situation.
1 Tumour confined within the parietal pleura: ipsilateral pleura, lung, pericardium or Localized 16 months
diaphragm
2 Tumour invades chest wall, mediastinal structures plus N1 or N2 nodes Advanced 5 months
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Chapter | 25 | Tumours of the thorax
TUMOUR DESCRIPTION
(T)
T1b T1a but scattered foci of tumour involving the visceral pleura
T2 Tumour involving ipsilateral pleura (parietal, mediastinal, diaphragmatic and visceral) with at least one of the
following features:
involvement of the diaphragmatic muscle
confluent visceral pleural tumour (including the fissures) or
extension of tumour from visceral pleura into the underlying pulmonary parenchyma
T3 Locally advanced but potentially resectable tumour. Tumour involving all of the ipsilateral pleural surfaces with
at least one of the following:
involvement of endothoracic fascia
extension into mediastinal fat
solitary, completely resectable focus of tumour extending into soft tissues of the chest wall, non-transmural
involvement of the pericardium
T4 Locally advanced technically unresectable tumour. Involves all the ipsilateral pleural surfaces with at least one of
the following:
diffuse extension or multifocal masses of tumour in the chest wall with or without associated
rib destruction
direct trans-diaphragmatic extension of tumour to the peritoneum
through to the contralateral pleura
direct extension of tumour to one or more mediastinal organs
direct extension of tumour into the spine
tumour extending through to the internal surface of the pericardium with or without a pericardial effusion or
tumour involving the myocardium
N2 Subcarinal or ipsilateral mediastinal lymph nodes including the ipsilateral internal mammary nodes
MO No distant metastases
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Walter and Millers Textbook of Radiotherapy
Symptoms CONCLUSION
Thymoma can present as an incidental finding on x-ray but,
most commonly, presents in middle-aged females with Radiation therapy remains an effective modality in the treat-
symptoms secondary to compression or invasion of media- ment of thoracic tumours. Radical treatment can be delivered
stinal structures. Spread occurs via the lymphatics or by to surgically inaccessible sites, delivered postoperatively or as
428
Chapter | 25 | Tumours of the thorax
part of multimodality therapy. In addition, the technical For many patients, however, radiation provides effective
problem of treating an often-moving target surrounded by palliation from the symptoms of advanced cancers and, for
radiosensitive critical normal tissues remains challenging the majority of patients, it will be the only cancer therapy
for the clinical oncologist in the 21st century. they receive.
FURTHER READING
Mountain CF. Revisions in the lung cancer and good performance Gregor A, Cull A, Stephens R, et al.
international system for staging lung status. Clin Oncol 1996;8:16775. Prophylactic cranial irradiation is
cancer. Chest 1997;111:17107. Pignon JP, Arriagada R, Ihde DC, et al. Effect indicated following complete
Medical Research Council Lung Cancer of thoracic radiotherapy on mortality in response to induction therapy in small
Working Party. Inoperable non-small limited small cell lung cancer. A meta- cell lung cancer: results of a
cell (NSCLC): a Medical Research analysis of 13 randomised trials among multicentre randomised trial. Eur J
Council randomised trial of palliative 2,140 patients. N Engl J Med 1992;327: Cancer 1997;33:17528.
radiotherapy with two fractions or ten 161824. PORT Meta-analysis Trialists Group. Post
fractions. Br J Cancer 1991;63:26570. Turrisi A, Sherman CA. The treatment of operative radiotherapy for radically
Medical Research Council Lung Cancer limited small cell lung cancer: a report of resected N2 non-small cell lung
Working Party. A Medical Research the progress made and future prospects. cancer: systematic review and meta-
Council (MRC) randomised trial of Eur J Cancer 2002;38:27991. analysis of individual patient data
palliative radiotherapy with two Auperin A, Arriagada R, Pignon J-P, et al. from nine randomised controlled
fractions or a single fraction in patients Prophylactic cranial irradiation for trails. Lancet 1998;352:25763.
with inoperable non-small cell lung patients with small-cell lung cancer Wiggins J. Statement on malignant
cancer (NSCLC) and poor performance in complete remission. N Engl J Med mesothelioma in the
status. Br J Cancer 1992;65:93454. 1999;341:47684. United Kingdom. Thorax
Medical Research Council Lung Cancer Arriagada R, Le Chevalier T, Borie F, et al. 2001;56:25065.
Working Party . Randomised trial of Prophylactic cranial irradiation for Ramalingham S, Belani C. Systemic
palliative two-fraction versus more patients with small cell lung cancer in chemotherapy for advanced non-
intensive 13-fraction radiotherapy for complete remission. J Natl Cancer Inst small cell lung cancer: recent advances
patients with inoperable non-small cell 1995;87:18390. and future directions. The Oncologist
2008;(Suppl):513.
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Walter and Millers Textbook of Radiotherapy
Figure evolve 25.2 Planning target Figure evolve 25.4 Two-field plan for Figure evolve 25.6 Three-dimensional
volume peripheral tumour view of beams for peripheral tumour
Figure evolve 25.3 Three-field plan Figure evolve 25.5 Three-dimensional Figure evolve 25.7 Dose volume
applied to volume plan for peripheral tumour histogram: whole lung peripheral
tumour
430
Chapter | 26 |
Breast cancer
Ian Kunkler
ANATOMY
B
Most of the breast tissue extends from the edge of the ster- Figure 26.1 (A) The lymph nodes of the axilla. (B) Diagram of
num to the anterior axillary line and from the second or the principal pathways of lymphatic drainage of the breast.
third to the sixth or seventh costal edge. It overlies the sec- These follow the venous drainage of the breast to the axilla
ond to the sixth ribs. Breast tissue can be found beyond and to the internal mammary chain.
these areas as high as the clavicle and laterally to the edge (Reproduced with permission from Ellis, Clinical Anatomy, 5th edn,
of the latissimus dorsi muscle. Blackwells, 1975)
432
Chapter | 26 | Breast cancer
countries and low but rising in less developed countries Low risk polymorphisms
and in Japan. The risk of a woman developing the disease Much of the risk of breast cancer may be conferred by low
at some stage of her life is 1 in 12. The UK has the highest risk polymorphisms. Most of the polymorphisms relate to
age standardized incidence and mortality for breast cancer the alteration of the metabolism of steroid hormones or
in the world. carcinogenic compounds.
Female breast cancer is rare below the age of 30. The inci-
dence rises rapidly during the reproductive years. After the Acquired
age of 50, the incidence rises at a lower rate. The cumulative
incidence in women in Europe and North America is Benign breast disease
approximately 2.7% by the age of 55, 5% by the age of A number of benign conditions (e.g. fibroadenomas, pal-
65 and 7.7% by the age of 75. Male breast cancer is rare, pable cysts) in the breast increase the risk of breast cancer,
accounting for only 1% of breast cancer. although the effect is small. Overall, the risk of breast can-
Encouragingly, the mortality of breast cancer is declining cer is raised by a factor of 1.53 for women with previous
in the UK and USA and in much of western Europe. How- benign breast disease.
ever, the mortality from breast cancer in central and eastern
Europe and SE Asia continues to climb. Menstruation
The epithelium of the breast proliferates during ovulatory
cycles. This may be due to the stimulus of either proges-
Aetiology terone or oestrogen. This causes temporary growth of the
The aetiology of breast cancer is not fully understood, but a milk-secreting glandular tissue in preparation for possible
number of predisposing factors have been identified. pregnancy. If the menarche starts before the age of 12,
the risk of breast cancer is nearly double that of women
who begin to menstruate after the age of 13.
Genetic factors If menstruation continues above the age of 55, the risk of
High-risk mutations breast cancer is doubled compared with a normal meno-
It is estimated that up to 10% of breast cancers have pause at 45 years. Early menarche and late menopause
a genetic basis. The sisters and daughters of a woman with almost certainly confer an increased risk of breast cancer
breast cancer have a threefold increased risk of developing by prolonging the period in which both breasts are exposed
the disease. The risk of breast cancer for a woman to high levels of oestradiol (and possibly progesterone).
whose sister is affected is doubled. Women who have a
first-degree relative with premenopausal or bilateral Oral contraceptive pill and hormonal
breast cancer are at particularly high risk. At least five replacement therapy
germline mutations predispose to breast cancer. These The role of the ovarian oestrogens in the genesis of breast
include mutations in BRCA1, BRCA2, p53, PTEN and cancer is strongly suspected. Oral contraceptives suppress
ATM. BRCA1 and BRCA2 mutations confer the highest the production of oestradiol and progesterone. Reductions
level of risk of breast cancer and also predispose to ovarian in oestrogen levels may protect against breast cancer. Oral
cancer. Germline mutations in p53 give rise to the Li Frau- oestrogens, either as the contraceptive pill or as hormone
meni syndrome (childhood sarcomas, brain tumours and replacement therapy, may accelerate the development of
early onset breast cancer) and mutations in PTEN to Cow- breast cancer.
dens disease.
The mode of inheritance is usually autosomal dominant Pregnancy
with incomplete penetrance. It is important to note that the The risk of breast cancer in a woman rises with her age at
genetic susceptibility can be passed on by both males and first pregnancy. It is three times higher in women who have
females. Most cases of breast cancer with a genetic basis will their first baby over the age of 30, compared with those
have occurred by the age of 65. Those at substantial risk under the age of 18.
include women with:
three first- or second-degree relatives with breast or Lactation
ovarian cancer Women who have breast-fed their children are slightly less
one first-degree relative with bilateral breast cancer prone to breast cancer.
two first- or second-degree relatives with breast cancer
diagnosed under the age of 60 or ovarian cancer at any Age at first full-term pregnancy
age on the same side of the family. Pregnancy itself seems to have a protective role. Women
(First-degree relatives are mother, sister or daughter. Second- who first become pregnant before the age of 30 have a
degree relatives are grandmother, granddaughter, aunt or lower risk of breast cancer than women who first give birth
niece.) after the age of 30.
433
Walter and Millers Textbook of Radiotherapy
Diet and life style dose and incidence of breast cancer up to 4 Gy. Beyond this
Nutrition and lifestyle may be principally responsible for the incidence plateaus. It has been calculated that one extra
large variations in breast cancer between countries and cancer per year after 10 years may be caused by radiation
marked changes in these rates between migrating popula- from a single mammogram among 2 million women over
tions. Asian women, for example, experience much higher the age of 50. The risk of breast cancer is well validated for
rates of breast cancer after moving to the USA. women irradiated under the age of 40 with a relative risk of
The diet in the western hemisphere is dominated by fried 1.12.7 at 1 Gy. Women irradiated in their teenage years by
or grilled food whereas in the East boiled and steamed mantle radiotherapy for Hodgkins disease, where the
foods predominate. Dietary fat, whose effects are mediated mediastinal fields commonly treat the medial part of both
by oestrogens, is thought to be a key risk factor for breast breasts, have an increased risk of breast cancer by a factor of
cancer. An increased intake of calories, sugar, alcohol and 1 in 7 if aged 2029 when treated by mantle radiotherapy
saturated fats increases the risk of developing breast cancer. rising to 50% at the age of 50 for girls treated before 20.
Alcohol is known to increase the permeability of cell Children irradiated by the atomic bombs dropped on
membranes, so assisting the transport of carcinogens. It Nagasaki and Hiroshima showed an increased risk of breast
also induces the proliferation of mammary epithelia in ani- cancer with dose.
mal models. This results in higher serum concentrations of
estradiol in premenopausal women.
Ductal and lobular carcinoma-in-situ
Premalignant in situ carcinoma may occur confined to the
Vitamins and selenium lobules (lobular carcinoma-in-situ (LCIS)) or ducts (ductal
Derivatives of vitamins A (alpha-carotene, beta-carotene, carcinoma-in-situ (DCIS)) without evidence of penetration
retinol), B and E (tocopherol) and selenium are thought on light microscopy of the basement membrane. DCIS
to act as free radical scavengers. They protect lipids from occurs in 25% of breast cancers. With the advent of breast
peroxidation by free radicals and are involved in DNA repair. screening, the diagnosis of DCIS has increased three to four
However, prospective studies have not shown that these times and now accounts for 15% of cases detected by mam-
substances reduce the risk of developing breast cancer. mography. Ninety percent of DCIS is confined to one seg-
ment of the breast. DCIS is a heterogeneous disease based
Physical exercise on histology, genetic alterations and clinical course. Inacti-
Physical exercise also appears to have a protective effect vation of the tumour suppression gene, e-cadherin, is asso-
against breast cancer. This is probably due to non-specific ciated with the development of LCIS. Loss of the tumour
immune stimulation and reduced oestrogen levels during suppressor gene, p53, is associated with the development
recovery. A reduction in risk has been found in women of poorly differentiated DCIS. Most of the genetic altera-
between the ages of 30 and 35. However, the effect only tions seen in DCIS are also seen in invasive cancer which
becomes significant with at least 6 hours a week of moder- often accompanies DCIS. Progression from DCIS to inva-
ate exercise. The reduction in risk is about 30% in such sive is associated with the same degree of differentiation
women compared to no exercise. (i.e. poorly differentiated DCIS tends to progress to poorly
differentiated invasive cancer).
Smoking Most cases present with non-palpable calficifications.
Most studies of smoking and the incidence of breast cancer Although mammography may detect over 80% of cases
show no strong association between these factors. of DCIS, it commonly underestimates the extent of the dis-
ease. Magnetic resonance imaging (MRI) is more effective
Metabolic factors at detecting multifocality. Core biopsy is able to establish
In premenopausal women, epidemiological studies have a diagnosis in 90% of screen-detected cases. DCIS is asso-
shown that the risk of breast cancer is associated with high ciated with a substantial risk of progression to invasive car-
levels of insulin-like growth factor (IGF-1), with high levels cinoma, with a mean delay of about 7 years. There are two
of testosterone and with luteal insufficiency (i.e. low pro- principal histological groups: comedo and non-comedo
gesterone levels). Some studies suggest an association of type. The most common non-comedo types are solid, crib-
breast cancer with high blood levels of insulin, glucose riform, papillary and micropapillary.
and triglycerides. LCIS is associated with an increased risk of tumour in
both breasts, particularly infiltrating ductal carcinoma.
Ionizing radiation
Histology
The breast is one of the tissues most sensitive to the induc-
tion of malignancy by ionizing radiation. Exposure to ion- A lump in the breast may be benign or malignant. Benign
izing radiation increases the risk of breast cancer. This is lesions include cysts, fibroadenomas and papillomas. Malig-
true of women who underwent low-dose breast irradiation nant tumours mainly arise from the glandular epithelium
for benign mastitis. There is a linear relationship between (adenocarcinomas). Breast cancers are classified as of no
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Chapter | 26 | Breast cancer
DIAGNOSIS
435
Walter and Millers Textbook of Radiotherapy
STAGING
Figure 26.4 MRI scan showing recurrent cancer in the breast. Table 26.2 Clinical staging of breast cancer
(Courtesy of Mr M. Dixon, Edinburgh Breast Unit)
STAGE CLINICAL FINDINGS
mammography and (b) recurrent disease in the irradiated
I Freely movable (on underlying muscle). No
breast 18 months or more after radiotherapy has been
suspicious nodes
completed. MRI may show 1030% additional invasive
cancer in patients presenting with a unifocal lesion. How- II As stage I but mobile axillary node(s) on the same
ever, MRI may lead to the overestimate of the size of lesions, side
potentially resulting in unnecessary mastectomies.
III Primary more extensive than stage I, e.g. skin
invaded wide of the primary mass or fixation to
Breast ultrasound muscle. Axillary nodes, if present, are fixed; or
Ultrasound of the breast has an important role in supraclavicular nodes involved
helping to distinguish benign from malignant lesions, par-
IV Extension beyond the ipsilateral chest wall area,
ticularly when mammography is normal or equivocal. e.g. opposite breast or axilla; or distant metastases
Malignant tumours tend to show an abnormal echo pattern
436
Chapter | 26 | Breast cancer
Primary tumour
Tis Carcinoma-in-situ
T1b Tumour more than 0.5 cm but not more than Figure 26.6 Nodular local recurrence on the skin flaps of a
1 cm in greatest dimension mastectomy scar.
T1c Tumour more than 1 cm but not more than 2 cm
in greatest dimension
N1 Mobile ipsilateral nodes (c) T02N0 disease with symptoms which could be due to
metastatic disease (e.g. unexplained bone pain or weight
N2 Fixed ipsilateral nodes, fixed to each other or to other loss), a liver ultrasound and a bone scan are recommended.
structures All patients with locally recurrent disease following mas-
N3 Ipsilateral internal mammary nodes tectomy (Figures 26.6 and 26.7) or breast-conserving ther-
apy, regional or metastatic recurrence require bone scan
Distant metastases and liver ultrasound in addition to full blood count, liver
function tests and chest radiograph.
M0 No distant metastases
437
Walter and Millers Textbook of Radiotherapy
Survival Probability
with necrosis, and high grade with or without necrosis. 0
0.6
Following conservative surgery and radiotherapy, the 13
10-year actuarial disease-free survival is 100% for a score 0.4 410
of 34, 77% for score 57 and 37% for a score of 89.
The rationale for mastectomy or whole breast irradiation 1120
0.2
as treatment for DCIS is related to the potential for multi- > 20
centric disease and/or the presence of occult invasive
0
cancer. Multifocal disease in the same quadrant is not 0 2 4 6 8 10 12
unusual in patients with DCIS. Following wide excision Time (year)
and negative margins, 2443% of patients will have resid-
ual DCIS in the same quadrant. Mastectomy remains the Figure 26.8 Survival by axillary node status.
(Reproduced with permission from Veronesi U (ed.) Baillieres Clinical
treatment of choice for multicentric DCIS and for large uni-
Oncology, 1988)
centric lesions. Recurrence rates after mastectomy are less
than 1%. Regular mammography of the contralateral breast
should be carried out, since there is an increased rate of con- 100
tralateral breast cancer of approximately 7 per 1000. If the
extent of the lesion is not more than 34 cm, then an 90
attempt at conservative surgery may be made, aiming to 1 cm
achieve complete excision. The margins of clearance should
be at least 1 cm. For patients with high-grade DCIS, postop- 80
Percentage survival
Prognostic factors Figure 26.9 Age-corrected survival rates by tumour size for
patients treated for breast cancer apparently confined to the
While there are a large number of biological prognostic breast.
factors for breast cancer, none has surpassed the value of (Reproduced from Halnan, Treatment of Cancer, Chapman & Hall, 1982)
assessing the number of histologically involved nodes and
tumour size. There is a direct correlation between number with increasing tumour grade. Five-year survival falls from
of involved nodes and survival (Figure 26.8). Ten-year sur- 80% for grade 1 to 25% for grade 3.
vival is about 4065% with one to three positive nodes, Endocrine therapy is based on blocking the effects of oes-
and 2042% for those with 10 or more positive nodes. trogen which stimulates tumour growth or inhibiting its pro-
Ten-year survival is about 6570% in women with negative duction. Oestrogen passes through the cell membrane and
nodes. By contrast, in excess of 50% of all women who are binds the oestrogen receptor (ER). ER alpha, one of the
axillary node positive die within 10 years despite treatment. two species of ER binding to ligand, leads to phosphoryla-
Within any category of nodal status, tumour size is an tion and transcription. Most of the oestrogen is sited in the
independent prognostic factor. The decline in survival with nucleus but some probably exists in the cell membrane
increasing size of the primary tumour is shown in where it may interact with growth factors. Activation of
Figure 26.9. Less than 30% of patients with stage IIIb dis- membrane ER by either oestrogen or tamoxifen and the
ease (T4) are alive at 10 years. Similarly, survival declines ensuing activation of growth factor signalling may be a cause
438
Chapter | 26 | Breast cancer
DF Survival Probability
apy and growth factor receptor-targeted therapy might 0.8
reverse tamoxifen resistance. The strategy is being tested in
clinical trials. Cross-talk between growth factor receptor path- 0.6
ways and ER might elucidate the relationship between pro- ER+/PgR+
gesterone receptor (PR) expression and response to a 0.4
variety of hormonal therapies. As a result of an active growth ER+/PgR
factor kinase cascade, the transcription of the PR gene may be 0.2
inhibited. Hence, in some tumours, PR negativity may be a ER/PgR
surrogate for active growth factor signalling. This would sug- 0
0 2 4 6 8 10 12
gest that ER-positive, PR-negative tumours would respond Time (years)
better to aromatase inhibition than to selective oestrogen
receptor modulators (SERMs), as in HER2-positive tumours. Figure 26.11 Disease-free survival by oestrogen and
Indeed, the ATAC trial showed better outcomes in PR-nega- progesterone receptor status in pathological stage II patients.
tive tumours with anastrozole than tamoxifen. There is accu- (Reproduced with permission from Baillieres Clinical Oncology, Inter-
mulating data that ER-positive, PR-negative tumours are a national Practice and Research, 1988)
discrete subset with a tendency to higher growth factor recep-
tor activity, relative resistance to SERMs and greater sensitivity Of the biological markers of prognosis including p53,
to aromatase inhibitors, such as anastrazole and letrozole. cathepsin D, epidermal growth factor receptor and
Oestrogen receptor status is predictive for disease-free HER2/neu, HER2/neu is the most reproducible. Patients
and overall survival. Irrespective of stage, ER positivity pre- overexpressing HER2/neu have a higher risk of recurrence
dicts for longer disease-free (Figure 26.10) and overall sur- and shorter survival. There is evidence that tumours that
vival. Higher recurrence and lower survival rates are found overexpress HER2/neu are relatively resistant to chemo-
in ER-negative patients. About 60% of ER-positive patients therapy with cyclophosphamide, methotrexate and 5-
will respond to hormonal manipulation. Progesterone fluorouracil (5-FU) (CMF) and have greater responsiveness
receptor (PgR) status may also help. Oestrogen stimulates to anthracyclines. In addition, different gene profiles may
PgR production in normal reproductive tissue and in be found for ER-positive and ER-negative patients.
human breast cancer cell lines. The highest response and
disease-free survival rate is seen in ER/PgR tumours. Gene profiling
Very few tumours are ER/PgR, consistent with the pro-
duction of progesterone receptors being dependent on oes- More recently, microarray based gene profiling has enabled
trogen synthesis. Lowest response and disease-free survival thousands of genes to be studied in a one tumour. A micro-
rates are seen in ER/PgR tumours (Figure 26.11). array consists of known and unknown DNA samples on a
solid slide (Figure 26.12). The probes may be cDNAs or oli-
gonucleotides of varying length. The sequence hybridized
1 to probes on the array can be fluorescently labelled. Expres-
sion signatures based on the expression level of large nun-
0.8
bers of genes can be determined reflecting the properties of
Survival Probability
0
0 2 4 6 8 10 12 TREATMENT OF EARLY BREAST
Time (years) CANCER
Figure 26.10 Survival by axillary node status and oestrogen
receptor status in 854 patients: 1 negative nodes ER; Mastectomy or breast conservation
2 negative nodes, ER; 3 positive nodes, ER; 4 positive
nodes ER. The decision as to whether to perform a mastectomy or
(Reproduced with permission from Baillieres Clinical Oncology, Inter- breast-conserving surgery should be discussed preoperatively
national Practice and Research, 1988) in a multidisciplinary clinic by surgeon and oncologist, once
439
Walter and Millers Textbook of Radiotherapy
0.8
Sensitive
0.6
0.4 Lobular cancer
Resistant
0.2
Some histological forms of breast cancer, typically lobular
0.0
0 2 4 6 8 10 cancer, are commonly multifocal but poorly imaged by
Overall survival (yr) mammography. If a core or excision biopsy of an appar-
Further validation in larger patient cohorts
ently localized tumour shows lobular carcinoma, an initial
wide local excision may be carried out. If the margins are
involved with invasive cancer or there is evidence of multi-
Mature diagnostic tool
focal disease histologically, then breast conservation is not
safe and mastectomy is advised.
Figure 26.12 Development of microarray based diagnostic
tests for cancer. Primary or metastatic tumours are
resected from patients; DNA microarray profiling is used to Reconstruction after mastectomy
obtain gene-expression profiles of the tumours. Next, Mastectomy is a mutilating operation but much can be
genome-computational and statistical analyses are used to achieved in remodeling the breast by a variety of recon-
identify gene-expression markers of responsiveness or structive techniques. Most patients should be offered the
resistance to chemotherapy; multiplex quantitative reverse
possibility of immediate breast construction.
transcriptase-polymerase chain reaction (RT-PCR) assays are
developed for the best markers, and these assays are
applied retrospectively or prospectively to formalin-fixed, Conservation therapy (limited surgery
paraffin-embedded tissue sections. On the basis of the results, and postoperative radiotherapy)
researchers develop diagnostic and predictive models that can
be validated in large cohorts of patients, resulting in a mature In patients with T1 and small T2 tumours (up to 3 cm), some
diagnostic tool. form of local surgery should be considered. The most popular
(Reproduced with permission of the New England Journal of Medicine) choice is a wide local excision to obtain clear histological
440
Chapter | 26 | Breast cancer
margins. This involves excision of the tumour with a margin is the most accurate. In most patients, the sentinel node is
of 12 cm. If the margins are found to be involved, a re-exci- in the axilla but, in a few medially placed tumours, it may
sion to clear the margins is recommended. If re-excision of the be in the internal mammary chain. The axilla is normally
margins still shows tumour at the margin, breast conservation explored to identify the sentinel node either by the blue col-
is not appropriate and a mastectomy is advised. our of the dye within it or by the high radioactivity
Alternatively, a more extensive local excision of the scintillation count over it. If the sentinel node biopsy is
whole quadrant affected in the breast (quadrantectomy) positive, the surgeon may proceed to a complete axillary
may be carried out. The advantage of quadrantectomy is dissection or refer the patient for axillary irradiation. In
that local recurrence rates (about 1% at 5 years when com- specialist centres, sentinel node biopsy has 97% accuracy.
bined with postoperative radiotherapy) are lower than after For patients with tumours >2 cm or with ipsilateral palpa-
wide local excision and radiotherapy (about 5% at 5 years). ble nodes (N1), a level III axillary clearance up to the level of
The disadvantage is that the cosmetic result is generally the medial end of the first rib is recommended. Normally,
poorer because of the asymmetry caused by the greater vol- there should be at least 10 axillary nodes in a level III clear-
ume of tissue removed. Quadrantectomy or a very wide ance and commonly 2030. The local control in the axilla
local excision may be considered in patients refusing or from a level III clearance is similar to a selective policy of axil-
not fit for mastectomy or breast radiotherapy. This may lary radiotherapy in patients with one or more involved
be advisable in some older patients where co-morbidity nodes on a four node lower axillary sample. With either pol-
may compromise suitability for mastectomy. Criteria for icy the axillary recurrence rate is similar, 5% at 5 years.
breast conservation are summarized in Table 26.4.
Morbidity of axillary treatment
Local recurrence after breast-conserving Side effects of an axillary clearance include postoperative
therapy seroma and numbness in the upper limb. Lymphoedema
occurs in 78% of cases. If axillary radiotherapy is added
The treatment of choice of local recurrence after radical to the dissection, the risk of lymphoedema is substantially
radiotherapy is a mastectomy. higher (between 30 and 40%).
After conventionally fractionated radiotherapy (e.g.
Management of the axilla 4550 Gy in 2025 fractions) to the axilla, the risk of lym-
phoedema is about 35%, i.e. lower than after axillary dis-
Some form of surgical procedure to obtain nodal histology section. However, there is an increased risk of long-term
is advised in all women with operable breast cancer. The restriction of shoulder movement and a small risk of
surgical management of the axilla remains controversial brachial plexopathy (1% or less). This is a rare but serious
and practice varies. For tumours 2 cm or less in diameter complication and is usually irreversible. Very careful atten-
where the risk of axillary nodal involvement is lower than tion to radiotherapy technique with avoidance of overlap
in larger tumours, a lower axillary node sample (of a mini- between axillary and breast/chest wall fields or moving the
mum of four nodes) or sentinel node biopsy is advised. patient between the treatment of these fields is essential.
Sentinel node biopsy avoids the morbidity of axilllary
dissection. The sentinel node is the node most likely Postoperative radiotherapy
to drain the primary tumour. It is identified first by the
injection of a vital blue dye or a radioactive tracer, or a After breast-conserving surgery
combination of both. The combination of both techniques In general, postoperative whole-breast irradiation should
be delivered following wide local excision or quadrantect-
omy as part of breast-conserving therapy. A number of
Table 26.4 Criteria for breast-conserving therapy
randomized trials comparing wide excision alone with
1. Tumours up to 3 cm appropriate systemic therapy have shown overall a fourfold
reduction in local recurrence from the addition of
2. Satisfactory cosmetic result anticipated whole breast irradiation (Table 26.5). There is much less
randomized data on the role of postoperative radiotherapy
3. Postoperative whole breast radiotherapy technically
in older patients, particularly over the age of 65, receiving
feasible
adjuvant endocrine therapy. This is currently being evalu-
4. Medically fit for surgery ated by the PRIME trial.
Despite the evidence from clinical trials of a reduction in
5. Clear histological margins at primary excision or re-excision local recurrence after postoperative radiotherapy after
6. Able to attend for regular clinical and mammographic
quadrantectomy or wide local excision, there is no evidence
follow up from published trials of a survival advantage from the addi-
tion of radiotherapy.
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Walter and Millers Textbook of Radiotherapy
Table 26.5 Results of randomized trials of breast-conserving surgery (BCS) with or without radiotherapy (RT)
100 80
Overall survival (%)
80 60
Overall survival (%)
Radiotherapy 45%
+ CMF (54%)
60 40
36%
40 CMF (45%) 20
20 0 P = 0.03
P < 0.001
1 2 3 4 5 6 7 8 9 10
0
0 Time since mastectomy (years)
0 1 2 3 4 5 6 7 8 9 10
Patients at risk
Years after mastectomy
Radiotherapy 686 580 469 398 285 175
Radiotherapy + CMF 852 755 641 555 392 188 + tamoxifen
CMF 856 738 587 494 329 183 Tamoxifen only 689 598 479 378 251 136
Figure 26.13 Survival in Danish Cooperative Group trials of Figure 26.14 Survival in Danish Cooperative Group trials of
locoregional radiotherapy after adjuvant CMF in high-risk locoregional radiotherapy after adjuvant tamoxifen in high-risk
premenopausal women. postmenopausal women.
(Reproduced with permission of the Editor from Overgaard et al., 1997; (Reproduced with permission from Elsevier Ltd from The Lancet, 1999;
New England Journal of Medicine, 337: 949955) 353: 1642)
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Chapter | 26 | Breast cancer
postmenopausal women receiving locoregional regional of overlap of chest wall/breast with fields to the peripheral
irradiation in addition to adjuvant tamoxifen. However, lymphatics, and minimizing dosage to critical structures
the survival advantage of the benefits of radiotherapy (lung, heart and the brachial plexus).
only emerged late (i.e. at 10 years). In both the Danish This is not an easy task because of the variation in shape
and Canadian trials, all of the peripheral lymphatics (axilla, and thickness of the chest wall and breast in the craniocaudal
supraclavicular and internal mammary chain) were irra- and transverse planes. In addition, the sternum slopes when
diated. It is not clear whether irradiation of all of these areas, the patient is lying flat. The proximity of the lung to the target
particularly the internal mammary chain is essential. A trial volume means that some lung is commonly irradiated. As a
of the EORTC (European Organisation for Research and result, with conventional wedged tangential fields, it is diffi-
Treatment of Cancer) is evaluating the role of internal mam- cult to reduce the variation in dose distribution across the
mary irradiation. The radiotherapy technique in the Danish volume to the 5% that is achievable by radical radiother-
trial (see Figure 26.14) differed from the use of a pair of apy at other tumour sites. Dose variation across the target
tangential fields in most UK centres to treat the chest wall. volume may vary by up to 20%. Dose inhomogeneity is
A combination of electron beam with limited penetration exacerbated by lung effects due to scatter and lung transmis-
beyond the chest wall was used to treat the medial part of sion. The aim should be to achieve a variation between the
the chest wall and matched with a photon field to treat maximum and minimum dose of better than 15%.
the lateral half of the chest wall. Ten-year follow-up data
showed no excess of cardiac morbidity or mortality in the CT simulation
radiotherapy systemic therapy group compared to those
Conventionally, in UK centres, most adjuvant irradiation
receiving systemic therapy alone. The results of the Danish
has been planned without the benefit of CT planning or
trial emphasize the importance of good radiotherapy tech-
with only a single or limited number of CT slices.
nique in minimizing the dose to the heart.
Full CT scanning of the breast allows better selection of
Indications for postmastectomy radiotherapy beam arrangements to minimize cardiac and pulmonary
irradiation. This may require the patient to be planned with
International consensus supports the routine use of post-
the ipsilateral arm abducted behind the head or with both
mastectomy radiotherapy for patients who have a 20% or
hands holding a bar in front of the patient in order to fit
more risk of locoregional recurrence:
into the bore of most CT scanners.
1. tumours greater than 5 cm in diameter More recently, intensity modulated radiotherapy (IMRT)
2. four or more histologically involved axillary nodes. has become available to provide a more even distribution
In addition radiotherapy is indicated for: of radiation dose across the breast/chest wall while reducing
3. close or involved surgical margins unwanted irradiation of critical organs such as the lung and
4. chest wall recurrence following mastectomy. heart. IMRT allows the fluence intensity to be varied across
the beam. Virtual simulation, which incorporates a laser
Cumulatively, greater probability of local recurrence is con- positioning system and a CT scanner and treatment planning
ferred with the following risk factors: system, has replaced simulation in many centres. Constraints
1. axillary nodal involvement may be put on doses to critical organs and to the breast and
2. grade 3 histology chest wall. It has been shown that IMRT can reduce by 35%
3. lymphatic/vascular invasion. the dose to the top and bottom of the breast, where hot spots
How these factors should be weighted in the selection of commonly occur with conventional wedged fields using
patients for postmastectomy radiotherapy is not clear. It 2D planning. Despite the better target coverage and
is known that the risk of local recurrence increases with reduced cardiac dosage from 3-dimensional planning over
the cumulative number of risk factors (high tumour grade, 2-D planning, the normal tissue complication probability
nodal involvment and lymphovascular invasion). In the (NTCP) for lung may increase.
absence of definitive data, a reasonable policy is to offer
radiotherapy to patients with two or more of these factors. Respiratory gated radiotherapy
The role of postmastectomy radiotherapy in the group with One of the most promising techniques to reduce cardiac
one to three involved axillary nodes or negative with other and lung irradiation is active breathing control in which
risk factors, such grade 3 histology and lymphovascular there is computer controlled temporary suspension of
invasion, is unclear and is being evaluated by the interna- breathing in a reproducible cycle.
tional SUPREMO trial (BIG 2-04). Following respiratory training, the patient is positioned
in a CT scanner without immobilization (Figure 26.15).
Target volume and techniques for locoregional Radiotherapy is delivered in maximal deep inspiration
irradiation when the heart is maximally displaced posteriorly away
In choosing a technique, guiding principles should be from the treatment beams (Figure 26.16). The lung volume
homogeneous irradiation of the target areas, avoidance irradiated is also reduced.
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Walter and Millers Textbook of Radiotherapy
C D
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Chapter | 26 | Breast cancer
For the large or very mobile breast, some additional form fractionation are within cord tolerance. The lower border
of immobilization (shell or sling) is needed. The very of the shoulder field should be non-divergent to avoid
mobile breast tends to fall laterally, moving the posterior overlap with the tangential fields.
beam edge further back than the midaxillary point and The axillary and supraclavicular nodes are commonly
increasing the volume of lung irradiated. The immobilizing at the same depth and, therefore, a single anterior field
device will bring the breast medially and reduce the volume may suffice. Some centres use a small direct posterior field
of lung irradiated. (posterior axillary boost) to supplement the dose to the
Separate fields (Figure 26.18) are planned to cover: (1) axillary nodes. The given dose to the posterior axilla
supraclavicular fossa, axilla and, if desired, the upper inter- is calculated to bring the mid-axilla to the prescribed
nal mammary chain and (2) chest wall/breast. Whether it dose. With 6 MV photons, roughly 80% of the prescribed
is necessary to irradiate the internal mammary chain is still midaxillary dose is delivered from the anterior field and
controversial and most UK oncologists do not attempt to 20% from the posterior field. The posterior field is often
include it in the target volume. If the internal mammary treated on alternate days unless the mid-axillary separation
nodes are to be irradiated, it is best to use a direct anterior exceeds 20 cm.
field using a mixture of photons and electrons of appropriate
energy to cover them. Individualized CT planning is needed Supraclavicular field
to ensure adequate coverage while limiting transmitted dos- Where the axillary clearance shows the nodes to be invo-
age to the underlying heart and lungs. Trying to include the lved, irradiation of the ipsilateral supraclavicular nodes
internal mammary nodes within tangential fields is not should be considered. A threshold of at least four involved
recommended because of the greater risks of pneumonitis nodes is commonly adopted for medial supraclavicular
from the larger volume of lung irradiated and the uncer- irradiation. If the axilla is to be cleared, the surgeon
tainty of adequate coverage. A computer plan of the dose dis- should be asked to place metal clips up to the medial extent
tribution over the breast or chest wall should be derived of the axillary dissection to ensure that the lateral margin of
from a CT-derived outline through the central plane. the supraclavicular field abuts on, but does not overlap, the
Three-dimensional treatment planning, which gives a field of the axillary clearance. The superior border of
greater appreciation of dose delivered to the heart and lung, the supraclavicular field is the cricothyroid notch. The infe-
is to be encouraged. In addition, it gives a greater apprecia- rior border is the lower border of the clavicular head.
tion of the extent of breast tissue, often extending beyond
anatomical landmarks used for 2-dimensional planning. Chest wall and breast
The chest wall or breast is treated isocentrically and can
Shoulder field
normally be encompassed in a pair of wedged tangential
A direct anterior megavoltage field (see Figure 26.18) cov- fields (Figure 26.19) keeping the posterior beam edges par-
ers the supraclavicular fossa and axilla. The upper margin allel to minimize divergence into the lung. This should cover
should be at the level of the thyrohyoid groove. The lateral the scar of local excision or of the mastectomy. It normally
margin should encompass the lateral border of the axilla. extends from the level of the second costal cartilage down to
The length of the shoulder field should rarely exceed 12 cm below the inframammary fold. The medial margin is
10 cm, since the volume of lung irradiated rises as the lower the midline. The lateral margin is normally the mid-axillary
edge of the treatment volume is extended inferiorly. This line. Occasionally, the lateral margin may be slightly more
increases the risk of pneumonitis.
The shoulder joint and the part of the larynx within the
field should be shielded by lead blocks. Some centres angle
the shoulder field 15 degrees to exclude the spinal cord,
although this is not essential as long as the dosage and
match
plane 1
3 2
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Walter and Millers Textbook of Radiotherapy
ANT
posterior in the conserved breast for a laterally placed the chest wall, either for the whole or part of the course
tumour or if the mastectomy scar extends beyond this point. of radiotherapy. It is not clear which approach is optimal.
Some compromise is necessary in defining these field mar-
gins, balancing adequate coverage of the target volume with Field matching
the need to avoid excessive lung irradiation. A typical dose One of the main challenges in breast/chest wall planning
distribution in the breast is shown in Figure 26.20. is to match the tangential fields to the shoulder field.
Immobilization should minimize movement between the
Internal mammary node irradiation treatment of fields to avoid the risk of overdosage or under-
The internal mammary chain (IMC) lies deep to the mid- dosage at the junction. Fields may be matched using the
line and about 23 cm to each side of the midline. If the light beam and lasers by eye using couch rotation (usually
internal mammary nodes are to be irradiated, a separate 56 degrees) and some collimator rotation. Alternatively,
direct electron internal mammary field should be used. one can use:
This will need to cross the midline. It will result in a cold
1. a half beam block (Figure 26.21A) to counteract beam
spot beneath the match line with the photon field. Rotation
divergence, allowing the field edges to be abutted.
of the electron beam so that it lies parallel to the photon
Asymmetric jaws facilitate this. The match plane can be
beam to eliminate the area of underdosage should be
vertical (Figure 26.21B) or angled (Figure 26.21C)
avoided So doing will increase the volume of lung irra-
2. a vertical hanging block
diated and risk of pneumonitis significantly.
3. a single isocentre with blocks, avoiding the need for
couch movement between fields.
Limitation of lung volume irradiated
At the time of simulation, the thickness of lung encom- Dosimetry
passed in the tangential fields should be measured (the cen- Planning is normally on a single CT slice. However, multi-
tral lung distance perpendicularly from the inner aspect of slice CT scanning of the breast gives a better appreciation of
the chest wall to the posterior beam edge). The central lung the volume of lung and heart irradiated. 6 MV photons are
distance should not exceed 3 cm. If it exceeds 3 cm, consid- adequate for most patients. Wedges are needed to compen-
eration should be given to bringing the medial and/or lat- sate for missing tissue. Lung transmission increases the
eral margins of the fields inwards, as long as this does not dose to the posterior breast. A correction factor of 10%
involve skimping on the coverage of the wide excision or may be needed. Variations in depth dose across the breast
mastectomy scars. To avoid divergence into the lung, the may be 20%, particularly in larger breasts. Build-up to
posterior beam edges should be kept parallel. 100% is 510 mm from the skin surface for 6 MV photons.
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Chapter | 26 | Breast cancer
Supraclavicular
Match plane
Tangential fields
A B
B A
C D
Figure 26.21 Matching fields in a breast treatment. (A) Using a rotated half beam block to counteract beam divergence between
cervico-axillary and breast fields. (B) Lead block to trim superior edge of the tangential fields to form a vertical match plane. (C) Match
plane vertical on an inclined breast board. (D) Match plane angled in supine position.
(Reproduced with permission of the Editor of the British Journal of Radiology, 1984, 57: 737)
adopted under the influence of Professor Gilbert Fletcher of with fraction sizes of 2.252.67 Gy were used delivering
the MD Anderson Hospital in Texas. For much of North 45 Gy in 20 daily fractions over a month or 40 Gy in 15
America and continental Europe, 50 Gy in 25 fractions over fractions over 3 weeks.
5 weeks is the international standard for postoperative Clinical trials, Table 26.6 such as the UK START trial based
locoregional radiotherapy. In the UK, shorter regimens on radiobiological modeling, have compared the impact of
447
Walter and Millers Textbook of Radiotherapy
448
Chapter | 26 | Breast cancer
Table 26.7 Local control and overall survival in randomized trials of boost irradiation after whole breast radiotherapy
50 Gy/2t5fr/5 wks
boost 10 Gy/5fr/1 wk
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Walter and Millers Textbook of Radiotherapy
Intraoperative radiotherapy (IORT) treated by local excision alone will develop a second local
recurrence. For multiple spot recurrences this is unlikely to
Intraoperative radiotherapy (IORT) can be delivered by
be practical. Radical radiotherapy (4050 Gy convention-
photons or electrons. A mobile linear accelerator can be
ally fractionated) to the chest wall and the supraclavicular
used in the operating theatre to deliver electrons (ELIOT
fossa is recommended. If irradiation of the supraclavicular
(electron intraoperative radiotherapy)) directly into the
fossa is omitted, recurrence rates at this site may be as
tumour excision cavity. The skin margins are pulled out
high as 28%.
of the treatment field. Doses ranging from 10 to 21 Gy
For an isolated axillary recurrence, a level III clearance
have been given. This extends the duration of surgery by
should be considered. Axillary irradiation is only consid-
1520 minutes. A trial in Milan is evaluating the role of
ered if there is macroscopic disease remaining after a clear-
intraoperative electrons as a perioperative single fraction
ance or a previous clearance has been undertaken. Most of
of electrons. This has potential advantages in countries
the available evidence does not support the use of axillary
where accessibility of patients to radiotherapy centres is dif-
irradiation for patients with extracapsular spread in
ficult or expensive. Long periods of radiotherapy may
patients who have undergone a level III axillary clearance.
impact adversely on quality of life and are a heavy drain
on limited healthcare resources.
A photon radiosurgery system delivering 50 kV x-rays has General care
been used to deliver doses of 520 Gy into the operative
site. The system used a range of spherical applicators of During treatment
different sizes (Figure 26.24). A dose of 15 Gy prescribed If the margins of the treatment fields are marked by a small
at 2 mm from a 3.5 cm diameter applicator delivers number of tattoos, the patient can wash the treatment area
7.5 Gy at a depth of 5 mm. during a course of radiotherapy. Shoulder exercises to keep
There are no uniformally agreed criteria for eligibility for the joint supple should be taught by a physiotherapist and
partial breast irradiation. Suggested criteria include tumour practised by the patient during and after treatment.
< 3 cm, unifocal, without an extensive intraduct component,
close or negative margins and zero to three involved nodes. After treatment
It should be emphasized that large randomized studies
Apply an emollient cream, such as oilatum or aqueous
will be needed to assess the clinical and economic effective-
cream, to areas of dry desquamation and antibiotic oint-
ness of partial breast irradiation techniques.
ment (e.g. graneodin) or flamazine to areas of moist
desquamation.
Local recurrence after mastectomy
If local recurrence occurs on the chest wall, spot recurrence
should be locally excised if feasible. Sixty to 70% of patients Morbidity of radical radiotherapy
Intact breast
1. Breast oedema is common, particularly in the first year
after radiotherapy. It is commoner in patients who
have had an axillary clearance.
2. Subcutaneous fibrosis is common and may give rise to
progressive shrinkage of the irradiated breast over a
period of years.
Postmastectomy
1. Skin telangiectasia.
2. Lymphoedema of the ipsilateral arm.
3. Rib fractures. These occur in 12% of patients
4. Pneumonitis and lung fibrosis. Occasionally, transient
cough occurs during radiotherapy but usually settles
within a few weeks. Some degree of fibrosis is observed
on chest radiograph. The features of clinical
pneumonitis are dry cough, dysponea and fever 612
weeks after completion of radiotherapy. The risk
increases with the number of fields treated and the use
of chemotherapy. For patients treated by tangential
fields alone without systemic therapy the risk is less
Figure 26.24 Intra beam intra-operative radiotherapy. than 1%.
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Chapter | 26 | Breast cancer
5. Fibrosis of the shoulder joint can occur if the axilla is Recommendations based on prognostic factors are sum-
irradiated, restricting shoulder movement. marized in Table 26.8
6. Cardiac morbidity. Patients, particularly if irradiated
over the age of 60, are at increased risk of coronary Who benefits?
artery disease and potentially of disease of other cardiac
structures. The Early Breast Cancer Trialists Group has provided a series
7. Radiation-induced sarcoma. This is an extremely rare of 5-yearly meta-analyses of over 75 000 women with early
complication with a mean latency of 13 years from the breast cancer. The overview shows clearly that both hor-
time of radiotherapy. Prognosis is very poor. Mean monal (tamoxifen or oophorectomy) and cytotoxic therapy
survival is 15 months. (CMF or anthracycline-containing combination chemother-
8. Hypothyroidism may occur because of inclusion of apy) reduce the relative risk of relapse or death by up to 30%
the thyroid gland in the shoulder or medial at 10 years. The overall survival benefits are more modest,
supraclavicular field. with a 412% gain in overall survival. The benefits in overall
survival are greater in premenopausal than postmenopausal
women. In women over the age of 70, there are few data on
the benefit of adjuvant chemotherapy and some evidence
that the degree of benefit falls with increasing age.
ADJUVANT HORMONAL AND Following polychemotherapy, women aged 5059 gain a
CYTOTOXIC THERAPY 14% reduction in risk of death compared to 8% in women
aged 6069. The survival gains in the under 50 and 5069
age groups are shown in Figure 26.25. Life expectancy is likely
Rationale
to be prolonged on average by 4 years for women under the
It is generally accepted that a substantial number of age of 50 and by 13 years in women over the age of 50. Adju-
patients with apparently localized breast cancer harbor sys- vant chemotherapy reduces 10-year breast cancer mortality
temic micrometastases. These are currently beyond the by 27%. For a woman who has a 50% chance of dying from
detection of the conventional staging. breast cancer under the age of 50, the approximate reduction
All patients should be considered for some form of adju- in risk of death is 13.5%. For a woman with a 10% risk of
vant systemic therapy to try to eradicate micrometastases. death at 10 years, the risk of death is about 8%.
Table 26.8 Recommendations for adjuvant systemic therapy based on prognostic factors
Prognostic factors
Treatment
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Walter and Millers Textbook of Radiotherapy
60
oestrogen receptor (ER)-rich tumours have 310 times
Node-positive
the benefits of ER-poor patients. Life expectancy is
40
increased by 23 years in women on tamoxifen for 23
Polychemotherapy years. If tamoxifen is added to chemotherapy in ER-rich
20 tumours, additional benefit accrues, as also happens when
Control chemotherapy is added to tamoxifen. In addition, tamoxi-
0 fen reduces the risk of contralateral breast cancer.
The optimal duration of administration of tamoxifen is
0 5 10
Follow-up (years) not clear, but most of the current evidence suggests that
(ii) 5 years is probably optimal.
Figure 26.25 Survival with and without adjuvant
polychemotherapy in early breast cancer in women under the Aromatase inhibitors
age of 50 years and 5069 years.
(Reproduced from Parmar M K B, Adjuvant Therapy, Medicine 1999;
The role of aromatase inhibitors as an alternative to tamox-
27:12: 3234 by kind permission of The Medicine Publishing Company)
ifen or in combination with it was explored in the ATAC
trial. The trial of over 9000 postmenopausal node-negative
and predominantly oestrogen receptor-positive patients
There is evidence that anthracyline-containing regimens showed a statistically significant 2.4% gain in recurrence-
increase the probability of survival compared to non- free survival at 4 years in the anastrazole alone group over
anthracycline-containing regimens such as CMF but at tamoxifen alone. In addition, there was a highly significant
the cost of greater toxicity, particularly myelosuppression. reduction in risk of contralateral breast cancer in the ana-
Taxanes have been widely adopted in the adjuvant setting strazole alone group. In addition, the incidence of endome-
in the USA for high-risk younger woman. To date there trial cancer, vaginal bleeding and discharge, venous
is no published evidence of the superiority of taxane- thromboembolism and cerebrovascular accidents was
containing regimens over anthracyline-containing regimens. reduced in the anastrazole treated group (Table 26.9).
However, musculoskeletal symptoms and bone fractures
were more common with anastrazole At 5 years, there
Adjuvant tamoxifen
was still a better disease-free survival with anastrazole com-
Adjuvant tamoxifen (20 mg orally daily) reduces the risk pared to tamoxifen. However, there was no difference in
of death by about 15%. The survival benefits of adjuvant breast cancer-specific survival. It is uncertain whether the
tamoxifen are shown in Figure 26.26. Women with findings can be extrapolated to node-positive patients.
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Chapter | 26 | Breast cancer
Table 26.9 Toxicities in ATAC trial comparing adjuvant Adjuvant hormonal therapy after
tamoxifen (T) and anastrazole (A) 5 years of tamoxifen
There is an emerging body of data to suggest that additional
TYPE OF TOXICITY HAZARD RATIO A%/T% adjuvant hormonal therapy with the more recent and more
Endometrial ca 0.29 0.2/0.8 potent aromatase inhibitors, such as letrozole and exemes-
tane, may reduce the risk of recurrent breast cancer in
Vaginal bleeding 0.50 5.4/10.2 patients treated initially with tamoxifen.
In the National Cancer Institute MA17 trial, over 5000
Arthralgia 1.32 35.6/29.4 postmenopausal patients, mainly ER positive, were rando-
Fracture 1.49 11/7.7 mized after 5 years of adjuvant tamoxifen to either 2.5 mg
of letrazole or placebo.The disease-free survival was supe-
Ischaemic (cardiac) 1.23 4.1/3.4 rior in the letrazole group with a 4-year disease-free survival
of 93% compared to 87% with placebo which was highly
Ischaemic (cerebral) 0.70 2/2.8
statistically significant. Overall survival was improved by
Thromboembolism 0.61 2.8/4.5 2% in the letrazole group (96% versus 94%) but was not
statistically significant. In the Intergroup exemestane trial,
patients were randomized after 23 years of tamoxifen to
either a further 23 years of tamoxifen or the aromatase
In the BIG 1-198 trial, 8028 postmenopausal patients inhibitor, exemestane 25 mg orally for a further 23 years.
with endocrine sensitive breast cancer were randomized to There was an absolute benefit in disease-free survival of
5 years of tamoxifen (20 mg daily), 5 years of letrozole 4.7% which was statistically significant and led to early
(25 mg daily), 2 years of tamoxifen followed by 3 years of closure of the trial. Overall survival was not significantly
letrozole or 2 years of letrozole followed by 3 years of tamox- different.
ifen. Analysis of the comparison of the tamoxifen (5 years) Tamoxifen confers a similar reduction in risk of death in
and letrozole (5 years) with a median follow up of 35.5 node-positive and node-negative women. However, the
months showed a significant advantage in disease-free sur- absolute reduction in risk is greater in node-positive women.
vival of letrozole over tamoxifen (Table 26.10). Patients The absolute gain in 10-year survival between 5 years of
on tamoxifen had significantly more thromboembolic tamoxifen and no tamoxifen is 6% for node-negative and
events. Patients on letrozole had significantly more bone 11% in node-positive women. It confers benefit in both
fractures and deaths from cardiac or cerebrovascular causes. premenopausal and postmenopausal ER-positive women.
Rx Postop Postop 23 yr T 2 yr T 5 yr T
% N 34 41 50 27 46
% CT 21 25 32 ? 100
Rx: treatment; A: arimidex; T: tamoxifen; Let: letrozole; Exem: exemestane; N: node positive; HR: hormone receptor positive
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Walter and Millers Textbook of Radiotherapy
Beyond 5 years the reduction in risk by tamoxifen is thought Medical ovarian suppression by goserelin (3.6 mg given
to decline and has to be balanced against the small risk of subcutaneously monthly) provides a reversible means of
tamoxifen-induced endometrial cancer. Adding tamoxifen stopping ovarian function. Goserelin is commonly given
to chemotherapy in ER-positive patients confers additional for 2 years. It has the advantage that, if the patient finds
benefit. All patients who are ER positive regardless of their the premenopausal symptoms intolerable (e.g. flushing
menopausal or nodal status should be considered for adju- and sweating), it can be stopped. If after 6 months of goser-
vant endocrine therapy for 5 years. elin, menopausal symptoms are found still to be tolerable,
the alternatives are to stay on goserelin or to proceed to
an oophorectomy. If the patient prefers to stay on gosere-
Toxicity of tamoxifen lin, it can be stopped after 2 years to check whether the
Postmenopausal symptoms of hot flushes, vaginal dryness patient is menopausal (raised LH and FSH with reduced
and sexual dysfunction are experienced by 2040% of estradiol levels).
patients. Cognitive deficits also occur (as they do after cyto-
toxic chemotherapy). These symptoms can significantly
interfere with a patients quality of life. Transient thrombo-
Ovarian suppression and
cytopenia occurs in 510% and vaginal bleeding in 5%. chemotherapy
Tamoxifen increases the development of benign endome- Most trials show no difference in disease-free survival
trial changes, such as hyperplasia. The risk of endometrial between ovarian suppression and chemotherapy in ER-
cancer, particularly in women who have been on tamoxifen positive premenopausal patients.
for 5 years or more, is increased three- to fourfold, although
the risk remains very small. The risk of endometrial cancer
is 0.02%. Adjuvant combination chemotherapy
Care should be taken to avoid giving tamoxifen concur- (polychemotherapy)
rently with chemotherapy since it increases the risk of a
stroke. Tamoxifen should therefore only be started once The 2000 Oxford overview shows no significant reduction
chemotherapy has been completed. in recurrence or risk of death comparing prolonged single-
agent chemotherapy versus no chemotherapy. Prolonged
combination chemotherapy (typically CMF) shows highly
Tamoxifen plus chemotherapy significant reductions in recurrence and death in women
Treatment with both tamoxifen and chemotherapy gives under the age of 50 and those aged 5069. The reduction
added benefit in patients with ER-positive disease in in risk of recurrence emerged in the first 4 years following
both node-positive and node-negative women. This also treatment and the advantage in survival persists up to
applies to postmenopausal ER-positive patients. However, 15 years. The age-specific benefits do not appear to be
in ER-negative, node-negative women, the NSABP B-23 influenced by the ER status of the primary tumour, meno-
trial showed no benefit of the addition of tamoxifen to pausal status or the administration of adjuvant tamoxifen.
chemotherapy. The proportional reductions in risk were similar in
node-positive and node-negative patients. The absolute dif-
ferences in 10-year survival are 1112% for node-positive
Adjuvant ovarian suppression
patients and 45% for node-negative disease. For the
Suppression of ovarian function is one of the longest estab- 5059 and 6069 age groups, combination chemotherapy
lished of adjuvant therapies. It was Sir George Beatson, improved 10-year survival by 4% and 2% respectively.
a surgeon in Glasgow who, in 1895, first showed that oopho- More recently, the use of anthracycline-based chemo-
rectomy could reduce the activity of breast cancer. A small therapy (e.g. containing doxorubicin or epirubicin) has
randomized trial conducted in Edinburgh comparing increased. The Oxford overview shows highly significant
patients with operable breast cancer treated by adjuvant additional reductions in recurrence or death from anthra-
oophorectomy or CMF chemotherapy showed that oopho- cycline-containing regimens compared to CMF. The pro-
rectomy had a significant advantage over CMF in ER-positive portional reduction in risk did not appear to be affected
patients and CMF over oophorectomy in ER-negative by the age at diagnosis or by axillary nodal status. There
patients. The Oxford overview showed a highly significant were absolute gains of approximately 4% in survival, which
increase in recurrence-free survival (25%) in premenopausal persisted to 10 years.
women under the age of 50 treated by oophorectomy. Advances in adjuvant chemotherapy focus on (i) the
For node-positive premenopausal women the gains in introduction of non-cross resistant cytotoxic drugs, manip-
recurrence-free and overall survival at 15 years were ulation of the size of dose, dose density and total cumula-
10.5% and 13% respectively. Much smaller but still statis- tive dose of the most active agents, (ii) the development of
tically significant benefits in both these parameters were molecular markers predictive of response, and (iii) identi-
seen in premenopausal node-negative women. fication of women most likely to benefit from therapy.
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Chapter | 26 | Breast cancer
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Walter and Millers Textbook of Radiotherapy
epirubicin (at a dose of 100 mg/m2) and cyclophospha- the best prognosis. Nonetheless, it has yet to be proven that
mide (FEC 100) is 2% at 8 years. The risk of cardiac death pathologic response or measures of cell division reliably
is less than 1% if guidelines on maximum cumulative dose predict patient outcomes.
are respected. There appears to be no added risk of cardio- To date six randomized trials have compared primary
toxicity from combining taxanes with anthracyclines. With systemic therapy to adjuvant chemotherapy (Table 26.13)
cumulative doses of anthacyclines, the long-term risk of in patients with operable breast cancer. The findings of
inducing leukaemia increases. However, if a total dose of these trials are the basis of primary systemic therapy in both
720 mg of epirubicin is not exceeded, there is no increased operable and inoperable breast cancer to achieve downsta-
risk of leukaemogenesis. More recently, cognitive dys- ging. The largest, conducted by the NSABP (National Adju-
function has been recognized as a complication of chemo- vant Breast and Bowel Project (NSABP)), B-18 trial
therapy caused by damage to the frontal cortex. The risk randomized 1523 patients with T03,N01 operable breast
factors for this are unknown. cancer to either four cycles of Adriamycin and cyclophos-
phamide before or after primary surgery. For primary sys-
temic therapy, the clinical response rate was 80% with a
Primary systemic therapy complete response rate of 36%. In the primary systemic
The rationale for the use of preoperative chemotherapy in therapy arm, there were significantly fewer patients found
locally advanced breast cancer is that, in animal models, to have pathologically involved axillary nodes (41% versus
resection of the primary tumour accelerates metastatic 57%). However, there was no difference in overall or
growth. The application of preoperative systemic therapy disease-free survival. In subset analysis, patients who were
might reduce or sterilize metastatic disease. Other benefits younger (49 years) had significantly better disease-free
include increased resectability of the tumour either by mas- and overall survival (55% versus 46% and 71% versus
tectomy or breast conserving surgery and improving locor- 65% respectively). An important additional finding was
egional control. Pathological response is usually based on that a pathological complete response conferred a better
the response of the primary tumour and not the nodes. If a prognosis. Patients with a pathological complete response
pathological complete response can be obtained, it confers had a significantly better 5-year survival. The disease-free
Table 26.13 Randomized trials of primary systemic therapy versus adjuvant chemotherapy for breast cancer
TRIAL STAGE NO. PATIENTS PST AND ADJUVANT cCR pCR DFS OS
ASSESSABLE THERAPY (%) (%) (%) (%)
RT-S-FAC 41 NR 55 78
760 S-AC 53 69
PST: Primary systemic therapy; cCR: complete clinical response; pCR: complete pathological response; DFS: disease-free survival; OS: overall
survival; S: surgery; RT: radiotherapy; TMF: thiotepa, methotrexate, fluorouracil; EVM: epirrubicin, vincristine, methotrexate; MTV: mitomycin,
thiotepa, vinblastine; FAC: 5-fluorouracil, doxorubicin, cyclophosphamide; MT: mitoxantrone, mitomycin, methotrexate, tamoxifen; FEC:
5-fluorouracil, epirubicin, cyclophosphamide; C: doxorubicin, cyclophosphamide; NR: not recorded
From Hutcheon A W and Heyes S ASCO, 2004
456
Chapter | 26 | Breast cancer
and overall survival for such patients at 9 years were 85% Principles of management
and 75% respectively.
The management of LABC should be multidisciplinary.
Surgery, radiotherapy and systemic therapy in different
MANAGEMENT OF LOCALLY combinations need to be tailored to the clinical features
ADVANCED BREAST CANCER (LABC) of the patients cancer to maximize locoregional control
and reduce the risk of distant metastases.
For patients with operable IIIA disease, the choice is
Locally advanced breast cancer (LABC), or stage III breast can- between modified radical mastectomy followed by adju-
cer, refers to tumours >5 cm in diameter (T3) or associated vant systemic therapy and radiotherapy or preoperative
with involvement of the skin or chest wall ( T4) or with fixed chemotherapy followed by surgery and radiotherapy.
axillary nodes or ipsilateral supraclavicular nodes. LABC still
presents a major challenge in management. It accounts for
between 5% and 30% of patients presenting to the breast Role of surgery
clinic. A typical example in shown in Figure 26.27. These
Surgery has a limited role in the management of locally
are a very heterogeneous group of tumours with widely differ-
advanced disease. It encompasses: (i) initial core biopsy
ing natural histories. Results with surgery and radiotherapy
for diagnosis and ER status; (ii) mastectomy and axillary
were disappointing with high levels of locoregional and sys-
clearance in operable patients; (iii) mastectomy (ideally with
temic failure. Substantial improvements have been achieved
myocutaneous flap reconstruction) for residual masses after
with the addition of systemic therapy. Nonetheless, long-
chemotherapy and radical radiotherapy; and (iv) palliative
term survival is only about 50%. The evidence base is much
debriding of infected and/or necrotic areas to reduce odour.
weaker than for early breast cancer. Much of the published lit-
For inflammatory breast cancer (T4d), only patients with
erature is based on case series, with mixed populations of
complete clinical resolution of inflammatory changes fol-
patients some including patients with inflammatory breast
lowing chemotherapy should be considered for mastectomy.
cancer and others not. Often, in studies of systemic therapy,
Mastectomy as the primary procedure or when inflammatory
locoregional therapy is not well defined. However, long-term
changes persist after neoadjuvant systemic therapy is likely to
survival remains poor at about 50% and systemic failure
be followed rapidly by recurrence in the skin flaps.
remains a major problem.
Trials of adjuvant chemotherapy in patients with stage
III disease are rare. The Oxford overview of randomized trials
Clinical features of adjuvant systemic therapy does contain some patients
with large operable cancer. It showed that all patients gained
The main features of LABC are skin nodules, peau dorange from adjuvant chemotherapy irrespective of tumour size.
(T4b), inflammatory changes (T4d), ulceration and fixity On this basis, it is reasonable to extrapolate the results of
to the chest wall (T4a), fixed axillary nodes (N2) or lym- the overview to patients with operable stage IIIA disease.
phoedema (N3). Local pain, bleeding, ulceration and
infection are common symptomatic problems. The natural
history of locally advanced disease varies widely. In some Primary chemotherapy followed
patients, distant metastatic disease will rapidly supervene, by surgery
in others the disease remains locoregional and relatively
indolent. There are a limited number of case studies and randomized
trials which have compared preoperative chemotherapy to
postoperative chemotherapy. These were predominantly in
stage I and II disease but did include some patients with T3
tumours. While preoperative chemotherapy did downstage
some patients sufficiently for their cancer to be managed by
breast conserving surgery rather than mastectomy, there
was no difference in disease-free or overall survival. Indeed,
some trials showed downstaging followed by conservative
surgery resulted in a higher risk of local recurrence and sur-
vival was poorer.
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Walter and Millers Textbook of Radiotherapy
of anthracycline-containing chemotherapy over no sys- possible. In addition, there are selected patients with very
temic therapy. One trial showed no difference in disease- small tumours which involve the skin early due to their
free or overall survival between a combination of CMF with proximity to the inframammary fold where the amount
epirubicin and vincristine to CMF alone. The recommenda- of breast tissue is small.
tions for anthracycline-based chemotherapy for LABC are There is limited information on the role of breast recon-
largely extrapolated from studies of node-positive, meta- struction at the time of mastectomy. Reconstruction is
static breast cancer. generally best delayed until after the completion of che-
Based on trials of adjuvant chemotherapy, six cycles of motherapy and radiotherapy. If undertaken at the time
cyclophosphamide, Adriamycin (CAF) or cyclophospha- of mastectomy, complications may delay chemotherapy
mide, epirubicin and 5-fluorouracil (CEF) is probably and radiotherapy.
better than six cycles of CMF. In a trial of women with
LABC randomized to CEF or epirubicin plus cyclophos-
phamide, there was no difference in survival at a median Target volume
follow up 5.5 years (53% and 51% respectively). It is
important to confirm continuing response up to six The target volume should include the chest wall or breast
cycles of chemotherapy. In non-responders, chemother- (in the case of conservative surgery) and, if the axilla has
apy should be stopped to avoid further toxicity. If suffi- not been cleared, the peripheral lymphatics.
cient tumour debulking has been achieved for surgery,
this should be followed by postoperative radiotherapy.
If there is no response and the tumour remains inopera-
Technique
ble, radical radiotherapy should follow. The principles of radical radiotherapy for early breast can-
Taxane-containing regimens are under evaluation and cer apply also to locally advanced disease, both for the
there is some evidence that an anthracycline-containing intact breast or following mastectomy. The only difference
regimen followed by a taxane may improve clinical and is that 0.51 cm of skin bolus should be applied to the
pathological response in LABC. One study comparing a breast or chest wall to ensure that the skin receives a full
combination of a taxane (doxetaxel) to FAC, showed supe- dose (to overcome the skin-sparing effect of megavoltage
rior disease-free survival and overall survival with TAC. It is, radiotherapy). Axillary surgery is not normally carried
however, premature to provide definitive guidance on the out at staging and, therefore, the peripheral lymphatics will
use of taxanes in this setting. normally be irradiated. If mastectomy and a level III axillary
clearance have been carried out, the axilla should not be
irradiated. Where there is macroscopic disease which
Hormonal therapy
would cross the conventional breast/shoulder field junc-
Patients with LABC who are oestrogen and/or progesterone tion, it is best to use an en bloc technique, treating both
positive should receive tamoxifen at the end of chemother- the breast and the peripheral lymphatics in a perspex jig
apy. For patients who are not suitable for chemotherapy (see Figure 26.15).
and are hormone receptor positive, primary treatment with
tamoxifen (20 mg daily) or the aromatase inhibitor letra-
zole (2.5 mg) is recommended. Responses to hormonal Dosage and fractionation
therapy may take 68 weeks to occur. Patients who are pre-
menopausal and hormone receptor positive and are not While there is evidence of a dose response effect in locally
suitable for chemotherapy should receive a luteinizing hor- advanced disease, escalating dosage beyond 6070 Gy is
mone releasing hormone agonist (goserelin, 3.6 mg subcu- associated with an increased risk of major complications.
taneously monthly). Hyperfractionated radiotherapy may have advantages in
reducing repopulation during radiotherapy. The long-term
results of studies of hyperfractionated radiotherapy are
Locoregional therapy awaited. Until there is convincing evidence of improved
If erythema of inflammatory changes or peau dorange local control, conventional dosage and fractionation are
resolve with chemotherapy, mastectomy and axillary clear- recommended.
ance should follow. Postoperative radiotherapy is given to 1. Post-mastectomy
the chest wall and, if there are four or more involved axil- 40 Gy in 15 fractions over 3 weeks or 45 Gy TAD in 20
lary nodes, to the medial supraclavicular fossa. There is no fractions over 4 weeks or 50 Gy in 25 fractions over 5 weeks
good evidence to determine whether or not the internal (6 MV photons) (applying skin bolus)
mammary nodes should be irradiated. Breast conserving 2. Intact breast
therapy for LABC is not standard therapy. However, there 40 Gy in 15 fractions over 3 weeks 45 Gy TAD in 20
are some patients where the degree of debulking achieved fractions over 4 weeks or 50 Gy in 25 fractions over 5 weeks
by chemotherapy does make breast conserving therapy (6 MV photons) (applying skin bolus)
458
Chapter | 26 | Breast cancer
BONE METASTASES
459
Walter and Millers Textbook of Radiotherapy
460
Chapter | 26 | Breast cancer
Indolent Aggressive
Disease Disease
Tamoxifen or Tamoxifen
Salvage
Ovarian Ablation
Chemotherapy
Secondary or Tertiary
Endocrine Therapy
in Responders
Progression
(Reproduced with permission from Holland JF, Frei E III, Bast RC et al (eds) Cancer Medicine, 4th edn. Vol 2, Williams & Wilkins, 1997)
461
Walter and Millers Textbook of Radiotherapy
462
Chapter | 26 | Breast cancer
463
Walter and Millers Textbook of Radiotherapy
100
30 80
169
62 Stages I & II (306)
20
117
46
86
% Survival
7
39
5
1
0 5 10 15 20 25 30 35
Years
Figure 26.29 Long-term survival of women with breast cancer. Survival curves for all patients and for stages I and II only.
(Reproduced with permission from The Lancet, 1984)
Recurrence rates within the treated breast remain constant 10 years seems reasonable. Beyond 10 years the guidelines
at 1% per year up to 15 years. This argues that the frequency are as for patients managed by breast conservation.
of follow up does not need to be any more frequent in the
early years after completion of treatment than in later years.
Most studies of follow up after breast-conserving therapy BREAST CANCER IN PREGNANCY
have been with annual mammography. Optimum duration
of follow up is unclear. However, annual follow up to 10 The diagnosis of breast cancer in pregnancy is uncommon
years seems reasonable. At this point, women who still lie but presents difficult decisions for patient, oncologist and
within the UK screening age group (i.e. up to 69 years) obstetrician. Close liaison between oncologist and obstetri-
should be returned to the 3-yearly breast-screening cian is essential. The interests of both mother and child
programme. For women 70 years or older, further follow need to be taken into account.
up should be decided on an individual basis between the Most tumours are high grade and lymphovascular invasion
patient and their surgeon/oncologist. is common. Lymph node involvement is reported to be
as high as 79%. Most tumours (over 70%) are oestrogen-
receptor negative. On average, delay in diagnosis of breast
Follow-up after mastectomy
cancer is 8.2 months during pregnancy compared to 1.9
Local recurrences on the chest wall are commonest in the months in non-pregnant women. Management will be
first 2 years after mastectomy and 80% of chest wall and influenced by the stage of pregnancy, the preference of
axillary recurrences occur within the first 5 years. The the patient and the stage of the disease. However, it should
evidence-based guidelines of the American Society of follow as far as possible the protocol for non-pregnant
Clinical Oncology recommend a careful history and clini- patients. A subsequent pregnancy after the diagnosis of
cal examination every 36 months for 3 years, then visits breast cancer does not adversely afftect prognosis. Indeed,
every 612 months for 2 years, and then annually thereaf- there is some evidence that it may have a favourable effect
ter. Optimum duration of follow up is uncertain. However, on survival.
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Chapter | 26 | Breast cancer
With adequate shielding of the fetus, mammography Delivery between days 1 and 14 of the chemotherapy cycle
should not be harmful. However, the increased density should be avoided. Platelet count should be 80109/L.
of the breast during pregnancy may obscure the radiologi- Hormonal therapy, if indicated, should be started after deliv-
cal signs of malignancy. In the first trimester, termination is ery and after chemotherapy has been completed.
normally advised and followed by standard treatment.
Surgery can be safely performed during pregnancy. In
general, this is delayed until at least the 12th week of ges-
tation since, before this point, the risk of spontaneous BREAST CANCER IN MALES
abortion is highest. Breast conserving surgery should be
considered if possible with axillary lymph node dissection Breast cancer in men is rare, only representing 1% of breast
but not sentinel node biopsy using a radioactive tracer. cancer. Most cases occur in an older age group than in
No adjuvant radiotherapy or adjuvant systemic therapy is women, typically occurring over the age of 60. In some
given until the delivery of the baby. cases, there is a genetic predisposition. A variable propor-
In the second trimester, the choice is between conserva- tion of cases (320%) carry a mutation of the BRCA2 gene.
tive surgery or mastectomy or termination of pregnancy fol- A family history of male breast cancer is a major predispos-
lowed by standard adjuvant therapy. ing factor to female breast cancer. In addition, BRCA2
In the third trimester of pregnancy, the breast becomes mutations are associated with an increased risk of other
more vascular. Small tumours may be treated with wide local cancers such lymphomas, laryngeal and kidney cancer.
excision followed after delivery by postoperative radiother- Presentation is typically with locally advanced disease
apy. For larger tumours, simple mastectomy with axillary often affecting the nipple. Fixation to the chest wall is com-
node clearance is recommended. Elective induction or mon. The advanced state of the local disease is in part prob-
caesarean section at 36 weeks is followed, if indicated, by ably due to the limited amount of breast tissue that the
postoperative radiotherapy (same criteria as in the non-preg- tumour has to invade and the lack of awareness among
nant patient). men that they can develop breast cancer.
Adjuvant radiotherapy is not given during pregnancy Treatment where the disease is operable is by simple
since with a total dose of 50 Gy conventionally fractio- mastectomy and axillary node clearance. Postoperative
nated, the fetus will receive 2 Gy (i.e. excess of the radiotherapy is often needed because of skin infiltration.
0.05 Gy safe limit). Radiotherapy can be safely delayed Although the rarity of the tumour means that there are
up to 6 months after surgery. no trials of adjuvant therapy, the same principles should
Anthracyclines and cyclophosphamide can be safely deliv- apply as in female breast cancer. For ER-positive patients,
ered during pregnancy. The combination of 5-fluorouracil, tamoxifen is advised and for ER-negative disease, CMF che-
epirubicin and cyclophosphamide can be delivered without motherapy. The outcome of the disease is usually poor with
adverse effect on the infant. The last cycle of chemotherapy 5-year survival of about 40% reflecting the commonly
should be delivered around the 34th week of pregnancy. advanced nature of the disease at presentation.
FURTHER READING
Early Breast Cancer Triallists Hannoun-Levi JM, Courdi A, Marsiglia M, van der Vijver MJ, He YD, Vant Veer LJ,
Collaborative Group. et al. Breast cancer in elderly women: et al. A gene-expression signature as
Polychemotherapy for early breast is partial breast irradiation a good a predictor of survival in breast
cancer: an overview of the randomised alternative? Breast Cancer Res Treat cancer. N Engl J Med 2002;347:
trials. Lancet 1998;352:93042. 2000;81:24351. 19992009.
Early Breast Cancer Triallists Overgaard M, Hansen PA, Overgaard J, Clinical practice guidelines for the
Collaborative Group. Favourable and et al. Postoperative radiotherapy care and treatment of breast
unfavourable effects on long-term in high-risk premenopausal cancer: 15. Treatment for
survival of radiotherapy for early women who receive adjuvant women with stage III or locally
breast cancer: an overview of the chemotherapy. N Engl J Med advanced breast cancer. CMAJ
randomised trials. Lancet 1997;337:94955. 2004;170:98394.
2000;355:175770. Overgaard M, Jensen MB, Overgaard J, Chetty U, Jack W, Prescott RJ, et al.
Whelan TJ, Julian J, Wright J, et al. et al. Postoperative radiotherapy in Management of the axilla in operable
Does locoregional radiation therapy high-risk postmenopausal breast breast cancer treated by breast
improve survival in breast cancer? cancer patients who receive adjuvant conservation: a randomized clinical
A meta-analysis. J Clin Oncol chemotherapy. Lancet 1999;353: Trial. Edinburgh Breast Unit. Br J Surg
2000;18:12209. 16418. 2000;87:1639.
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Walter and Millers Textbook of Radiotherapy
Howell A, Cuzick J, Baum M, et al. Fossati R, Confalonieri C, Torri V, et al. OShaughnessy J, Miles D, Vukelja S, et al.
ATAC Trialists Group. Results of the Cytotoxic and hormonal treatment Superior survival with capecitabine
ATAC (Arimidex, Tamoxifen, Alone for metastatic breast cancer: a plus docetaxel combination therapy
or in Combination) trial after systematic review of published in anthracycline-pretreated patients
completion of 5 years adjuvant randomized trials involving with advanced breast cancer: phase III
treatment for breast cancer. Lancet 31,510 women. J Clin Oncol trial results. J Clin Oncol
2005;365:602. 1998;16:343960. 2002;20:281223.
466
Chapter | 27 |
Gynaecological cancer
Paul Symonds
Posterior vaginal
fornix
Recto-uterine pouch
Anterior fornix
Symphysis
pubis
Rectum
Vagina
Body of uterus
Muscle etc Table 27.1 Incidence of gynaecological cancer in UK
on pelvic wall Uterine canal in 2007 (CRUK)
Ovary
Vagina
Figure 27.2 Coronal section of the uterus and vagina. Note the
important relationship of the ureter to the cervix. CARCINOMA OF CERVIX
468
Chapter | 27 | Gynaecological cancer
partners. There is a lower incidence of cervical carcinoma in younger women. Some authorities feel adenocarcinoma
women using barrier methods of contraception. Male of cervix has a worse prognosis than squamous cancer
behaviour is also important. Partners of men in certain when treated by radiotherapy.
occupations, such as seamen, deep-sea fishermen and long Carcinoma of cervix spreads predominantly by direct
distance lorry drivers, have a higher incidence of cervical invasion and through the lymphatic system. Initially, the
cancer. So do those partners of men whose previous tumour spreads into the uterus or vagina and parametrium
partners have developed cervix cancer. Smoking and (the tissues around the uterus). Later, it can infiltrate
immunosuppression are also associated with cervical bladder or rectum. The tumour spreads to the iliac and then
cancer. Cervical neoplasia is more common in women para-aortic lymph nodes (Figure 27.4) Blood-borne spread
who are HIV positive. is less common and this may lead to liver, lung and bone
metastases.
Pathology of cervical cancer
100
Viral infection of the cervix may lead to premalignant
change which is called dysplasia. This can be detected in
exfoliated cells removed during a cervical smear. Cervical
80
dysplasia is graded mild, moderate or severe. The terms
CIN1, CIN2 and CIN3 are histological terms used to
describe increasing degrees of dysplasia, mild, moderate
% Surviving
60
and severe in biopsy material. In some women, there is a
progression from mild to severe dysplasia and then inva-
sive cancer. This often takes many years to develop and
40
can be detected during cervical screening. Treatment of pre-
malignant disease is highly effective. Patients with moder- _
Surgery <4cm
ate or severe dysplasia are offered ablative treatment Radiotherapy <4cm
_
20
using large loop excision, laser vaporization or cryotherapy. Surgery >4cm
However, in most cases, dysplasia is self-limiting. Even the Radiotherapy >4cm
most severe form of dysplasia, CIN3 (previously called
0
carcinoma in situ), will only progress to invasive cancer
0 20 40 60
in between 20 and 40% of women if left untreated.
Time since treatment [months]
Between 85 and 95% of cases of invasive cancer of cervix
are squamous carcinomas. The remainder are adenocarci- Figure 27.4 Survival stage 1b operable ca cervix in a
noma or adenosquamous tumours. There is some evidence randomized trial of 343 patients treated by surgery or
that the incidence of adenocarcinoma is increasing among radiotherapy.
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Walter and Millers Textbook of Radiotherapy
Symptoms and investigations advanced disease and suggests spread to adjacent organs
of cervical cancer around the cervix. Backache may be associated with para-
aortic lymph node spread.
Premalignant changes are usually asymptomatic. The cardi- Patients with cervical cancer are staged clinically accord-
nal symptom of invasive cervix cancer is irregular vaginal ing to the FIGO staging system (Table 27.2). Accurate
bleeding. This may be bleeding after intercourse or bleed- staging of cervical cancer is essential so that appropriate
ing in between periods. Sometimes, the women will have treatment can be planned. The cornerstone to staging is
a brown vaginal discharge. Pain is usually a symptom of an examination under anaesthesia (EUA). The cervix and
Stage III The carcinoma has extended to the pelvic wall. On rectal
examination, there is no cancer-free space between
the tumour and the pelvic wall. The tumour involves the
lower-third of the vagina. All cases with hydronephrosis
or non-functioning kidney are included, unless they are
known to be due to other causes
IIIa Tumour involves lower-third of the vagina, with no
extension to the pelvic wall
IIIb (Figures 27.9 and 27.10) Extension to the pelvic wall and/or hydronephrosis or
non-functioning kidney
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Chapter | 27 | Gynaecological cancer
Figure 27.5 Manual insertion of a long central tube and ovoids Figure 27.7 Impact of 1988 overhaul of UK cervical screening
containing cesium. programme on incidence and mortality of cervical cancer in UK.
2 cm
3 cm
A B
2 cm
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Walter and Millers Textbook of Radiotherapy
472
Chapter | 27 | Gynaecological cancer
Ib 4657 80.1
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Walter and Millers Textbook of Radiotherapy
Intracavity brachytherapy
The cervix was one of the first tumours to be successfully
treated by radium. A number of systems were developed,
in particular the Stockholm, Paris and Manchester methods.
Many of the modern afterloading techniques owe their ori-
gin to the Manchester technique in which a tube containing
Figure 27.15 Residual tumour in endocervical canal (cf Figures radium (latterly cesium) was placed within the uterus and
27.8 and 27.9). two rubber ellipses (ovoids) were placed against the cervix
474
Chapter | 27 | Gynaecological cancer
475
Walter and Millers Textbook of Radiotherapy
476
Chapter | 27 | Gynaecological cancer
Future trends
The irradiation of vulnerable tissue may be reduced further
by the increased use of conformal techniques and intensity
modulated radiotherapy (IMRT). As many departments
adopt HDR brachytherapy they also move to CT and
MRI imaging in order to plan brachytherapy. There is also
a move away from prescribing to point A and to calculate
the total dose delivered by external beam and brachyther-
apy to the tumour plus vulnerable organs such as bladder
and rectum. In Vienna, they aim to deliver 85 Gy to 90%
isodose line (D90) enclosing the tumour (including exter-
nal beam and brachytherapy dosage) as long as a volume of
2 cc of bladder or rectum does not receive doses of 76 and
63 Gy respectively. Drugs such as gemcitabine or capecita-
bine in addition to cisplatin when given along with radio-
therapy may further improve survival figures.
Figure 27.27 Large stage III tumour 3 months after
chemoradiotherapy. Complete response. This patient was
discharged from the clinic in 2007, 7 years after treatment. CARCINOMA OF ENDOMETRIUM
Routes of spread
Figure 27.28 Selection insertion. Central tube in uterus, ovoids Tumour may extend beyond the endometrial cavity to
against cervix, pack under ovoids to reduce close to bladder. involve the cervix or vagina. Parametrial spread is extremely
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Walter and Millers Textbook of Radiotherapy
uncommon. Distant spread is first to iliac lymph nodes radiotherapy prior to an interuterine insertion can be
or occasionally directly to para-aortic nodes without selected by MRI scanning which is good at showing myo-
iliac involvement. Blood stream spread is unusual. Staging metrial invasion by tumour. Doses used are similar to those
takes into account pathological features and the pattern of used to treat carcinoma of cervix.
spread. The current FIGO staging is shown in Table 27.4.
Over 80% of patients have stage I tumours.
Postoperative radiotherapy
Treatment Both the Dutch PORTEC trial and the Medical Research
Council (MRC) ASTEC trials showed no survival advantage
The mainstay of treatment is simple hysterectomy. The for routine postoperative radiotherapy for patients with
prognostic effect of removal of pelvic lymph nodes (lym- immediate risk (grade I FIGO Ib, G2 Ib, G3 Ia) tumours.
phadenectomy) is the subject of current clinical trials. There was a statistically significant decrease in pelvic recur-
Patients with well- or moderately well-differentiated rence compared to observation alone after surgery but no
tumours confined to the inner half of the myometrium overall survival benefit.
require no further treatment. Patients with more aggressive tumours may benefit from
postoperative radiotherapy. A meta-analysis and systematic
review by Johnson and Cornes showed postoperative radio-
Radiotherapy therapy increased survival by 10% for patients with poorly
Radiotherapy may be given as an alternative to surgery, as differentiated tumour penetrating more than half way
postoperative adjuvant treatment or to treat pelvic or vault through the myometrium (stage Ib G3). When planning
recurrence. Patients who are treated primarily by local radiotherapy, the target volume should include the internal
radiotherapy are often extremely obese or have serious and external iliac lymph nodes plus the upper two-thirds of
intercurrent disease which are both contraindications for the vagina. Field arrangements and volume irradiated are very
surgery. Five-year survival of 72% has been reported in this similar to those used in the treatment of cervical cancer. Doses
group of patients treated by two interuterine cesium inser- of 4045 Gy are given in 1.8 or 2 Gy fractions (Figure 27.29).
tions in Manchester. Patients who require external beam Radiotherapy can be used with curative intent if previ-
ously unirradiated patients develop an isolated pelvic
recurrence. Five-year survival rates of 5080% have been
reported in patients with isolated vaginal vault recurrence,
Table 27.4 FIGO 2009 staging: carcinoma of the
endometrium
although this falls to about 20% in patients with pelvic
side-wall disease.
Stage I Tumour confined to the corpus uteri
Ia No or less than half myometrial invasion
Ib Invasion equal to or more than half of the
myometrium
478
Chapter | 27 | Gynaecological cancer
Aetiology
Results of treatment
In the majority of cases, the cause of ovarian cancer is
The majority of patients suffer from stage I cancers. Five-year
unknown. However, epithelial ovarian cancer is more
survival for patients with stage Ia disease is over 90%.
common in women who have never been pregnant or
This falls to about 70% for patients with stage Ic disease.
had an early menarche or late menopause. Conversely,
Reported 5-year survival for patients with stage II disease
the incidence of ovarian cancer is reduced in women
is between 85 and 60% and stage III disease between
who have had multiple births and there is good evidence
75 and 40%, depending on the treatment modality and
that oral contraceptives reduce the incidence of this dis-
degree of histological differentiation of the tumour.
ease. The protective effect of birth parity and oral contra-
ceptives is probably through suppression of ovulation.
About 5% of ovarian cancers are familial. The most impor-
Future trends
tant hereditary syndromes are associated with carriage of
About 20% of patients with endometrial cancer will die, the BRCA1 complex on chromosome 17 and the BRCA2
usually from distant metastases rather than pelvic recur- complex on chromosome 13. The BRCA 1 2 genes are
rence. A trial conducted by the Nordic Society of Gynaeco- also associated with breast cancer and sometimes colon
logical Oncology (NSGO) showed an 8% improvement and endometrial cancer. Familial tumours tend to develop
in 5-year progression-free survival after chemotherapy at a younger age than sporadic cancers. Women with two
and postoperative radiotherapy (82%) compared to 74% or more first degree relatives who have developed ovarian
(radiotherapy only) in high risk (G3 IbIII) patients. cancer or one who has developed breast cancer and one
479
Walter and Millers Textbook of Radiotherapy
other relative who has developed ovarian cancer before is excellent for demonstrating primary tumour with signif-
the age of 50 may be offered genetic counselling and, if icant peritoneal spread and involvement of the omentum.
possible, testing for the BRCA1 and 2 genes. These patients CT scanning can also show the degree of spread to adjacent
may also be offered screening for ovarian and breast organs and is useful for predicting operability. As many as
cancer. Prophylactic oophorectomy may also be recom- 6070% of patients have spread beyond the pelvis at diag-
mended in certain cases. nosis and are placed in stages III or IV. FIGO staging of this
disease is listed in Table 27.5.
Needle biopsy under CT control from the primary
Pathology tumour or omental metastases can confirm the diagnosis
Benign or malignant ovarian tumours may be solid or cys- in inoperable cases. Ascites may have to be drained to
tic. Some benign ovarian cysts may exceed 30 cm in diam- relieve discomfort and shortness of breath. Ascitic fluid
eter and weigh many kilograms. About 10% of ovarian should always be examined cytologically for the presence
tumours may be classified as borderline. These are tumours of malignant cells.
that have some histological features of malignancy but lack
stromal invasion. Treatment
Malignant ovarian tumours are subdivided into epithe-
lial, germ cell and sex cord. Eighty-five percent of ovarian Surgery
tumours are classified as of epithelial origin and develop The role of surgery is both diagnostic and therapeutic. At lapa-
from the surface epithelium of the ovary. Some histological rotomy, the full extent of peritoneal spread must be assessed,
subtypes are more aggressive than others and have a worse particularly the subdiaphragmatic areas and the paracolic gut-
prognosis. Undifferentiated and clear cell tumours tend to ters (the areas adjacent to the large bowel). The aim of surgery
have the worse prognosis. Mucinous tumours tend to pres- is to remove as much tumour as possible. If possible, both
ent with earlier stage disease and have a better outlook. ovaries and the uterus should be removed along with the
omentum. All macroscopic disease should be removed if pos-
sible. If not, residual peritoneal disease should be debulked
Method of spread
to leave individual residual tumours of less than 1 cm. There
Ovarian cancer tends to be a disease of the abdominal cav- are numerous non-randomized studies which indicate that
ity and rapidly spreads across the peritoneal cavity to optimal debulking improves prognosis but there have been
involve the omentum, a fatty apron close to spleen and left no randomized controlled trials comparing aggressive
kidney. There may be also multiple peritoneal deposits, debulking against more conservative surgery.
particularly in the subdiaphragmatic areas. These perito-
neal deposits may produce large volumes of ascitic fluid. Chemotherapy
A potentially fatal consequence of peritoneal disease is
intestinal obstruction. The cancer may also spread to pelvic Following surgery, the mainstay of treatment is chemother-
and para-aortic lymph nodes, the liver and pleural cavity of apy. Primary debulking surgery is only possible in 4050%
the chest by direct spread across the peritoneum or via the of women. A large number of patients have bulk residual
blood stream. Involvement of lung parenchyma is less disease after surgery. Patients with stage III or IV disease
common. Metastasis to other sites, particularly bone and even after optimal surgery will rapidly relapse without fur-
brain, is exceedingly rare. ther treatment but, fortunately, epithelial ovarian cancer
is fairly chemosensitive. Regimens such as carboplatin
and paclitaxel or carboplatin alone will give response rates
Clinical features of 6070% in advanced disease. Currently, there is consid-
Late stage diagnosis is the rule rather than the exception erable controversy over which is the best chemotherapeutic
and, justifiably, ovarian cancer has the nickname the regimen in this disease. In the USA and Germany, a combi-
silent killer. There are no typical symptoms. Women nation of paclitaxel and carboplatin is favoured. The Medi-
may complain of abdominal bloating or non-specific cal Research Council ICON3 study, which recruited
gastrointestinal symptoms. One of the first signs may be over 2000 patients mainly from the UK and Italy, showed
the discovery of a large pelvic mass or ascites. that optimal dose carboplatin gave as good results as carbo-
platin and paclitaxel. Median survival was approximately
3 years in both arms of the study. Recently, randomized
Investigations and staging
controlled trials have shown an improvement of almost
Investigations in most cases are for a pelvic mass with or 9% 5-year survival by the use of adjuvant chemotherapy
without ascites. The tumour marker CA125 is elevated in stage I disease and there is now a case for treating patients
(above 35 international units per litre (iu/L)) in about with early stage disease, especially those with adverse fea-
50% of patients with early stage and 80% of patients with tures, such as poorly-differentiated histology, with adju-
more advanced stage disease. CT scanning of the abdomen vant chemotherapy.
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Chapter | 27 | Gynaecological cancer
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Walter and Millers Textbook of Radiotherapy
demonstrated 5-year survivals of up to 90% in this group of need very close follow up owing to the risks of developing a
women. The 5-year survival for stage II disease is 40 60%. True further tumour in the remaining ovary.
stage II cases are relatively uncommon. The bulk of women This tumour is extremely chemosensitive. The BEP regi-
have stage III disease which carries a 3040% 5-year survival. men (bleomycin, etoposide and cisplatin) is effective if
The 5-year survival for stage IV disease is about 510%. patients relapse after surgery with a 5-year survival of about
85%. The tumour is quite radiosensitive and, in the past,
patients have been treated with wide-field radiotherapy
RARE TUMOURS OF THE OVARY with doses between 20 and 40 Gy in 24 weeks. Good
long-term survival has been reported following wide-field
radiotherapy. However, my experience is that chemother-
Sex-cord tumours apy gives better results than radiotherapy. An added advan-
The most common of the sex-cord tumours are granulosa tage is that fertility is more likely to be preserved following
cell tumours. These display a spectrum of aggressiveness. chemotherapy than radiotherapy.
Some may behave in benign fashion and others extremely More than 98% of ovarian teratomas are benign, most
aggressively. They are found predominantly in post- commonly cystic teratomas or dermoid cysts. Malignant
menopausal women but can occur at any age including teratomas are rare and have a similar histological appear-
before puberty. These tumours often produce steroid ance to those arising in the testes. The same chemotherapy
hormones, particularly oestrogens, which can cause post- regimens used to treat the more common testicular terato-
menopausal bleeding in older women and precocious mas in males are also used in ovarian disease, particularly
puberty in young girls. Over 80% of patients present with the BEP regimen. The outlook for such patients is not as
stage I disease. Treatment is predominantly by surgery. Bilat- good as male testicular teratoma patients with a 5-year
eral disease occurs in up to 25% of patients. Usually, both survival of about 50%.
ovaries are removed along with the uterus. A single ovary
may be removed in young women with stage I disease pre-
serving fertility. Granulosa cell tumours can recur up to 30 TUMOURS OF THE VAGINA AND
years after initial surgery. The site of recurrence is usually VULVA
within the abdominal cavity or the liver. Metastases from
granulosa cell tumour can be hemorrhagic leading to internal
There were only 243 new cases of vaginal cancer in the UK
bleeding. Because of the rarity of this tumour there have
in 2007. This may be because the FIGO rules state that if
been few comparative studies of chemotherapy in this disease
the cervix or the vulva is involved the tumour should be
but cisplatin-based regimens, such as the BEP regimen (bleo-
assigned to either site. The staging of vaginal cancer is
mycin, etoposide and cisplatin) or CAP (cyclophosphamide,
listed in Table 27.6.
Adriamycin, cisplatin), can offer very useful palliation.
The majority of tumours are squamous and tend to occur
Most of the radiotherapy literature comes from the
in women over 60. Surgery as a primary treatment has a lim-
1960s, but this tumour is more radiosensitive than the
ited role and the majority of patients are treated in a similar
commoner epithelial cancers. Pelvic radiotherapy is some-
fashion to cervical cancer. Usually, such patients receive
times used as an adjuvant after surgery or in the palliation
of advanced disease. Pelvic fields are treated with doses
of 4550 Gy in 2025 fractions depending on the size of
Table 27.6 FIGO 2009 staging: carcinoma of the vagina
treated volume. Overall, the prognosis is good in the short
term with a 5-year survival of over 80%. Stage 0 Carcinoma in situ, intraepithelial neoplasia
Leydig-Sertoli cell tumours are rare. More than half of Grade III
these tumours produce male hormones that can cause vir-
ilization. The majority of these tumours behave in a benign Stage I The carcinoma is limited to the vaginal wall
fashion and present with stage I disease. Malignant lesions
are exceedingly rare. Stage II The carcinoma has involved the subvaginal
tissue but has not extended to the pelvic wall
Germ cell tumours Stage III The carcinoma has extended to the pelvic wall
Dysgerminomas account for 25% of all ovarian tumours Stage IV The carcinoma has extended beyond the true
and usually occur in women under 30 years old. Histologi- pelvis or has involved the mucosa of the bladder
cally, they are similar to seminoma of the testes in men and or rectum; bullous oedema as such does not
tend to spread in a similar way via the pelvic and para-aortic permit a case to be allotted to stage IV
lymph nodes. The majority of tumours present with stage I IVa Tumour invades bladder and/or rectal mucosa
disease, although up to 15% of tumours can be present in and/or direct extension beyond the true pelvis
both ovaries. Surgery is usually aimed at conservation of IVb Spread to distant organs
fertility with removal of only one ovary, but such patients
482
Chapter | 27 | Gynaecological cancer
Stage II Tumour of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with
negative nodes
Stage III Tumour of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina,
anus) with positive inguino-femoral lymph nodes
IIIa (i) With 1 lymph node metastasis (5 mm) or
(ii) 12 lymph node metastasis(es) (<5 mm)
IIIb (i) With 2 or more lymph node metastases (5 mm) or
(ii) 3 or more lymph node metastases (<5 mm)
IIIc With positive nodes with extracapsular spread
Stage IV Tumour invades other regional (2/3 upper urethra, 2/3 upper vagina) or distant structures
IVa Tumour invades any of the following:
(i) Upper urethral and/or vaginal mucosa, bladder mucosa, rectal mucosa or fixed to pelvic bone or
(ii) Fixed or ulcerated inguinofemoral lymph nodes
IVb Any distant metastasis including pelvic lymph nodes
pelvic radiotherapy, the target volume being the whole is administered to this region and patients develop a risk
vagina and the pelvic lymph nodes. If the patient is fit enough, of radiation reactions with moist desquamation after rela-
cisplatin should be given along with external beam radio- tively modest doses of radiotherapy such as 45 Gy in
therapy. This would be followed by an intracavity insertion 25 fractions. This limits the scope of radiotherapy in this
for tumours in the upper half of the vagina or iridium im- disease. Radiotherapy has been shown to reduce pelvic
plantation for tumours in the lower half of this structure. and groin recurrences when given postoperatively in
Results of treatment tend to be somewhat worse than in patients with one or more positive lymph nodes. There is
cervical cancer with about a 75% 5-year survival for stage I, also an improvement in 5-year survival.
60% for stage II, 30% for stage II and 15% for stage IV. Chemoradiotherapy is being used increasingly in
Vulval cancer tends to be a disease in elderly women patients who have initially inoperable disease. Drugs such
with a mean age of diagnosis of approximately 70 years. as cisplatin, 5-fluorouracil and mitomycin have been given
Seventy-five percent of vulval cancers are squamous carci- along with radiation therapy. A review of published data
noma and they predominantly metastasize via the lym- has shown that the complete response rate is 60% follow-
phatic system to the groins. Staging takes into account ing chemoradiotherapy but the complication rate for
the tumour size and whether lymph node metastases are this treatment can be high with up to a 10% death rate, par-
present (Table 27.7). The primary treatment of vulval car- ticularly secondary to neutropenic sepsis. Chemoradiother-
cinoma is surgery using the triple incision technique, a apy can shrink inoperable tumours and make such lesions
bilateral groin node dissection and radical vulvectomy. operable. However, wound healing may be impaired.
As many of the women with this disease are elderly and The most important factor in vulval cancer is the pres-
have intercurrent disease, some are not suitable for this ence of inguinal nodal metastases. Patients without nodal
treatment. However, there is difficulty in administering involvement have a 7080% 5-year survival. Survival falls
radiotherapy to this region. The folds of the groin and vulva to 3050% for those with involved inguinal lymph nodes
lead to loss of skin sparing when megavoltage radiotherapy (one to more than four positive lymph nodes).
FURTHER READING
[1] Pecorelli S. Revised FIGO staging for [2] Landoni F, Maneo A, Columbo A, cervical cancer. Lancet
carcinoma of the vulva, cervix and et al. Randomised study of 1997;350:2833.
endometrium. Int J Gynaecol Obstet radical surgery versus [3] Green J, Kirwan J, Tierney J, et al.
2009;105:1034. radiotherapy for Stage Ib-IIa Survival and recurrence after
483
Walter and Millers Textbook of Radiotherapy
concomitant chemotherapy and surgery alone for patients with stage I chemotherapy with either single
radiotherapy for cancer of the uterine endometrial carcinoma: multi-centre agent carboplatin or
cervix: a systematic review and meta- randomised trial. PORTEC study cyclophosphamide doxorubicin and
analysis. Lancet 2001;358:7816. group. Post operative radiation cisplatin: in women with ovarian
[4] Vale CL, Tierney JF, Davidson SE, therapy in endometrial carcinoma. cancer: the ICON 3 randomised trial.
Drinkwater KJ, Symonds P. Lancet 2000;355:140411. Lancet 2002;360:50512.
Substantial improvements in [7] International Collaborative Ovarian [9] McGuire WP, Hoskins WJ, Brady MT,
UK cervical cancer survival Neoplasm Trial 1 and Adjuvant et al. Cyclophosphamide and
with chemoradiotherapy: results of Chemotherapy in Ovarian cisplatin compared with paclitaxel
a Royal College of Radiologists Neoplasm. Two parallel and cisplatin in patients with
Audit. Clin Oncol 2010;22: randomised phase III trials of stage III and stage IV ovarian cancer.
590601. adjuvant chemotherapy in N. Engl. J. Med. 1996;334:16.
[5] Faust G, Davies Q, Symonds P. patients with early stage ovarian [10] Homesley H, Bundy BN, Sedilis A,
Changes in the treatment of carcinoma. J Natl Cancer Inst Adcock L. Radiation therapy versus
endometrial cancer. Br J Obstet 2003;95:10512. pelvic node dissection for
Gynaecol 2010;117:10436. [8] International Collaborative Ovarian carcinoma of the vulva with positive
[6] Creutzberg CL. Surgery and post Neoplasm (ICON) Group. Paclitaxel groin nodes. Obstet Gynecol
operative radiotherapy versus plus carboplatin versus standard 1986;68:73340.
Figure evolve 27.12 Four-field plan Figure evolve 27.25 Boost treatment
stage IIb ca cervix wedge pair to large external iliac node
from endometrial cancer
484
Chapter | 28 |
Kidney, Bladder, Prostate, Testis, Urethra, Penis
Duncan B. McLaren
Treatment 490
CHAPTER CONTENTS
Superficial Ta and T1 tumours 491
Kidney 486 Invasive bladder cancer (T2 and T3) 491
Anatomy 486 Adenocarcinoma and squamous carcinoma of the
Pathology 486 bladder 491
Spread 486 Neoadjuvant chemotherapy 491
Clinical features 487 Radical radiotherapy 492
Investigation and staging 487 Palliative radiotherapy 493
Treatment 487 Chemotherapy 493
Surgery 487 Results of treatment 493
Embolization 488 Prostate 493
Radiotherapy 488 Anatomy 493
Chemotherapy 488 Pathology 493
Immunotherapy 488 Hormonal sensitivity 494
Tyrosine kinase inhibitors (TKIs) 489 PSA and screening 494
Results of treatment 489 Clinical features 495
Bladder 489 Diagnosis and staging 495
Anatomy 489 Treatment 495
Pathology 489 Clinically localized disease T12N0M0 495
Aetiology 489 Locally advanced T3N0M0, T4aN0M0 499
Epidemiology 489 Metastatic disease 499
Macroscopic appearance 489 Testis 500
Microscopic appearance 490 Anatomy 500
Clinical features 490 Pathology 501
Investigation and staging 490 Aetiology 501
Urine 490 Tumour markers 501
Biochemistry 490 Clinical features 502
Radiology 490 Diagnosis and staging 502
Cystourethroscopy 490 Treatment 502
486
Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
Clinical features
Presentation is usually with local symptoms. Painless
hematuria is the commonest or colicky pain secondary to
clots of blood. Other symptoms are aching or a mass in
the loin which may be noticed by the patient. A coinciden-
tal finding following radiological imaging of the abdomen
is an increasingly common presentation. Distant metastasis
may be the first presentation, such as pathological bone
fracture, haemoptysis from pulmonary metastases or symp-
toms of raised intracranial pressure from cerebral deposits.
Systemic features such as anaemia, loss of weight and unex-
plained fever may occur. The kidney may be palpably
enlarged.
Surgery
Nephrectomy is indicated for tumours confined to the kid-
ney and/or regional nodes. Extension into the inferior vena
cava is not necessarily a contraindication to surgery. There
is debate as to the role of nephrectomy in the presence of
metastatic disease. Bulky, symptomatic tumours with small
volume metastases should still be considered for nephrec-
tomy prior to starting TKIs at subsequent radiological pro-
gression. In selected patients, aggressive surgical removal of
the primary tumour together with solitary metastases, par-
ticularly in lung and bone, may be followed by up to 35%
5-year survival. Palliative removal of the kidney may be
Figure 28.2 CT scan showing a typical renal cell carcinoma in required to control pain or haemorrhage or if a painful syn-
the right kidney. drome following embolization occurs.
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Walter and Millers Textbook of Radiotherapy
488
Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
Tyrosine kinase inhibitors (TKIs) associated with 2-naphthylamine, now recognized as a pro-
carcinogen. Workers in these industries are now offered regu-
The most exciting agents in the treatment of renal cancer
lar cytological examination of urine to detect abnormalities or
are the oral tyrosine kinase inhibitors, sunitinib and pazopa-
tumours at an early stage.
nib which are now used as first line therapy. TKIs inhibit
Smoking is perhaps the commonest factor that predis-
a number of tumour cell proliferations and angiogenesis
poses to bladder cancer. Bladder cancer is up to six times
pathways, particularly vascular endometrial growth factor
commoner in smokers than non-smokers and increases
receptor (VEGFR), platelet derived growth factor receptor
in frequency with the number of cigarettes smoked. Phen-
(PDGFR) and the stem cell receptor c-kit. Sunitinib has been
acetin, formerly used as an analgesic drug, and the cytotoxic
shown to give a longer median progression-free survival (11.9
alkylating agent cyclophosphamide may give rise to urothe-
months versus 5 months) than alpha interferon in a large
lial tumours. Squamous carcinoma tends to complicate
randomized trial of previously untreated patients with meta-
chronic irritation of the bladder including a parasitic dis-
static renal cancer plus a higher objective response rate (31%
ease, schistosomiasis (formerly known as bilharziasis),
versus 6%). Diarrhea, skin marks (handfoot syndrome) and
which is common in Egypt and Central Africa. Adenocarci-
hypertension are the most common adverse effects. At pro-
noma occurs on the dome of the bladder in relation to
gression second line agents both TKIs and mTor inhibitors
embryological remnants of the urachus, and also from
appear to offer potential further survival benefit.
the trigone at the bladder base.
Genetic alterations in bladder cancer are common.
Results of treatment Deletion of markers on chromosome 9 is an early event.
Subsequent mutation in p53 allows cells with DNA damage
The outlook depends on the stage at diagnosis. For tumours
to proceed through the cell cycle, replicating genetic errors.
confined to the kidney, 5-year survival varies from 50 to
Loss of the pRb (retinoblastoma) gene product disrupts cell
80%. Extrarenal or renal vein invasion, lymph node and
cycling and increases the mitotic index. Patients with both
blood-borne metastases all confer a poor prognosis.
mutations have higher-grade more advanced disease and a
Patients with metastatic disease at presentation have a
poor response to treatment.
median survival of only 12 months, with 20% remaining
alive 2 years from diagnosis.
Epidemiology
BLADDER Bladder cancer is common and accounts for 4.4% of all
cancers and 3.4% of cancer deaths. The male to female ratio
is 3.8:1 and it has a peak incidence at the age of 65. The
Anatomy impact of smoking in women has seen a greater rise in inci-
The bladder is related anteriorly to the pubic symphysis, dence in this group over the last 10 years compared to men.
superiorly to the small intestine and sigmoid colon, later- It is twice as common in Caucasians as in Blacks. Over 90%
ally to the levator ani muscle, inferiorly to the prostate are transitional cell carcinomas.
gland and posteriorly to the rectum, vas deferens and semi-
nal vesicles (see Figure 28.7) in the male and to the vagina Macroscopic appearance
and cervix in the female. At cystoscopy, the bladder mucosa
and ureteric orifices can be inspected. Lymphatic drainage The chief types on inspection of the bladder are (1) papil-
is to the iliac and para-aortic nodes. lary and (2) solid. Multiple growths are common.
Papillary carcinoma has a base with surface fronds. The
tumours tend to be multiple and to appear in crops. Confined
Pathology at first to the mucosa and submucosa, they eventually invade
The bladder, ureters and renal pelvis are lined by transitional the submucosa, muscle coat and then outside the bladder.
cell epithelium (urothelium). The same type of tumours Solid carcinoma is nodular, often ulcerated, grows more
may arise anywhere along the urinary tract but cancers in rapidly and infiltrates early.
the renal pelvis and ureter are rare compared with those From the point of prognosis, a division can be made
in the bladder. Prostatic adenocarcinoma and other pelvic between superficial (papillary) and invasive (solid) bladder
tumours also sometimes secondarily involve the bladder. cancer. Superficial bladder tumours are the commonest
(80%) and become invasive in 1020% of cases. By con-
trast, invasive cancer, untreated, carries a very poor progno-
Aetiology
sis. The degree of invasion correlates with the risk of
In the majority of cases of bladder cancer, the aetiology is metastatic disease. Invasion of the lamina propria (the
unknown. However, as discussed in Chapter 14, occupational layer of tissue between the epithelium and the muscle layer
exposure to certain carcinogens has accounted for some cases. of the bladder), superficial and deep muscle is associated
The production of aniline dyes and processing of rubber are with 20%, 30% and 60% incidence of lymphatic invasion.
489
Walter and Millers Textbook of Radiotherapy
Microscopic appearance higher up in the renal tract. Obstruction at the lower end of
the ureter(s) will be shown by dilatation of the ureter and
Benign tumours of the bladder are very uncommon. How-
renal pelvis (hydroureter and hydronephrosis). Filling
ever, low-grade transitional cell malignant tumours are
defects in the bladder can also be shown. A CT scan of
often erroneously referred to as papillomas.
the abdomen and pelvis may demonstrate extravesical
Malignant tumours of the bladder include:
spread or lymphadenopathy. Magnetic resonance imaging
transitional cell carcinoma; papillary and solid variants (MRI) scanning is the more effective modality to demon-
adenocarcinoma (uncommon) strate deep muscle invasion and spread to pelvis lymph
squamous carcinoma (rare in the UK) nodes.
sarcomas (all very rare).
Transitional carcinoma accounts for 90% of bladder cancer
Cystourethroscopy
and is classified histologically into grades 13 corresponding
to well-, moderately- and poorly-differentiated tumours. The This is the most important investigation of all. Under gen-
degree of differentiation is important. High-grade tumours eral anesthesia, the urethra and the whole of the bladder are
grow faster and infiltrate sooner. inspected. The number, site, size and character of the
After muscle has been invaded, lymphatic spread is to the tumours are noted and a biopsy taken. While the patient
pelvic and then para-aortic nodes. Blood-borne metastases is relaxed under the anesthetic, a bimanual examination
are common to lung, liver and bone. of the pelvis is made, with a finger in the rectum and the
other hand on the lower abdomen. In this way, the tumour
may be palpated and any extravesical spread assessed.
Clinical features Clinical staging of bladder cancer is according to the
The presenting symptom is usually painless frank hematu- TNM classification (Figure 28.4 and Table 28.2).
ria. Occasionally, clots of blood are passed and are even
more suggestive of the diagnosis. Papillomatous types grow
Treatment
slowly and may cause no other symptoms for a long time.
When aggressive carcinomas invade muscle, there may be Treatment will depend on the stage, histology, size and
urinary frequency, dysuria and pain, especially when there multiplicity of tumours and the age and general medical
is extravesical (i.e. outside the bladder) spread into the pel- condition of the patient.
vic soft tissues. Bacterial cystitis may be associated with the
tumour and may aggravate symptoms.
Obstruction of one or both ureters can occur at any time, 1 - Epithelium
2 - Subepithelial connective tissue
with no symptoms at first. Later, there may be upper uri- 3 - Muscle
4 - Perivesical fat 1/
nary tract infection, pain in the flank(s) and eventual renal 2
failure from backpressure. In localized bladder disease,
clinical examination is usually unremarkable.
Biochemistry
Serum urea, creatinine and electrolytes are measured for
evidence of renal impairment.
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
Tumour T2 tumours
Tis Carcinoma in situ Endoscopic resection (TURBT) alone is inadequate to con-
trol these tumours. Additional radical treatment with either
Ta Papillary non-invasive carcinoma cystoprostourethrectomy (removal of the bladder and
T1 Invasion into submucosa but not beyond the prostate with diversion of the ureters onto the abdominal
lamina propria wall) or radical radiotherapy is required. Local practice will
determine treatment. Europe and America have favored
T2a Invasion into superficial detrusor muscle cystoprostourethrectomy as the treatment of choice. In
the UK, radical radiotherapy with salvage cystectomy for
T2b Invasion into deep detrusor muscle
those patients with persistent or recurrent tumour remains
T3a Invasion into perivesicular tissues microscopically a valid option. This policy has the advantage that the
patient has a better chance of tumour control with the blad-
T3b Invasion into perivesicular tissues macroscopically der intact. If radiotherapy fails, there is a 30% chance of
successful salvage by cystectomy. By contrast, if primary
T4a Invasion of prostate or vagina
cystectomy fails, radical radiotherapy is rarely successful
T4b Invasion of pelvic side-wall or abdominal wall for recurrent disease. Each policy carries a similar 5-year
survival of about 5060%.
Nodes
N0 No evidence of nodal involvement T3 tumours
If bimanual palpation and/or radiological imaging have
N1 Single node <2 cm diameter demonstrated macroscopic extension of disease outside the
N2 Single nodal metastasis 25 cm diameter or bladder, cure rates fall to around 40% at 5 years. Such
multiple nodes none exceeding 5 cm patients are more commonly treated with radical radiother-
apy than with surgery. Combined modality treatment with
N3 Node >5 cm concurrent chemotherapy (5FU and mitomycin C or nicotin-
amide and carbogen) and radiotherapy appears to improve
Metastases local control at 2 years in comparison to standard conformal
M0 No metastases radiotherapy alone in patients with T2-T3 disease.
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Walter and Millers Textbook of Radiotherapy
Radical radiotherapy
The following are criteria for accepting patients for radical
radiotherapy:
age <80 years (unless particularly fit)
adequate general medical condition
no inflammatory bowel disease or symptomatic
adhesions Figure 28.5 Simulator radiograph showing anterior treatment
good bladder function volume for radical radiotherapy of a transitional cell carcinoma
minimal or no CIS of the bladder.
transitional cell carcinoma
single tumour <7 cm maximum diameter
1
100
no metastases. 104 104
70
Plod Batha 5mm gc Id
Isodoses (%)
50
60
70
95
Target volume 3
70
50 50
100
104
100 60
60 50 60
bladder is emptied before CT planning and before each 104
70
100 50
60
treatment. 50
492
Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
the BCON study has improved local control and survival in Technique
comparison to RT alone. A parallel-opposed anterior and posterior pair of fields are
used. A cystogram is recommended for bladder localization
Radiation reaction preferably or virtual simulation if available. The treatment
Before radiation begins, attention is paid to the patients volume includes the bladder with a 2 cm margin or bladder
general condition and nutrition. The patients hemoglobin and pelvic nodes if involved.
level should be maintained over 12 g/dL, by blood transfu-
sion if necessary, since anaemia will reduce the amount of Dose and energy
oxygen available to the tumour. It is known that reduced
30 Gy in 10 daily fractions over 2 weeks (916 MV)
oxygenation in parts of the tumour contributes to resis-
or 21 Gy in 3 fractions over 1 week (916 MV).
tance to radiation. Urinary infection should be treated with
antibiotics. The urine should be made sterile if possible
before radiation begins, since inflammation has adverse Chemotherapy
effects on radiation response. However, with an ulcerated
Response rates of greater than 50% have been reported
mass this may not be possible until the tumour has shrunk
using cisplatin-based regimens, such as cisplatin, metho-
in response to radiation.
trexrate and vinblastine (CMV), methotrexrate, vinblastine,
doxorubicin and cisplatin (MVAC) or gemcitabine and cis-
Acute reactions platin (GC) for metastatic disease. Median survival follow-
1. Frequency and urgency, from radiation cystitis ing chemotherapy depends on sites of disease. Nodal
during and after the course, are common but not usually disease carries a relatively good prognosis with a median
serious unless bacterial infection is gross. Painful spasm survival of 24 months, in comparison, median survival
may require an antispasmodic drug. Fluid intake must for disease in organs such as the liver, remains disappoint-
be strongly encouraged. The patient should be warned ing at <12 months.
that he or she might pass fragments in the urine (blood
clot and tumour) and a little fresh blood.
2. Bowel reactions are also to be expected in almost every Results of treatment
case usually mild diarrhea and tenesmus. If they are The 5-year survival for radical radiotherapy is 80% for T1,
severe, treatment may have to be suspended or dosage 5560% for T2, 4045% for T3 and 2530% T4 tumours.
reduced.
Palliative radiotherapy
Palliative radiotherapy should be considered in the follow-
Pathology
ing circumstances: age (>80 years) or poor general condition Cancer of the prostate gland is the second commonest
with either significant local symptoms (e.g. hematuria) or malignancy in men in the UK. In total, 37051 new cases
symptomatic metastases, e.g. bone and skin. and 10168 deaths were recorded in 2008. There has been
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Walter and Millers Textbook of Radiotherapy
Post. aspect of
bladder Gleasons Pattern Scale
Vas deferens
Well
1. Small, uniform glands. differentiated
1
2. More space (stroma)
between glands.
2 Moderately
differentiated
Ureter 3. Distinctly infiltration of
cells from glands at margins.
3 Poorly differentiated
Anaplastic
4. Irregular masses of neoplastic
cells with few glands.
Seminal vesicle 4
5. Lack of or occasional glands,
5 sheets of cells.
Prostate
Figure 28.8 Gleason grading system for carcinoma of the
Figure 28.7 Prostate, seminal vesicles and vas deferens in a prostate.
posterior view of the bladder. (Reproduced with permission from Kirby R S, Brawer M K and Denis L J
(Redrawn from Ellis, Clinical Anatomy, 5th edn, Blackwells, 1975) (eds) 2001 Prostate Cancer Fast Facts, 3rd edn, Health Press)
a significant rise in the incidence of prostate cancer in the readily invades the pelvic veins and thence the pelvic
last twenty years due to a combination of increased aware- bones and vertebrae. Bone secondaries are typically of
ness, PSA testing and an ageing population with the oppor- sclerotic type, showing as an increased density on the
tunity to develop the disease. radiograph because they induce new bone formation.
The exact aetiology of prostatic cancer is unknown. It is The natural history of the disease is very variable. It may
commonest in the seventh and eighth decades and rare be indolent in the elderly patient with a well-differentiated
under the age of 40. Marked worldwide variations in inci- tumour and an incidental finding at post-mortem. The dis-
dence exist. In particular, Japan has rates considerably ease tends to run a more aggressive course in younger men,
lower than in the USA. A correlation with diet and, in par- particularly with poorly-differentiated tumours.
ticular, high fat consumption is directly implicated. Genetic
factors have a role; siblings are at increased risk with a pos-
itive family history and USA Blacks have higher levels of Hormonal sensitivity
disease noted compared to USA Whites. Environmental
The prostate has analogies with the breast and is under
factors include exposure to radiation, heavy metals and
hormonal control. Removal of male hormones by orchi-
chemical fertilizers, although no definitive link has been
dectomy, or administration of female hormones (oestro-
determined.
gens), causes shrinkage of the normal gland, and of 80%
Over 95% are adenocarcinomas, 70% arising from the
of tumours.
peripheral part of the gland. The differentiation of prostate
cancer is graded according to the Gleason grading system. It
is based on the extent to which the tumour cells are
PSA and screening
arranged into recognizable glandular structures, grade 1
tumours forming almost normal glands while grade 5 Prostate-specific antigen is a glycoprotein that liquefies
tumours consist of sheets of cells (Figure 28.8). Because semen. Approximately 20% of men with PSA levels above
of the heterogeneity in prostate cancer, the two most com- the normal range of 4 ng/mL have prostate cancer, and this
mon grades seen are added together to give a Gleason score. risk increases to more than 60% in men with a PSA level
Before the advent of PSA testing and greater patient above 10 ng/mL. PSA levels increase in proportion to the vol-
awareness, in 75% of cases the tumour had spread beyond ume of disease and can be used to monitor the response to
the gland at the time of presentation, and 50% had distant treatment and development of metastatic disease. PSA has
metastases. The introduction of PSA screening in countries largely superseded the use of an enzyme, acid phosphatase,
such as the USA, however, has dramatically reduced the secreted by normal and malignant prostate tissue, in the
numbers of patients presenting with advanced disease. diagnosis and assessment of response to treatment.
Prostate cancer may spread directly to the bladder, semi- The benefits of screening for prostate cancer are as yet
nal vesicles and rectum. Lymphatic spread is to the obtura- unproven. The results of two large screening randomized
tor, presacral, internal and external iliac nodes. Further controlled trials (RCTs) were conflicting. The European
spread is to the common iliac and para-aortic nodes. It study improved prostate cancer survival by 20% but at
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
Treatment
Clinically localized disease T12N0M0 undertreatment may lead to potentially curable disease caus-
There are no randomized controlled trials to determine the ing significant morbidity or cancer-related death. Balancing
optimum treatment for early prostate cancer. The PRO- these issues requires time and experience.
TECT study randomized patients to either active monitor- Treatment options include:
ing, radical prostatectomy or radical radiotherapy and active surveillance (radical treatment still offered at
may help address the relative roles of these treatments progression)
for localized early prostate cancer in due course. watchful waiting (non curative hormonal therapy
The clinical behavior of the disease is unpredictable, a sit- offered at progression)
uation made worse by the lack of accurate prognostic indi- radical radiotherapy
cators of disease behavior. Aggressive treatment of indolent prostate brachytherapy
disease exposes patients to the toxicity of treatment, whereas radical prostatectomy.
495
Walter and Millers Textbook of Radiotherapy
Factors that should influence the choice are the age combination with neoadjuvant hormonal therapy versus
and general condition of the patient, the likelihood of dose escalation alone.
progression to symptomatic disease and the morbidity Intensity modulated radiotherapy (IMRT) may offer
of treatment, particularly on sexual function. In general, even greater gains. The ability of intensity modulated
patients should have a life expectancy of greater than 10 radiotherapy tightly to sculpt dose to the prostate, partic-
years before being treated radically. This is because ularly at the prostaterectal interface is of particular value.
untreated, it may take several years for there to be any Doses in excess of 80 Gy have already safely been adminis-
symptoms from their disease, and several years beyond tered with excellent PSA relapse-free survival without
that before death ensues. Generally, the higher the PSA, additional neoadjuvant hormonal therapy.
Gleason score and T stage, the higher the chance of In order for these radiation doses to be delivered,
tumour progression and the need for radical treatment. tight treatment margins are required which in turn
Elderly, medically unfit men with less-aggressive histolog- requires accurate tumour localization. Using online por-
ical features may be managed by watchful waiting (with tal imaging to localize bony anatomy ensures accurate
deferred hormonal therapy and/or palliative radiotherapy field set-up only. The prostate is a mobile organ, the posi-
for symptomatic progression). Younger fitter men with tion of which is influenced by changes in rectal and blad-
low risk prostate cancer may be treated with active moni- der filling. The two most popular methods of image
toring initially with radical treatment offered on progres- guided radiotherapy to ensure accurate treatment deliv-
sion of disease based on an increase in gleason grade on ery are daily mv or kv imaging of fiducial markers placed
repeat biopsy or significant rise in PSA. The philosophy within the prostate via transrectal ultrasound or the use
behind this approach is to spare treatment related toxicity of weekly cone beam CT.
in men who may have indolent disease.
There is evidence that radical therapy can cure loca- Radical radiotherapy
lized prostate cancer, with survival curves flattening off Target volume
between 10 and 15 years from treatment. The chance of
local control with radiotherapy decreases with increasing If the tumour staging demonstrates that the tumour is
PSA, grade and stage of disease. Neoadjuvant hormonal confined to the prostate and there is no obvious involve-
therapy for 3 months before radiotherapy has demon- ment of the pelvic nodes, the target volume is confined to
strated improved local control and survival for Gleason the tumour and any local extension (e.g. seminal vesi-
33 tumours over radiotherapy alone. The hormonal cles), with a 1 cm margin of normal tissue around it.
treatment reduces the size of the prostate by 30% and At the rectalprostate interface a margin of 0.6 cm is sat-
hence the treatment volume. It also reduces the number isfactory. The role of additional pelvic radiotherapy is
of tumour cells to irradiate, possibly through synergistic unclear, however, an increasing number of protocols
apoptotic mechanisms. treat the pelvis if there is a risk of nodal involvement
of at least 15%.
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
outline from anus to rectosigmoid junction, bladder and <30% to receive 67 Gy i.e 90%
femoral heads are marked and a plan produced. With con- <50% to receive 55.5 Gy i.e 75%
formal treatment, the volume is shaped to follow the pros- remainder to receive up to 44 Gy, i.e 60%
tate and, in so doing, shield as much of the normal tissues It is recommended that the 60% isodose should not cross
such as the rectum as possible (Figure 28.9). A typical iso- the posterior rectal wall.
dose distribution is shown in Figure 28.10. Dose escalation For bladder:
requires a two- phase technique. The PTV is shrunk to treat
the prostate and base of seminal vesicles with a 5 mm mar- <25% to receive 74 Gy, i.e 100%
gin after 56 Gy in 28 fractions if treating to 74 Gy. Dose vol- <50% to receive 67 Gy, i.e 90%
ume histograms are used to limit the dose to critical Dose and energy
structures such as rectum and bladder.
Hypofractionation 55 Gy in 20 daily fractions over 4 weeks
Typical dose volume constrainsts are outlined below.
(916 MV photons)
For rectum:
or
Up to 3% to receive 74 Gy i.e 100% 57 Gy-60 Gy in 19 to 20 daily fractions within the CHHiP
<25% to receive 70 Gy i.e 95% trial
Figure 28.9 Conformal radiotherapy for prostate cancer, anterior field without blocks (A) and with blocks (B).
1
50
50
50
60 50
70
70 95
100
60
100
95
50 80 50
70
90
RIGHT 50 50 LEFT 95
2
50
70
80
6070 50 100
70 60
50
50
A
B
Figure 28.10 Isodose distribution for radical radiotherapy of the prostate using anterior and two lateral fields. (A) Transverse section;
(B) sagittal section.
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Walter and Millers Textbook of Radiotherapy
Dose escalation: 74 Gy in 37 daily fractions over 7.5 weeks may lead to pubic arch interference at the time of implan-
(916 MV photons). tation. In these cases, a volume of up to 70 ml may be
reduced by 30% and so be suitable for subsequent implan-
Acute reactions tation after 3 months of androgen deprivation therapy.
About half way through a radical 4-week course, urinary Once the volume study has been performed, the images
frequency and, occasionally, dysuria occur. These can often are transferred to the planning computer. The exact seed
be relieved an anti-inflammatory agent, such as Froben location and number of needles required to deliver the
50 mg t.d.s. and normally settle within 4 weeks of the implant is then determined using 3D planning. The x
end of treatment. Diarrhea and tenesmus from acute and y coordinates are provided by the template grid against
proctitis have a similar time course and are treated with the perineum and the z coordinate set by the transrectal
a low-residue diet, Fybogel and, on occasion, steroid probe position in relation to the base of the prostate. Dose
suppositories. constraints to the rectum and urethra are built into the plan.
The second phase of the procedure is the implant itself.
Late reactions The patient is repositioned as for the volume study and the
Significant late reactions may occur in 35% patients. The prostate position is checked. The brachytherapist guides the
main late urinary effects are chronic cystitis, urethral stric- implant needles directly into the prostate through a closed
ture or incontinence. Loss of sexual potency also occurs. transperineal approach (Figure 28.11). Each needle is
At 2 years from completion of combined neoadjuvant hor- loaded with either iodine-125 or palladium-103 seeds. It
monal therapy and radical radiotherapy, 50% of previously has been suggested that palladium should be used for
potent men will be impotent. Bowel morbidity includes higher grade tumours owing to its greater dose rate. In prac-
rectal ulceration or stricture and small bowel obstruction. tice, however, there are no data to demonstrate any differ-
Symptoms are tenesmus, rectal bleeding or incontinence. ence in PSA relapse-free survival using either isotope. In the
Proctitis may respond to steroid (Predsol) enemas but, ulti- UK, the majority of centres use iodine-125. A dose of
mately, a defunctioning colostomy is required in excep- 145 Gy to a PTV of the prostate capsule plus 3 mm is deliv-
tional circumstances. ered. The inverse square law determines that the dose to the
rectum, bladder and neurovascular bundles is very low,
Results of radical radiotherapy with resultant decreased toxicity in comparison to external
The 5-year survival for T1 is 90%, T2 is 78% and, for T3, beam and surgery. The procedure takes approximately one
59%. hour and the patient is discharged the next day with rapid
resumption of normal activity.
Pelvic lymph node irradiation An alternative and increasingly popular approach to the
The treatment of pelvic lymph nodes remains controversial two-phase technique is intraoperative planning. With this
but is increasingly being adopted for high risk patients technique, the whole treatment is delivered in a single visit.
within the UK. A Radiation Therapy Oncology Group The patient is positioned in theater as before. The bra-
(RTOG) trial has shown better progression-free survival chytherapist places the needles under transrectal ultrasound
when pelvic irradiation (45 Gy in 25 fractions) is combined control into the prostate, usually adopting a modified
with definitive irradiation to the prostate (72.2 Gy). Many
centres offer whole pelvic radiotherapy if the risk of nodal
metastases exceeds 15%. The risk of pelvic lymph node
involvement is calculated by the following formula:
2=3 PSA Gleason score 6 10
percentage risk of nodal spread:
Seeds
Ideally, the pelvic nodes and the prostate should be treated
using an IMRT technique.
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
peripheral loading pattern. A plan is produced based around due to improved surgical visualization of the urethral anas-
the needle position. Optimization of the plan via adjust- tomosis and neurovascular bundles and potentially shorter
ment of the needle position is performed prior to loading inpatient postoperative stay. The use of robotic assisted
as an afterloading technique. Whichever technique is laparoscopic prostatectomy can shorten the surgical
adopted, the aim is to deliver a dose of 145 Gy to at least learning curve and is now available in a number of UK urol-
90% of the prostate (D90) on post-treatment dosimetry. ogy centres.
Appropriate selection criteria are listed below:
life expectancy of 10 years
Locally advanced T3N0M0, T4aN0M0
organ confined disease T1T2b on MRI
PSA less than 20 These patients have a greater risk of metastatic disease. The
Gleason score 7 combination of radiotherapy and hormonal therapy
international prostate symptom score (IPSS) <20 improves outcome. It is now accepted that for men with
(a high score indicates marked irritative or obstructive locally advanced prostate cancer (T3/4 Gleason Score
symptoms and predicts for post-treatment urinary 8-10), longer term hormonal therapy of at least 2 years
retention and significant urinary toxicity) improves survival over shorter 6 month therapy. It is
Q Max >10 cc/s (if below 10 cc/s then greater risk of important that hormonal therapy is given concurrently
post-treatment urinary retention) with the radiotherapy. In our institution, we offer 3 months
no previous TURP, (seeds fall into cavity and affect of neoadjuvant and concurrent hormonal therapy before
doseimetry) stopping the adjuvant hormonal therapy after 2 years if
prostate volume 50cc (above this the risk of pubic the PSA is 0.1 or less. PR07 has confirmed that the addition
arch interference increases). of radiotherapy to locally advanced disease improves sur-
vival over hormone therapy alone and is now the accepted
The major toxicity is radiation-induced urethritis that may
standard of care. The definition of treatment failure follow-
last some months. Frequency, dysuria and mild obstructive
ing radical radiotherapy is the nadir PSA value post treat-
symptoms are common. Urinary retention and proctitis
ment + 2ng/ml as per the Houston definition.
may be seen in 5% of patients. Patients are routinely placed
on an alpha blocker for 36 months and encouraged to
have a high fluid intake. Proctitis is treated as for external Metastatic disease
beam radiotherapy. In carefully selected patients, outcomes
appear very good with PSA relapse-free survival of greater Hormonal therapy
than 90% at 10 years of follow up in good prognosis Most prostatic tumours contain elements sensitive to the
patients. Clinical trials comparing radical prostatectomy androgenic hormone testosterone. Hormonal treatment is
to prostate brachytherapy have so far not been undertaken. designed to reduce levels of testosterone circulating in the
blood. This may be achieved in a number of different
Prostate BrachytherapyHigh Dose Rate HDR ways:
High dose rate brachytherapy is increasingly being adopted 1. removal of the testes, which secrete testosterone
as a treatment for men with high risk prostate cancer in (orchidectomy)
combination with external beam radiotherapy. A single 2. oral oestrogens, e.g. diethylstilbestrol
high dose 15 Gy HDR boost dose followed by 35.75 Gy 3. chemical compounds, similar to luteinizing
in13 fractions of external beam to the prostate and seminal hormone-releasing hormone (LHRH analogues),
vesicles two weeks later has been commonly used. For which diminish the pituitary production of
those Centres wishing to treat pelvic nodes in addition luteinizing hormone (LH) and thus reduce
then 46 Gy in 23 fractions following the implant are testosterone production these are administered by
required. HDR can deliver very high biologically effective monthly or 3-monthly depot injection
radiation doses in a shortened overall treatment time to 4. oral agents which block the cellular action of
the tumour while the rapid fall off in dose limits surround- androgens (e.g. cyproterone acetate, biclutamide).
ing normal tissue toxicity. About 80% of patients will respond to hormonal therapy.
The median duration of response is 1824 months. Early
Radical prostatectomy intervention with hormonal therapy reduces complications
Patients who are medically fit with organ-confined disease of the disease, such as pathological fractures; however, it does
are suitable for surgery. A nerve-sparing radical prostatec- not appear to improve survival. Median survival once patients
tomy has improved potency rates post-procedure. Severe become hormone refractory is 6 months. Maximum andro-
incontinence is noted in <5%, but a higher proportion gen blockade does offer a small survival advantage in the
may have mild stress incontinence. Positive surgical mar- order of 2.5% at 5 years but at greater cost and toxicity.
gins in at least 30% of carefully staged patients are com- For this reason, it has not gained uniform acceptance. Inter-
mon. Laproscopic prostatectomy is gaining popularity mittent hormonal therapy is still under investigation.
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Walter and Millers Textbook of Radiotherapy
Cytotoxic chemotherapy the first hemibody irradiation to allow the systemic effects
There is renewed interest in cytotoxic chemotherapy in to settle and the blood count to recover.
hormone refractory patients. Recent randomized trial data Technique. The patient is treated supine. Parallel-opposed
comparing docetaxel (Taxotere) chemotherapy versus mitox- anterior and posterior fields are used at extended focus skin
antrone has for the first time demonstrated a survival benefit distance (FSD) (140 cm).
of nearly 3 months for the Taxotere arm. Taxotere 75 mg/m2 Dose and energy. Lower half of body
q21 with prednisolone 5 mg bd continuously over six to 10 8 Gy midplane dose in a single fraction (910 MV photons)
cycles would now be considered the gold standard regimen. Upper half
Introduction of chemotherapy at early stages of disease is an 6 Gy midplane dose in a single fraction (910 MV photons)
area of ongoing research. Second line treatment with Cabazi-
Strontium-89. Strontium-89 is a pure beta emitter with a
taxel chemotherapy and oral targeted hormonal Cyp17
half-life of 50 days. It is selectively taken up by bone metas-
blockers such as Aberaterone Acetate have further extended
tases. After a 150 MBq dose, relief of bone pain may occur
survival in men post Taxotere chemotherapy.
in 6070% of patients, with little hematological toxicity. It
is best avoided in those with a super-scan, as little benefit
Palliative radiotherapy can be expected. If used early in the metastatic process,
Radiotherapy has a useful role in relieving pain from bone strontium can delay the onset of symptoms in new sites
metastases. It can also shrink advanced local disease caus- of bone disease. Alpharadin or radium223 is an alpha emit-
ing symptoms of outflow obstruction and pelvic nodes ter that gives high dose irradiation to the bone and has
causing lymphedema and nerve compression. shown a survival advantage for men with hormone refrac-
tory disease over best supportive care in a recent rando-
Technique mized controlled trial. Biphosphonate therapy has been
Parallel-opposed field or single fields. demonstrated to reduce bone pain and risk of pathological
fractures in men with hormone refractory disease.
Dose and energy
1. Prostate: 30 Gy in 10 daily fractions over 2 weeks TESTIS
(910 MV photons)
2. Bone metastases confined to a limited area, e.g. lumbar
spine: single fraction of 8 Gy or 20 Gy in five daily Anatomy
fractions (46 MV photons) Each testis (the diminutive form testicle is also in common
use, with its adjective testicular) lies within a fibrous capsule
Widespread
(tunica albuginea) within the scrotum (Figure 28.12). In the
Hemibody irradiation. Where there are widespread painful
bony metastases, hemibody irradiation may be considered
to encompass all the painful areas. Improvement in pain
control tends to be prompt and may last the few months
Spermatic cord
until death. Treatment of the lower half of the body is better (Paratesticular
tolerated because the side effects are minimal. rhabdomyosarcoma) Cremasteric fascia
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
embryo, the testes arise on the posterior abdominal wall important. The first group of nodes to be invaded is the
and migrate downwards through the inguinal canal to the upper para-aortic, at the level of the renal hilum. Further
scrotum. lymphatic spread may be upward to the mediastinum and
The testis is divided into 200300 lobules. Each of these even the supraclavicular nodes through the thoracic duct,
contains one to three seminiferous tubules. These drain or downward to the lower para-aortic and pelvic nodes.
into the epididymis, which lies on the posterior border If extratesticular tissues of the scrotum are invaded,
of the testis. The lymphatic drainage of the testis is to the including the scrotal skin, their draining inguinal lymph
para-aortic nodes. It is important to note that the skin of nodes may be invaded. Blood-borne spread is much less
the scrotum drains to the inguinal nodes. To avoid surgical common.
contamination of the scrotal skin, the testis is surgically Spermatocytic seminoma is uncommon and generally
removed through an inguinal incision. seen in older men. The tumour cells show differentiation
to spermatocytes, and their behavior is benign. Metastases
Pathology are extremely rare.
Aetiology Teratoma
The main factor predisposing to the development of germ cell Teratoma accounts for the remainder of germ cell tumours.
tumours of the testis is an undescended testis. This accounts Strictly speaking, a teratoma shows differentiation towards
for 10% of cases. The risk is increased fivefold if one testis is all three embryological germ cell layers of ectoderm (e.g.
maldescended and 12-fold if both are maldescended. How- skin, neural tissue), endoderm (e.g. gut, bronchi) and
ever, even if one testis is maldescended, there is an increased mesoderm (e.g. fat, cartilage). In practice, the British classi-
risk of testicular cancer in the normally descended testis on fication applies the term more widely (while American ter-
the other side. Intratubular germ cell neoplasia or carcinoma minology refers to this group as non-seminomatous germ
in situ is a premalignant condition which gives rise to malig- cell tumours). Teratomas are subtyped according to their
nancy in 50% of patients within 5 years. cell constituents as:
Testicular cancer is the commonest form of malignancy
teratoma differentiated
in men between the ages of 20 and 40. The incidence is
malignant teratoma intermediate
rising, possibly through increased exposure to environ-
malignant teratoma undifferentiated
mental oestrogens. Currently, there are about 2005 new
malignant teratoma trophoblastic.
cases per year in the UK (year 2000 figures). It accounts
for 0.1% of deaths from cancer. The types of common Teratoma differentiated (TD) shows cysts lined by various
(germ cell tumours) and rarer tumours and their sites of mature-looking epithelium surrounded by smooth muscle,
origin in the testis are illustrated in Figure 28.12. with islands of cartilage and neural tissue. In infants,
its behavior is benign but, in adults, it is rare and can
Germ cell tumours give rise to metastases. Malignant teratoma undifferentiated
(MTU), by contrast, has no recognizable differentiated struc-
There are two main tumour types that arise from the germ
tures, but has undifferentiated rather than carcinomatous
cells: seminoma and teratoma. Teratoma occurs mainly
tissue. It often has tissue resembling yolk sac (YST), and
between the ages of 20 and 35, and seminoma between
there are frequently syncytiotrophoblast giant cells. These
25 and 40 years. Over the age of 50, tumours are more
account for secretion of alpha-fetoprotein (AFP) and human
likely to be non-germ-cell tumours. These are non-Hodg-
chorionic gonadotrophin (HCG), respectively, which can be
kins lymphomas and tumours arising from other struc-
measured in the blood and are invaluable as markers of
tures of the testis (Sertoli and Leydig cell tumours).
tumour load. It has an aggressive clinical behavior with early
Paratesticular rhabdomyosarcoma (see Figure 28.12)
metastasis via lymphatics to para-aortic lymph nodes, and
occurs in infancy and in young adult life.
blood-borne spread to the lungs. Malignant teratoma interme-
diate (MTI) has a mixture of differentiated and undifferenti-
Seminoma ated tissues. Malignant teratoma trophoblastic (MTT) has tissue
Seminoma is the commonest type (60%). It arises from the resembling gestational choriocarcinoma (i.e. syncytiotro-
cells of the seminiferous tubules. It is solid with a pale cut phoblast and cytotrophoblast), either throughout or in com-
surface like a potato. There are two principal types: classical bination with features of other teratomas. Large amounts of
and spermatocytic. The characteristic histological feature of HCG are secreted and the clinical course is very aggressive
classical seminoma is its uniform appearance. The cells with widespread blood-borne metastases.
are rounded with a central nucleus and clear cytoplasm.
The tumour is divided into lobules by a fibrous stroma,
associated with a variable infiltration of lymphocytes. Tumour markers
Spread of seminoma may be local to the epididymis The two tumour markers, alpha-fetoprotein (AFP) and
and to the spermatic cord, but lymphatic spread is more human chorionic gonadotrophin (HCG) are helpful in
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Walter and Millers Textbook of Radiotherapy
iu/I A B C D E F
10 000 AFP
HCG
1000
100
10
3 6 9 12 36
Months
Figure 28.13 Tumour markers in the management of testicular cancer. (A) Both HCG and AFP are elevated before orchidectomy but
fall following operation (HCG more rapidly because of its short half-life). (B) No evidence of recurrence, followed by a rise in marker
levels. (C) Combination chemotherapy for recurrence is followed by a fall in levels to normal (D). (E) A further rise in marker levels is
treated more intensively and the patient is disease free at 3 years (F).
(Reproduced with permission from Souhami & Moxham, Textbook of Medicine, Churchill Livingstone, 1990)
the diagnosis, staging and monitoring of response to and histological examination. Immunocytochemical
treatment (Figure 28.13). AFP has a half-life of about stains of the tumour for the presence of AFP and HCG
5 days. It is produced by yolk sac elements but is not spe- may be positive. Blood levels of AFP and HCG are
cific to teratoma. Elevated levels occur in the presence of measured pre- and postoperatively. A chest radiograph
liver damage. HCG is mainly a marker of trophoblastic is required (for overt lung metastases), together with a
neoplasms; it can, however, occur in seminoma. The CT scan of the thorax (for small-volume lung and medias-
half-life of HCG is 24 hours and of the beta subunit tinal metastases) and of the abdomen (abdominal nodal
45 minutes. Markers for the presence of seminoma are and liver metastases).
much less reliable. Serum placental alkaline phosphatase The Royal Marsden staging classification (Table 28.5),
(PLAP) is often raised in the presence of seminoma, par- based on the extent of spread and bulk of disease, has been
ticularly if there is bulky disease. However, false-positive widely used for determining management. Although still
and false-negative results for PLAP are common. Lactate useful for seminoma stage II nodal size subgrouping, it has
dehydrogenase (LDH) is an important non-specific been largely superseded by the IGCCC prognostic grouping.
marker of disease volume and has been incorporated into
the International Germ Cell Consensus Classification Treatment
(Table 28.4).
Seminoma good prognosis
Clinical features Stage I and IIa
The usual presentation is a gradually enlarging painless tes- Postoperative abdominal node irradiation should be con-
ticular swelling, although atrophy of a testis may occur. The sidered. An alternative is a single cycle of carboplatin
tumour feels hard. A third of patients describe pain in the AUC5 which can reduce the risk of relapse on a par to radio-
testis, a third a dragging sensation, 10% give a history of therapy. Surveillance with chemotherapy for relapse is also
trauma. The first symptoms and signs may be of metastatic an option for selected men although the pattern of relapse
spread (hemoptysis from lung metastases, back pain from is less predictable than with teratoma and long term follow
para-aortic metastases, loin pain from ureteric obstruction up and scanning required.
or neck lymphadenopathy). Malignant teratoma tropho-
blastic (choriocarcinoma) may produce gynaecomastia Target volume
(breast enlargement). For stage I and IIa uncomplicated disease, postoperative
radiotherapy to the para-aortic nodes alone is still fre-
quently used. The 23% of patients who will relapse in
Diagnosis and staging
the pelvis following irradiation can then be salvaged with
The diagnosis is made by surgical removal of the testis chemotherapy. The upper margin of the para-aortic field
through an inguinal incision (inguinal orchidectomy) is at the level of the junction of the 10th and 11th thoracic
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
TERATOMA SEMINOMA
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Walter and Millers Textbook of Radiotherapy
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
patients with stage I disease following orchidectomy will Dosage and scheduling. Normally four courses of BEP
have subclinical metastases and will relapse (80% of whom are given at 3-weekly intervals. Patients with good risk dis-
will relapse in the first 12 months). To avoid overtreatment ease can be cured with just 3 cycles as demonstrated in the
of the majority of patients, a policy of close surveillance MRC TE20 trial without compromising the 90% overall
with treatment at relapse is recommended. Patients with survival. For those patients in the intermediate- or poor-risk
lymphatic or vascular invasion are at greater risk of relapse IGCC groups, survival is 4070%. Efforts to increase the
(40%) and are not suitable for surveillance. Such patients efficacy of chemotherapy schedules through dose intensifi-
are best treated by two cycles of adjuvant combination cation and new combinations are ongoing. As yet, there has
chemotherapy. been no improvement over standard BEP.
Surveillance Monitoring response to treatment. Clinical examina-
tion, chest radiograph, tumour markers, full blood count,
For patients for whom a surveillance policy is adopted,
and renal function tests are repeated before each cycle of
tumour markers, chest x-ray (CXR) and clinical examina-
treatment to monitor the response to and toxicity of
tion are performed monthly in the first year with 3-
treatment.
monthly CT scans of chest and abdomen. In the second
Following surgery, a fall in tumour marker levels in line
year, follow up should be 2-monthly with CT scans at 18
with their half-lives usually indicates that there is no resid-
and 24 months. Subsequent follow up should be 3-
ual disease. A slower fall or rising levels suggest residual
monthly for the third year, 6-monthly to the fifth year
disease.
and annually thereafter to 10 years.
It may be necessary to delay the next cycle of chemo-
Stages IIIV therapy or modify its dosage if blood count, renal func-
tion or hearing deteriorate below certain thresholds.
These stages should be managed by combination chemo- Every effort should be made to deliver the chemotherapy
therapy (see below). on schedule and granulocyte colony-stimulating factor
Cytotoxic chemotherapy (GCSF) support may be required. Chemotherapy should
not be given if the neutrophil count is below 1.0 109/
The development of curative combination chemotherapy L. CT scan of chest and abdomen is repeated after
for advanced testicular cancer in the 1980s has been one three cycles to confirm that the disease is responding.
of the most important advances in oncology. Rapid resolution of disease is usual after the first course.
The combinations of drugs used for treating seminoma Residual 24 cm masses may, however, persist for
are the same for teratoma. The most effective regimens several years.
contain cisplatin. Cisplatin was successfully combined
with vinblastine and bleomycin (PVB). Now vinblastine Management of residual abdominal masses
is replaced by etoposide, which is less myelotoxic, with-
out loss of efficacy. This regime is known as BEP Resection of residual abdominal masses following chemo-
(see Table 28.6). An attempt to reduce toxicity by replacing therapy is indicated for teratoma. Seminoma resection is
cisplatin with carboplatin has proved to be less effective. difficult and usually not indicated due to a lack of tissue
Before each course of chemotherapy, a number of investi- planes and tumour infiltration beyond resection margins.
gations are carried out to assess fitness to treat, and to A policy of observation is usually recommended. Resec-
modify dosage, if necessary, because of the toxicity of the tion of residual masses after treatment for teratoma
agents. A full blood count is required because of the mye- shows that most of them (44%) are due to differentiated
lotoxicity of etoposide. (mature) teratoma or to fibrosis and necrosis (34%).
Cisplatin is toxic to the kidney and to hearing. Renal Residual tumour is found in 22%. If recurrence occurs,
function tests (serum urea, electrolytes and creatinine, as it does in 1020% of patients, it is most likely to
24-hour urine creatinine clearance or formal EDTA GFR) develop at a site of initial involvement. If surgical expertise
and hearing (audiometry) should be measured before, dur- is available, resection of residual masses is desirable. It
ing and after treatment. serves both as a diagnostic and therapeutic procedure. Fur-
Bleomycin can be toxic to the lung (see below). Full lung ther chemotherapy is indicated if residual disease is
function tests (including gas transfer factor) are carried out found, but the outlook is poor, with less than 50% of such
before treatment and repeated if toxicity is suspected. patients remaining free of disease.
Sperm storage, if available, is desirable for men wishing
to father children following chemotherapy since sterility is Toxicity
commonly induced. Normally, an initial sample is exam- In addition to renal damage and ototoxicity (impaired
ined to count the number and motility of the sperm. If sat- hearing), cisplatin causes severe nausea and vomiting
isfactory, two additional samples are taken for sperm and peripheral neuropathy. The 5-HT antagonists (ondan-
banking. However, chemotherapy, if urgently required, setron and granisetron) can reduce nausea and vomiting.
should not be delayed to await this procedure. Intravenous hydration is required 24 hours before cisplatin
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Walter and Millers Textbook of Radiotherapy
is given and for 24 hours afterwards to reduce the risk of Female urethra
renal damage. Nonetheless, the majority of patients will
experience temporary renal damage. A 2025% reduction The tumour is twice as common in women as in men. In
in glomerular filtration rate is usual. the proximal third, transitional carcinoma predominates
Etoposide causes alopecia and myelosuppression. The and, in the distal two-thirds, squamous carcinoma predo-
incidence of septicemia with etoposide is less than with minates. The distal urethra drains to the inguinal nodes
vinblastine since it is less myelosuppressive. and the proximal urethra to the iliac nodes. Presenting fea-
Bleomycin may cause pneumonitis. Presentation is with tures are offensive discharge, bleeding or a mass.
progressive dysponea. This complication may occur after
relatively modest doses (e.g. 200 mg). It can be progressive, Treatment
is irreversible and carries a 1% mortality. Other side
effects are fever, skin rashes, pigmentation and Raynauds Surgery in the form of a cystourethrectomy is perhaps the
phenomenon. treatment of choice. In those who are unsuitable, then
attempts at organ preservation can be considered. For
Results of treatment superficial squamous carcinoma of the urethral orifice,
Ninety percent of patients with small-volume disease are three iridium hairpins are an alternative treatment. A dose
cured following chemotherapy. For large-volume disease of 6065 Gy is given in 67 days. For more proximal
in extralymphatic sites, the probability of survival is lesions, radical external beam irradiation using an anterior
reduced to 5070%. and two lateral wedged fields is used. A dose of 55 Gy is
The 5-year survival is 90% for stages I and IIa, 70% for given in 20 daily fractions over 4 weeks using megavoltage.
stages IIb and III, and 5060% for stage IV.
Results of treatment
TESTICULAR LYMPHOMA The cure rates with surgery and radiotherapy are similar at
about 50%.
Testicular lymphomas are rare (4% of testicular tumours).
They are mainly non-Hodgkins lymphomas. Clinical fea-
tures that help to differentiate them from germ cell tumours PENIS
are bilaterality (20% at presentation or subsequently),
older age group (over 50 years), different pattern of metas-
Cancer of the penis is a rare tumour responsible for 0.4% of
tases, absence of maldescent and of gynaecomastia. They
all cancers and 0.1% of cancer deaths. It occurs in older men,
are usually of high grade (diffuse large B cell). Stages IAE
typically between 50 and 70 years old. The disease is com-
and IIAE are only cured in 50% of cases with three cycles
moner in South-east Asia, China and Africa. In Uganda,
of CHOP chemotherapy and radiotherapy to the scrotum
penile carcinoma is the second commonest male cancer.
(IA) and involved nodes (IIA). For this reason, six cycles
of chemotherapy are recommended followed by radiother-
apy. For stage III and IV disease, CNS chemoprophylaxis is Pathology
required in addition to scrotal irradiation.
Aetiology
The disease rarely occurs among peoples who practice
Dose and energy circumcision. There is a high incidence in Hindus, who
35 Gy in 20 daily fractions over 4 weeks (610 MV photons) are never circumcised. Phimosis is present in up to
50% of cases. Poor penile hygiene is thought to be an
Results of treatment important predisposing factor. There is a strong association
with human papilloma virus infections. There are several
The prognosis is poor. Overall 5-year survival is 20%. For premalignant conditions, including viral warts (condy-
stage IAE and IIAE, it is 50%. Average survival with stage loma acuminata) and erythroplasia of Queyrat. The pri-
IV disease is about 8 months. mary tumours are squamous carcinomas, usually well
differentiated. Secondary deposits are rare but can occur
from prostate and bladder cancer.
URETHRA
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Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
more before presentation. The first sign may be an infected to distinguish tumour from infection. A CT scan of the pel-
or bloody discharge from beneath the prepuce. Growth is vis may show the extent of abdominal lymphadenopathy.
superficial at first, then by invasion of the penile shaft.
If the lesion is visible, the diagnosis is usually obvious. If
phimosis hides it, the glans must be exposed by incising
Treatment
and peeling back the prepuce (dorsal slit) or by complete Surgery and radiotherapy are the main treatments for
circumcision, under anesthesia. A biopsy is taken at the penile cancer. Factors which influence the choice of treat-
same time. ment, are the age and general condition of the patient,
Lymphatic spread occurs early to the inguinal nodes, the extent of the disease, the desire to retain sexual function
though enlargement here may simply reflect infection. and the capacity to pass urine in the standing position for
The nodes may eventually ulcerate. Blood-borne metas- young males.
tases are rare and late.
Surgery
Staging Specialized surgical techniques are now available which
Both TNM and Jackson staging systems are in use can excise early invasive tumours and reconstruct the
(Table 28.7). If inguinal nodes are enlarged, fine needle penis with a split skin graft for an excellent cosmetic
aspiration of the node with cells sent for cytology can help and functional result. More advanced tumours involving
the deeper corpora and urethra require amputation of part
or the whole of the penis. Although curative if the inguinal
nodes are not involved, the procedure is associated with
Table 28.7 TNM and Jackson staging systems considerable psychological morbidity, especially for
for penile cancer young males.
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Walter and Millers Textbook of Radiotherapy
Megavoltage
Treatment volume. If there is evidence of spread on to the
shaft of the penis, the whole of the penis should be treated.
Technique. A rectangular wax block with a central cylin-
drical cavity is made to encompass the penis and ensure
homogeneous irradiation of the whole volume. The penis
is treated en bloc by a parallel-opposed pair of lateral fields.
Dose and energy. 5055 Gy in 20 daily fractions over
4 weeks at megavoltage (46 MV photons)
or 60 Gy in 30 daily fractions over 6 weeks at 46 MV
photons.
Acute reactions
These are like skin reactions elsewhere but more marked
Figure 28.16 Afterloading rigid iridium wire implant of T1 and moist desquamation is commoner. The urethral reac-
penile cancer. tion causes discomfort and dysuria. If very severe it may
result in acute retention requiring catheterization.
Late reactions
Superficial or orthovoltage therapy These include telangiectasia, skin atrophy, urethral stricture
For very small (T1) superficial tumours 100 kV or 250 kV and necrosis. Urethral dilatation is required for stricture.
x-ray therapy may suffice. A 0.5 cm margin of normal sur- Necrosis occurs in less than 10% of cases.
rounding tissue is included in the treated volume. A dose of
50 Gy is given in 15 fractions over 3 weeks. Alternatively,
low-energy (6 MeV) electrons can be used using an appro- Management of regional nodes
priate thickness of Perspex over the lesion to bring up the If inguinal nodes are found to be histologically involved at
surface dose to 100%. presentation, a block dissection of the groin should be
508
Chapter | 28 | Kidney, Bladder, Prostate, Testis, Urethra, Penis
carried out, followed by radical radiotherapy to the pri- Dose and energy
mary. There is no value in giving prophylactic groin node 30 Gy in 10 daily fractions over 2 weeks at megavoltage.
irradiation. The only role for radiotherapy in the treatment
of groin nodes is for palliation. For fixed inoperable nodes Palliative chemotherapy
neoadjuvant chemotherapy for downstaging prior to lym-
phadenectomy for locally advanced patients can be Cisplatin-based chemotherapy can be considered for fit
considered. patients. Response rates of 3040% have been reported.
Results of treatment
Palliative radiotherapy
Early superficial tumours have a high cure rate: 5-year sur-
Technique vival for stage I disease is about 90%. This falls to 60% in
A simple parallel-opposed pair of fields to the affected groin. stage II and 3040% in stage III.
FURTHER READING
Bolla M, Van Tienhoven G, Warde P, et al. Schroder FH, Hugosson J, Roobol MJ, Motzer RJ, Hutson E, Tomczak MD, et al.
External irradiation with or without et al. Screening and prostate cancer Overall survival and updated results
long-term androgen suppression for mortality in a randomized European for sunitinib compared with
prostate cancer with a high metastatic Study. N Engl J Med 2009;360 interferon alfa in patients with
risk: 10-year results of an EORTC (13):13208 Epub 2009 Mar18. metastatic renal-cell carcinoma. J Clin
randomized study. Lancet Oncol De Wit R, Roberts JT, Wilkinson PM, et al. Oncol 2009;27(22):358490. Epub
2010;11(11):106673. Epub 2010 Equivalence of three or four cycles of 2009 Jun 1.
Oct 7. bleomycin, etoposide and cisplatin Rini BI, Escudier B, Tomczak P, et al.
Bolla M, De Reijke TM, Van Tienhoven G, chemotherapy and of a 3- or 5-day Comparative effectiveness of axitinib
et al. Duration of androgen schedule in good prognosis germ cell verses sorafenib in advanced renal cell
suppression in the treatment of cancer; a randomized study of the carcinoma (AXIS): a randomised
prostate cancer. N Eng J Med EORTC and treatment of phase 3 trial. Lancet 2011;378
2009;360(24):251627. genitourinary tract cancer group and (9807):19319. Epub 2011 Nov 4.
Warde P, Mason M, Ding K, et al. the MRC. J Clin Oncol 2001;19 Sawhney R, Bourgeois D, Chauhary UB.
Combined androgen deprivation (6):162940. Neo-adjuvant chemotherapy for
therapy and radiation therapy for Oliver RT, Mason MD, Mead GM, et al. muscle-invasive bladder cancer: a look
locally advanced prostate cancer: a Radiotherapy verses single dose ahead. Ann Oncol 2006;17:13609.
randomized phase 3 trail. Lancet carboplatin in adjuvant treatment of Mosconi AM, Roila F, Gatta G,
2012;378(9809):210411. Epub stage I seminoma; a randomised trial. Theodore C. Cancer of the penis. Crit
2011 Nov 2. Lancet 2005;366(9482):293300. Rev Oncol Hematol 2005;53:16577.
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Chapter | 29 |
Lymphoma and disease of bone marrow
Gillian D. Thomas, Matthew Ahearne, Martin J.S. Dyer
Treatment 520
CHAPTER CONTENTS
Chronic lymphocytic leukaemia 520
Introduction 512 Clinical features 520
Malignant lymphomas 512 Treatment 520
Aetiology and epidemiology 512 Myeloproliferative disorders 520
Pathological characteristics 512 Haemopoietic stem cell transplantation
Hodgkins lymphoma 512 (HSCT) 521
Non-Hodgkins lymphoma 513 Radiotherapy doses, techniques and toxicities 521
Clinical features 514 Hodgkins lymphoma 521
Diagnosis and staging 514 Non-Hodgkins lymphoma 522
Clinical prognostic factors 515 Diffuse large B cell lymphoma 522
Treatment 515 Indolent lymphoma: follicular and marginal zone 522
Initial management 515 Mantle 522
Hodgkins lymphoma 515 Toxicity 524
Non-Hodgkins lymphoma 515 Leukaemia 524
Special situations 517 Total body irradiation (TBI) 524
Multiple myeloma 517 Splenic radiotherapy 525
Pathology 517 Myeloma 525
Clinical features 517 Palliative treatment of multiple myeloma 525
Diagnosis 518 Mycosis fungoides 525
Investigations 518 Local 525
Prognostic factors 518 Total body electron therapy (TBE) 525
Treatment 518 Chemotherapy regimens and toxicities 526
Radiotherapy in myeloma 518 Hodgkins lymphoma 526
Leukaemia 519 ABVD 526
Acute leukaemia 519 ChlVPP 526
Clinical features 519 Stanford V 526
Treatment of AML 519 BEACOPP 526
Chronic myeloid leukaemia 519 Non-Hodgkins lymphoma 526
Clinical features 519 Follicular grade 1 and 2 and marginal zone 526
512
Chapter | 29 | Lymphoma and disease of bone marrow
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Walter and Millers Textbook of Radiotherapy
514
Chapter | 29 | Lymphoma and disease of bone marrow
Clinical prognostic factors Chemotherapy was first used in HL for disease incurable
with radiotherapy. Although side effects were severe with
Early HL is very favorable if stage 1A, NS or LP type, age <40 MOPP (mustine, vincristine, procarbazine and predniso-
and female, and unfavorable if age over 50, four or more lone), additional cures were achieved and six to eight cycles
sites involved, raised ESR and a large mediastinal mass. of chemotherapy plus extended field radiotherapy became
Advanced HL is unfavorable if stage 4, age over 50, low routine. After 38 years up to 10% developed secondary
lymphocyte count, eosinophilia, low hemoglobin, low acute myeloid leukaemia (AML) and from 8 to 20 years,
serum albumin and male. other secondary malignancies particularly in irradiated
In NHL, the international prognostic index (IPI) is a areas. Heart disease was also increased. After 1015 years,
widely accepted prognostic score from 0 to 5, with one the risk of death from these causes was greater than from
point for each of the following features: relapse of HL, with many patients rendered infertile. The
1. age 60 most common second tumour is lung cancer, with an
2. more than one extranodal site enhanced risk in smokers. In young women treated with
3. stage III or IV disease mantle fields, the risk of breast cancer increases with age
4. high LDH from 8 years after treatment up to as high as 50% in middle
5. WHO performance status 24. age for those treated in their early teens, or up to 25% if
There is an increased risk of CNS relapse in DLBCL of the treated aged 2029, and early screening is now offered.
testis, paranasal sinuses, breast, and orbit, and in patients Thyroid cancer, colon cancer and sarcomas are also seen.
with heavy bone marrow involvement or with a high IPI Cure rates have been maintained using less toxic chemo-
score, and in Burkitts and lymphoblastic lymphomas. therapy to reduce leukaemia and infertility, and smaller
radiation fields with lower doses to minimize second malig-
Treatment nancies and cardiotoxicity. Chemotherapy is used in young
patients for all stages except very favorable stage 1A, where
Initial management it would be acceptable to use radiotherapy alone. ABVD
(doxorubicin, bleomycin, vinblastine and dacarbazine) has
It is important to avoid treatment before any biopsy. If await-
become standard, although it causes acute myelotoxicity, a
ing results then steroids may be given (e.g. prednisolone
small risk of cardiomyopathy and a 1% risk of fatal bleomycin
60 mg daily) to arrest clinical deterioration. In an emergency,
lung toxicity. Two to four cycles plus involved field radiother-
such as airway obstruction, treatment may have to be given
apy is used in stage 1A and 2A and six to eight cycles RT for
with radiotherapy. Urgent chemotherapy can rescue very ill
others. PET scanning helps to define complete response and
patients despite toxicity. Rapid tumour breakdown can cause
the need for RT. Current trials are focusing on the use of early
a tumour lysis syndrome due to release of cytokines and
PET imaging during treatment to stratify patients into good
intracellular products causing raised serum urate, phosphate
and poor risk. Good-risk patients may go on to receive
and potassium, reduced calcium and impaired renal and,
less demanding chemotherapy while poor-risk patients are
rarely, lung function. To prevent this, patients should start
escalated to more intensive regimens, such as BEACOPP
allopurinol (300 mg daily), ideally, at least 24 hours before
(bleomycin, etoposide, etoposide, doxorubicin, cyclophos-
chemotherapy, and be very well hydrated. Individuals
phamide, vincristine, procarbazine, and prednisone).
deemed at very high risk of tumour lysis (very high tumour
Extended field radiotherapy is used after a partial
burden as in Burkitts lymphoma) may receive Rasburicase, a
response to chemotherapy with disease at several sites, or
synthetic enzyme that breaks down the damaging urate.
where chemotherapy has had to be curtailed, especially
Men should be offered sperm storage, but there are pro-
in patients who would be unsuitable for HSCT. For elderly
blems in the storage of ova. Eggs which have been individ-
and unfit patients with early disease, radiotherapy alone
ually frozen cannot be successfully fertilized. It is currently
may be the treatment of choice.
necessary to store embryos, which might be attempted for
The overall 5-year survival is 7080%.
instance between a first line and a consolidation therapy.
Relapsed cHL may be cured with HSCT or sometimes fur-
Preservation of ovarian tissue is under study.
ther conventional chemotherapy or radiotherapy. Anti-CD30
antibodies are a promising new treatment for relapsed/
Hodgkins lymphoma refractory disease. Brentuximab vedotin, a novel antibody-
Radiotherapy (RT) was the first curative treatment for stage drug conjugate has shown promising results in early studies.
IIII HL. Staging originally involved laparotomy with multi-
ple biopsies and splenectomy, and then total nodal irradia- Non-Hodgkins lymphoma
tion (TNI) was given using extended fields a mantle field
covered all supradiaphragmatic nodes and an inverted Y Aggressive NHL
field the infradiaphragmatic nodes and spleen or splenic For more than 20 years, six to eight cycles of CHOP-21
pedicle. This exploited the tendency for HL to spread along (cyclophosphamide, hydroxydaunorubicin, oncovin (vin-
node chains. cristine) and prednisolone once every 3 weeks) was the best
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Walter and Millers Textbook of Radiotherapy
treatment for DLBCL despite many trials of more intensive Indolent NHL
regimens. The recent addition of an anti-CD20 human/ Truly localized (15%) follicular NHL may be cured with
mouse monoclonal antibody (rituximab) to each cycle radiotherapy alone. For palliation, low doses can achieve
(R-CHOP) has increased complete response rates from 63 lasting control.
to 76% and overall survival at 3 years from 51 to 62% with In widespread disease, a watch and wait approach is
minimal toxicity, so is the new gold standard. R-CHOP-14 acceptable for asymptomatic patients. Immediate treat-
fortnightly treatment is under investigation, using granulo- ment with rituximab is under study. On symptomatic pro-
cyte colony stimulating factor (GCSF) to avoid neutropenic gression, for elderly patients, oral chlorambucil (e.g. 10 mg
sepsis. Newer generation anti-CD20 monoclonal antibo- daily for 2 weeks every 4 weeks for six cycles) is appropriate.
dies are available (Ofatumumab and GA-101) and cur- Younger patients should avoid alkylating agents and
rently under investigation. anthracyclines as first-line therapy. Currently, R-COP
In high-risk groups, prophylactic CNS treatment is given (R-CHOP without Adriamycin; also called R-CVP) is
concurrently as intrathecal or high-dose intravenous meth- often used; rituximab prolongs remission, although there
otrexate. Radiotherapy to sites of bulk is conventional. is no known survival benefit as yet. R-CHOP is appropriate
For stage IA or IIA DLBCL, including extranodal sites, for follicular grade 3 or very bulky disease.
radiotherapy alone is curative in about 50%, but adding There is now increasing evidence that following induc-
three cycles of chemotherapy increases the cure rate to tion and second-line chemotherapy, maintenance rituxi-
80% in chemosensitive patients. Eight cycles of CHOP mab (375 mg/m2 every 23 months for up to 2 years)
seemed as effective as CHOP 3 plus RT in one pre- significantly improves progression-free survival. However,
rituximab trial but others show an advantage for RT and to date, survival benefits have not been shown.
the combination is preferred. Full-course chemotherapy At relapse, re-biopsy is advisable to detect high-grade
should be given if there is bulky disease or B symptoms transformation. Selection and timing of treatment depends
or a high IPI score, usually with RT afterwards. Only on the disease-free interval, extent of relapse, age and gen-
40% of DLBCL are truly localized. In testicular DLBCL, eral condition, and includes HSCT. Rituximab alone
the contralateral testis should be irradiated to reduce the (375 mg/m2 weekly for 4 weeks) gives a 50% response rate
risk of recurrence. with 1317 months median time to progression in heavily
At relapse after full-course chemotherapy, HSCT can be pretreated patients and can be repeated with equal effect.
curative if chemosensitivity can be shown with salvage regi- Fludarabine is an effective oral agent.
mens (IVE, ICE, ESHAP, DHAP). Time to relapse is the Anti-CD20 monoclonal antibodies radiolabeled with
most important predictive factor with rituximab refractory yttrium-90 (a pure beta-emitter) or iodine-131 (beta and
disease showing the worst outcome. Alternatives are oral energetic gamma) are very promising new agents for refrac-
etoposide and palliative radiotherapy. Radiolabeled anti- tory and transformed indolent NHL, with response rates of
CD20 antibody is under investigation for DLBCL. around 80% and remissions of several years in some
Burkitts lymphomas are treated with mores intensive patients. Zevalin (90Y-ibritumomab tiuxetan) is the
regimens, such as the CODOX-M/IVAC regimen, now murine parent of rituximab attached by the chelating agent
combined with rituximab, and can cure around 50% of tiuxetan to the radiolabel. It is given over 10 minutes with
patients. no need for hospital admission. Bexxar (131I tositumo-
In primary cerebral lymphoma, standard chemotherapy mab) is also a mouse antibody and seems equally effective
can cross the bloodbrain barrier initially while there is but with more radiation protection issues; further research
oedema around the tumour. CNS-penetrating drugs will establish the relative roles and optimal timing of these.
(high-dose methotrexate, cytarabine) are also used. Steroids Side effects include hypersensitivity reactions, delayed
are effective. Radiotherapy may prolong remission but immunosuppression and secondary AML/MDS in 6%,
causes lethargy and also significant cognitive impairment. partly due to previous chemotherapy.
Optimal chemotherapy, and the role of radiotherapy, are Marginal zone NHL are described as three types: splenic,
under investigation; prognosis is poor. nodal, and those of MALT (mucosa-associated lymphoid
The optimal treatment of mantle cell lymphoma remains tissue) origin. Splenectomy is appropriate for the first,
controversial and unsatisfactory. The benefit of mainte- and the others respond to the same agents and general
nance Rituximab is currently under investigation. High-risk approach as follicular NHL. Although the pattern of disease
younger patients may be considered for consolidation with is different with more extranodal sites, radiotherapy can
HSCT. Rare patients with localized disease may be consid- still be curative for disease truly localized to e.g. the stom-
ered for radical radiotherapy. Newer agents currently being ach or parotid. Anti-helicobacter therapy is potentially
tested alone and in combination with chemotherapy curative in gastric MALT NHL. Gastric MALT can be moni-
include lenalidomide, bortezemib, and temsirolimus. tored by regular endoscopies.
Peripheral T-cell NHL is treated as DLBCL without ritux- Mycosis fungoides has a median survival of 10 years. In
imab as T cells lack CD20. Etoposide may be added to the the early stages, topical steroids can be used, then often
CHOP regimen (CHOEP).
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Chapter | 29 | Lymphoma and disease of bone marrow
photochemotherapy using long-wave ultraviolet light with Post-transplant lymphoproliferative disease (PTLD) is an
oral psoralens (PUVA). Radiotherapy can be local or to the often localized NHL presenting after organ transplantation.
whole skin surface using low-energy electrons. Systemic It usually remits on gradual withdrawal of immunosup-
treatments include CAMPATH (anti-CD52 antibody) pressive therapy but, if not, then options include infusion
which targets T cells. Combination chemotherapy with a of HLA-matched cytotoxic T lymphocytes.
CHOP-type regimen is used in visceral disease but com-
plete response rates are low (2025%).
MULTIPLE MYELOMA
Special situations
Multiple myeloma accounts for 0.9% of all cancers and
Lymphoma in children 1.3% of cancer deaths. Its incidence is 3 per 100 000 per
Radiotherapy in children causes growth retardation in the year with about 3000 new cases annually in the UK. The
treated area and they are particularly susceptible to second median age at diagnosis is 62 years and the male to female
malignancies, so chemotherapy is used alone wherever ratio is 1.5:1. The aetiology is unknown. Median survival is
possible. Lower radiation doses have been shown to be ade- 34 years from diagnosis with wide variations.
quate in paediatric Hodgkins and extranodal presentations
are rarer: lymphadenopathy is the presenting feature in 90%.
Pathology
Lymphoma in pregnancy Myeloma is a tumour of plasma cells, which are
HL is the most common diagnosis. Staging should avoid immunoglobulin-producing B lymphocytes. Their bone
exposure to ionizing radiation, using magnetic resonance marrow microenvironment is increasingly well understood
imaging (MRI) or ultrasound in preference to CT. Radio- and new molecular targets for treatment identified as a
therapy is potentially teratogenic during the first trimester. result. Myeloma cells potentiate osteoclast activity and
Above a dose of 0.1 Gy to the fetus there is a risk of induc- inhibit differentiation of osteoblast precursors, uncoupling
ing an abnormality. Chemotherapy has an unquantified bone formation from resorption so multiple lytic bone
risk of teratogenesis or carcinogenesis to the fetus. lesions are characteristic. They also produce a specific
Termination should be considered if treatment is essen- immunoglobulin (Ig) or paraprotein, detectable by immu-
tial before the early second trimester, if the fetal dose would noelectrophoresis and useful for diagnosis and treatment
exceed 0.1 Gy or chemotherapy is indicated. If the diagno- monitoring. While an intact immunoglobulin molecule
sis is made late in the second or in the third trimester, it may is too large to enter the renal tubules, free light chains
be possible to postpone treatment until delivery is induced (Bence Jones protein) may be produced and are found in
at 3234 weeks. Localized radiotherapy above the dia- the urine. Normal immunoglobulins are reduced resulting
phragm can be safely given, and single agent chemotherapy in recurrent infections (immune paresis). In 5%, there is no
may control symptoms in HL for a few weeks but, if the dis- secreted protein and the disease is termed non-secretory.
ease is life threatening, then combination chemotherapy is Bence Jones only is found in 20%, while Ig subtypes are
best. With ABVD, the risk of carcinogenesis or infertility in found with frequencies reflecting normal levels, i.e. IgG
the child should be low. in 5060%, IgA 2025%, IgD 2%, IgE and IgM <1%. Para-
Patients who have been successfully treated for Hodg- proteinemia is also found in lymphoma. IgM is associated
kins disease should be advised to avoid pregnancy for with Waldenstroms macroglobulinemia or marginal zone
2 years after the end of treatment, because after this the risk lymphoma. In the normal population, paraproteinemia is
of relapse falls markedly. Subsequent pregnancy does not found in 1% aged over 25, 3% over 70 and 25% over 90
increase the risk of relapse. years old. This is monoclonal gammopathy of uncertain
significance (MGUS) and carries an annual risk of 1% of
Lymphoma in HIV and post-transplant progression to multiple myeloma. Asymptomatic early
HIV-associated lymphoma is usually aggressive, presenting myeloma is termed smoldering.
with high IPI scores and often CNS disease. Patients are
more prone to succumb to infective complications of
Clinical features
treatment. NHL is an AIDS-defining illness but HL is
not. Median survival is 718 months with standard chemo- The commonest presenting feature is bone pain (70%)
therapy. Highly active antiretroviral therapy (HAART) in from a rib or vertebra. The destruction of cortical bone
combination with chemotherapy has improved complete leads to pathological fractures in about 25% and hypercal-
response rates and early studies suggest that adding rituxi- cemia in 30%. Alkaline phosphatase is normal, and bone
mab may improve 2-year survival further from less than 50 lesions lytic. Spinal cord compression is occasionally the
to around 60%. Lymphomas of the Burkitt type are asso- presenting feature and is an emergency. Humoral and
ciated with a poorer outcome. cell-mediated immunity are impaired and recurrent
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Walter and Millers Textbook of Radiotherapy
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Chapter | 29 | Lymphoma and disease of bone marrow
more appropriate so surgical consultation should be Chromosomal abnormalities and translocations are
considered. numerous and useful in defining prognostic groups; their
Total body irradiation (TBI) is sometimes used as part of absence after treatment verifies remission.
HSCT.
Clinical features
LEUKAEMIA The clinical features of ALL and AML are similar and are
described elswhere along with the treatment of ALL.
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Walter and Millers Textbook of Radiotherapy
of myeloid cells at varying stages of differentation and less deletions, high CD38/ZAP-70 expression and having an
than 5% blasts, with this picture reflected in the marrow. unmutated IgVH gene.
The platelet count is normal or raised. CLL is slowly progressive although, occasionally, notably
The natural history is of a chronic stable phase of 46 with mutations of the p53 gene, resistant to all conven-
years, although this can be 120 years. A 6-month acceler- tional therapy. In some patients, the disease is stable for
ated phase precedes the terminal blastic phase. over 20 years.
Treatment Treatment
In younger patients, the treatment of choice is allogeneic Treatment is indicated for symptoms or if critical organs are
HSCT, the only curative option. Oral imatinib is highly threatened. Oral chlorambucil has historically been given
effective at inducing both clinical and cytogenetic complete first line, at doses of e.g. 10 mg daily for 2 weeks out of
remission in chronic phase, in 95% and 70% of patients, 4. Fludarabine induces more rapid responses and is given
repectively (less if in accelerated phase) and is the best in combination with cyclophosphamide (with which it
non-transplant treatment. However, many patients relapse seems to synergize). Recently, the combination of fludara-
eventually due to the leukaemia cell developing resistance bine and cyclophosphamide with rituximab has been
to the drug. Newer tyrosine kinase inhibitors (dasatinib, approved for first-line treatment. Sometimes, CLL can
nilotinib) have been developed and have a role in imatinib transform into a high-grade lymphoma (Richters transfor-
resistance. Hydroxurea is useful to control high white cell mation) and is treated as for DLBCL.
counts during end-stage disease. After HSCT in chronic The CD52 monoclonal antibody, alemtuzumab (CAM-
phase, 50% are disease free at 4 years, but if in accelerated PATH), is effective though immunosuppressive. It is partic-
phase, only 12%. Thus, treatment is aimed at controlling ularly useful in patients with certain molcular markers (p53
the disease until transplantation can be arranged. Timing abnormalities), often in combination with steroids if bulky
can be very difficult and research is addressing ways to disease is present.
select high-risk patients for early HSCT. New therapies that interfere with the B-cell receptor sig-
nalling on the CLL cells are being developed including inhi-
bitors of Bruton tyrosine kinase (BTK), Syk, and PI3 kinase.
Chronic lymphocytic leukaemia With conventional treatment, the 5-year survival of CLL
is about 60% overall.
CLL is the commonest form of leukaemia in the western
world. Its incidence in the UK is five per 100 000. The male
to female ratio is 2:1. It is usually seen in middle age, with
the incidence increasing with age. About 5% of cases
exhibit some family history of B-cell lymphoproliferative
MYELOPROLIFERATIVE DISORDERS
disease, but the nature of the involved gene(s) remains
unknown. It is not linked to radiation or chemical exposure This is a related group of disorders including CML (above),
or chemotherapy. polycythemia vera (PV), essential thrombocythemia (ET)
and idiopathic myelofibrosis (IMF). They are slowly pro-
gressive with median survival of about 10 years. PV (excess
Clinical features red cells) and ET (excess platelets) can lead to myelofibrosis
Symptoms are mainly due to anaemia or infection though and to AML.
diagnosis is often made incidentally on a full blood count. PV causes pruritus, splenomegaly and gout due to hyper-
The white cell count is usually between 30 and 300 109/L uricemia, and PV and ET cause thromboses, particularly
and composed of small mature lymphocytes with arterial, and less often hemorrhages.
condensed nuclei and scant cytoplasm. The bone marrow Treatment is with antiplatelet drugs and hydroxyurea
is hypercellular with an infiltrate composed of mature lym- (a cytotoxic drug). Interferon is used less but has a role
phocytes. Biopsy of enlarged nodes shows monotonous in selected patients unable to take hydroxyurea. Anagrelide
sheets of cells with characteristic proliferation centres. is useful in ET as it prevents the maturation of platelets.
Enlargement of lymph nodes of the neck and other Busulphan and radioactive phosphorus (P32) injections
peripheral sites, spleen and liver is common: staging sys- are effective but rarely used now because of the increased
tems are currently based on the number of these and on risk of leukaemia. Repeated venesection is used in PV to
normal and abnormal cell counts into A, B and C. Adverse prevent the hemotocrit rising to dangerous levels.
prognostic factors include stage B or C, male gender, age >60, In IMF, there is bone marrow fibrosis and failure with
lymphocyte doubling time <12 months, diffuse marrow associated splenomegaly. It may due to stimulation of
infitration and >10% circulating prolymphocytes. Molecu- fibroblasts by abnormal megakaryocytes. Irradiation is
lar markers of prognosis are p53 abnormalities, 11q23 effective at very low doses in shrinking the spleen.
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Chapter | 29 | Lymphoma and disease of bone marrow
It has recently been discovered that a mutation in diarrhea and weight loss) or chronic (arthritis, liver disease,
another tyrosine kinase, JAK2, can be found in 90% of malabsorption, oral mucositis and sicca syndrome, lung
patients with PV and around 50% of ET and IMF. JAK2 inhi- disease, pericardial and pleural effusions, scleroderma, skin
bitors are now well developed and undergoing clinical rashes) and has a high mortality. The incidence is reduced
trials. They may soon become standard care for these by immunosuppression with cyclosporin A or tacrolimus
patients. and by depleting the donor T cells using monoclonal anti-
bodies such as alemtuzumab (CAMPATH) and antithymo-
cyte globulin (ATG). Blood products are irradiated to kill
HEMOPOIETIC STEM CELL any T lymphocytes which may precipitate GvHD.
New treatments for GvHD include antibodies to tumour
TRANSPLANTATION (HSCT) necrosis factor and interleukin-2, and extracorporeal
photopheresis. Immunodeficiency due to defects of T-cell
This term is used to describe the collection and transplan- and B-cell functions occurs during the first 6 months and
tation of HSC from bone marrow, peripheral blood or for longer in the presence of GvHD. Viral, bacterial and fun-
umbilical cord blood. It is essential to the delivery of gal infections may be fatal.
high-dose treatments used increasingly in the haematologi- In the event of relapse after transplantation, donor T lym-
cal malignancies and will be referred to throughout this phocytes can be used therapeutically for their graft-versus-
chapter. disease effect. This is exploited in mini-allografting in
Stem cells from the patients own marrow are autologous patients unfit to undergo a myeloablative transplant: after
and, if donated by another, HLA-matched person, alloge- reduced-intensity conditioning (no TBI), the host normal
neic. Cells are transplanted by infusion through a central marrow survives and coexists with the donor marrow,
venous Hickman line and are then described as the graft. and the donor T cells control the leukaemia.
Autografting has a 12% mortality. Stem cells are har-
vested from the peripheral blood after stimulating them
to proliferate by giving conventional chemotherapy and RADIOTHERAPY DOSES, TECHNIQUES
granulocyte-colony stimulating growth factors (GCSF),
and they are reinfused after high-dose therapy which would
AND TOXICITIES
otherwise be fatally myelosuppressive. It may not be possi-
ble to harvest cells following prior chemotherapy especially INRT: planned volume with the clinical target volume
with alkylating agents and fludarabine and this problem (CTV) involved node/s with margin which follows node
has altered first-line treatments. Plerifixor inhibits a mole- chains.
cule in the bone marrow releasing stem cells into the ISRT: planned volume with the CTV the involved site
peripheral blood and has shown to increase the success (may be nodal as above) with defined margins.
of harvesting procedures. IFRT: parallel-opposed beams covering the classical defined
Allografting has about a 30% mortality, lower with a sib- involved field, encompassing a node region.
ling than with a matched unrelated donor (MUD), but is EFRT: extended field encompassing all node regions on one
the only curative option when there is residual disease in side of the diaphragm: mantle (nodes above) and inverted
the marrow or where autografting has failed. High dose Y (nodes below).
conditioning therapy is given to eradicate the underlying Megavoltage is used (410 MV photons). Palpable masses
disease and to immunosuppress the patient enough to pre- are outlined with wire; bolus may be needed to ensure an
vent rejection of the transplant, e.g. cyclophosphamide adequate dose to superficial nodes. Reference to pre-chemo
100 mg/kg over 2 days and total body irradiation (Cy/ PET-CT and contrast enhanced CT is essential.
TBI). Chemotherapy may be used alone, e.g. cyclophos-
phamide and busulphan (Bu/Cy). Donor harvesting may
Hodgkins lymphoma
be from peripheral blood or directly from bone (multiple
punctures under general anesthesia) which gives a better Following chemotherapy: 30 Gy in 15 fractions to involved
yield of cells. Allografting has the beneficial effect of donor node/site.
T lymphocytes recognizing residual malignant cells as for- Young patients with stage 1A/2A good risk and PET
eign and destroying them. negative after two cycles of chemo: 20 Gy in 10 fractions
Following chemoradiotherapy, the white cell and plate- may be adequate.
let counts drop within 10 days and recover after 36 weeks Radiotherapy alone: 35 Gy in 20 fractions to extended field
of intensive support with antibiotics, red cell and platelet 5 Gy in two fractions to site/s of bulk.
transfusions. Graft-versus-host disease (GvHD) occurs Palliative treatment: single fraction 5 Gy to small volume;
when T cells from the donor react with antigenic targets 10 20 Gy in 510 fractions over 12 weeks for larger areas
on host cells. It may be acute (jaundice, skin rashes, often adequate.
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Walter and Millers Textbook of Radiotherapy
Non-Hodgkins lymphoma underdosage. The rest of the spinal cord may be shielded
from the posterior beam after 21 Gy unless there is (or
Diffuse large B cell lymphoma was) central mediastinal adenopathy, in which case,
Radical: post-chemo: 30 Gy in 15 daily fractions over limited shielding is added to within 45 cm of any
3 weeks to involved node/site. enlarged nodes.
Radiotherapy alone: 30 Gy in 15 fractions to extended Shoulders: humeral heads and adjacent joint spaces are
field. Boost involved site to 40 Gy using a phase 2 volume. shielded from anterior and posterior beams throughout
Palliative: 2030 Gy in 510 fractions is usual, to involved treatment unless there is an adjacent axillary node mass.
field. Large single fractions, e.g. 8 Gy may be appropriate Shielding can be done using multileaf collimators (MLCs)
for, e.g. bone. or partly with customized lead blocks.
Tattoos are placed to avoid rotation of the thorax.
Indolent lymphoma: follicular
Dose distribution
and marginal zone
The axillae and neck receive 1020% more than the inferior
Radical: generally radiotherapy alone: 30 Gy in 15 fractions edge of the field. Shielding may be added over the relevant
over 3 weeks to involved field. If chemo has been given, areas for one or two fractions, or compensators used
treat involved site/nodes. throughout, unless inhomogeneity is effectively boosting
Palliative treatment: 4 Gy in two fractions can give residual disease.
prolonged remission in indolent NHL. Otherwise 24 Gy in
12 fractions is commonly used. Inverted Y
Extended fields for nodal HL or NHL no chemo/
chemoresistance/palliation Target volume: all infradiaphragmatic nodes: para-aortic,
Anterior and posterior at extended focus skin distance pelvic, iliac and femoral. In conjunction with a mantle field
(FSD) (140 cm). and if extended to include the spleen or splenic pedicle this
is TNI, while STNI omits the pelvic field from L5/S1.
Position: supine. Anterior and posterior fields are used at
Mantle extended FSD (140 cm).
Target volume: supradiaphragmatic nodes including
occipital, submental and submandibular, but excluding Field borders
preauricular/parotid nodes/Waldeyers ring. Superior: junction of the 10th and 11th thoracic vertebrae
Position: supine with neck extended. Arms abducted and or if matching to a mantle field, a gap (about 2 cm on skin)
supported with hands on hips. (Figure evolve 29.1, 29.2 & is calculated to have the 50% isodoses meet just posterior to
29.3 ). the vertebral bodies on a lateral x-ray.
Inferior: the inferior margin of the obturator foramen, or
Field borders covering involved nodes plus 5 cm.
Superior: at tip of chin, positioned level with external Lateral: the greater trochanters of the femora.
occipital protuberance and mastoid process. Record
distance from centre of top border on the chin to Shielding
suprasternal notch. Abdominal cavity: lateral to the paraortic nodes (810 cm
Inferior: junction of 10th and 11th thoracic vertebrae. central strip or 2 cm beyond any node mass). The medial
Lateral: lateral to the humeral head to include the 12 cm of each kidney may be irradiated.
whole axilla. Bladder and genitalia: a midline block protects the bladder
and urethra. Ovarian function is preserved by surgery
Shielding (oophoropexy) to move them centrally for shielding,
Lungs: superiorly shield from the lower posterior marking their position with clips. Lead cups over the testes
border of the fourth rib, to treat infraclavicular can reduce their dose to <0.6 Gy.
nodes, and laterally to 0.5 cm medial to the ribs
down to T7/8, to treat lower axillary nodes. Between Involved fields
the lungs, the minimum field width is 78 cm at the Target volume: all pretreatment macroscopic and PET-
inferior border, 910 cm at the hila and around any positive disease and at least one anatomical node group
bulky nodes leaving a 2 cm lateral margin (from such as the axilla or inguinal area, often two or three but
post-chemotherapy disease). less than mantle or inverted Y. Where a node mass with
Spine: anteriorly a 2 cm strip from the centre of the a well-defined edge has shrunk with chemotherapy away
superior border down to C5/6 shields the larynx, and a from an adjacent dose-limiting structure, such as lung, spi-
posterior strip down to C7 protects the cervical cord, nal cord or kidney, a 2 cm margin on residual disease is
adjusted if there is adjacent lymphadenopathy, to avoid adequate laterally. There should be at least a 5 cm margin
522
Chapter | 29 | Lymphoma and disease of bone marrow
along the lymph node chain above and below the preche- posterior nasopharynx, the adenoids, oropharynx and
motherapy disease, which may mean inclusion of part of adjacent upper cervical nodes down to the thyroid carti-
the adjacent region, e.g. where the superior mediastinum lage. For extensive nodal involvement and/or partial
was involved it is usual to treat both supraclavicular fossae. response to chemotherapy, this can be extended anteriorly
Position: as for mantle or inverted Y fields: involved and posteriorly to cover submandibular and occipital
fields are subsets of these (Figures evolve 29.429.14 ). nodes. A lower neck field is matched on using CT planning,
Technique: parallel-opposed fields, with borders partly avoiding junctions through sites of disease. Infraclavicular
those of extended fields. The medial border of a neck field fossae are shielded (Figures evolve 29.17 & 29.18 ).
may be in the midline or at the edge of the spinal canal. CT
planning may reduce normal tissue treated e.g. in the Thyroid
mediastinum. The thyroid gland and the cervical lymph node chains on
both sides are included, with anteroposterior fields extend-
Involved sites ISRT (if nodal, may be referred to as ing inferiorly into the superior mediastinum and superiorly
INRT). to the submandibular nodes. CT planning can be used for
Volumes are irregular in shape and a good knowledge of a second phase to minimize spinal cord dose.
anatomy is required to define them, with reference to stan-
dard atlases, radiological opinion, prechemotherapy PET Orbit
scans and contrast enhanced CT scans for planning (Figure The whole orbit is treated using CT planning. For small
evolve 29.15 ). lateral and conjunctival indolent NHL, a single beam
A CTV is defined on the CT planning system. Where there may suffice. Beams are angled to avoid the other eye
is a residual node mass adjacent to another tissue, such as (Figures evolve 29.1929.24 ).
lung, the CTV may be at the edge of this mass in the axial
plane, and does not need to encompass the original size. Nasal sinuses
However, in the direction of the lymph node chain, the Planning is as for carcinoma (Figures evolve 29.2529.29 ).
CTV is the pretreatment extent of abnormal nodes on PET-
CT plus a 1.5 cm margin. This direction may not be directly Brain
superior-inferior, for instance, at the junction between node
The whole brain is treated with a parallel pair of lateral
regions in the mediastinum/neck or abdomen/pelvis.
beams. As meningeal involvement is likely, the fields are
Where there is no residual mass, the volume describes
extended down the neck to C2/3 and to cover the posterior
the lymph node chain in the space bounded by other struc-
orbit and facial nerve root as for ALL. Craniospinal treatment
tures, such as muscle, large vessels, lung and bone.
is only very occasionally indicated in relapsed NHL (see acute
A margin is added to the CTV to give the required PTV
lymphoblastic leukaemia) (Figures evolve 29.30 & 29.31 ).
according to the site, set-up error, likely movement, and
local departmental practice, and might vary from 5 mm
GI lymphoma
to 1.5 cm.
ISRT for extranodal sites following chemotherapy is CT For gastric NHL, plan using barium and treat the stomach
planned in a similar way to involved nodes. The CTV empty. Anteroposterior fields are often optimal, but CT
may define the whole organ, e.g. stomach, spleen, thyroid, planning may spare the kidneys or spinal cord especially
where there were no adjacent nodes involved, or part of a for post-chemotherapy residual abdominal masses. Rectal
node chain may need to be outlined in addition. lymphoma is planned as for carcinoma.
Bone
Extranodal involved fields
The whole of the affected bone should be included in the
For radical treatment following response to chemotherapy, initial volume and a second phase used for the last
only involved sites need be treated as described above. 10 Gy. A parallel-opposed pair of fields is used, shielding
soft tissues with a 2 cm margin.
Head and neck
The patient is immobilized in a supine shell, and CT Breast
planning used for the whole treatment, for a second phase, The whole breast, axillary and supraclavicular nodes
or for matching of field edges (Figure evolve 29.16 ). should be included and planned as for carcinoma.
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Walter and Millers Textbook of Radiotherapy
524
Chapter | 29 | Lymphoma and disease of bone marrow
The spleen can be outlined clinically or using CT or simu- Acute side effects
lator screening. Nausea and vomiting, prevented with, e.g. granisetron
Technique 2 mg one hour before radiotherapy, dexamethasone 4 mg
bd, plus metoclopramide 10 mg prn. Pneumonitis is rare
Direct anterior or lateral fields (e.g. 15 10 cm) or a par- at 6 Gy but has an increasing incidence above this dose
allel pair can be used. to the whole lungs.
Diarrhea occurs in a third of patients 35 days after lower
Myeloma hemibody treatment, controllable with codeine or
loperamide.
Radical treatment of solitary plasmacytoma: 4050 Gy in 20 Pancytopenia is common and contributes to lethargy.
25 fractions. Rib deposits (Figures evolve 29.36 & 29.37 ). Blood and platelet transfusions may be required.
Soft tissue mass/spinal cord compression/ Total body electron therapy (TBE)
pathological fracture/severe pain This is a specialized treatment offered in regional centres,
20 Gy in five fractions. Consider 30 Gy in 10 fractions for and techniques vary.
e.g. soft tissue with extensive bone destruction when dis- 30 Gy in six fractions (once weekly) for 6 weeks.
ease is mainly in one area. Four fields can cover the whole body at extended source
to surface distance (SSD) (120 cm) with the patient supine.
Rib deposits Lead shielding is applied to protect the eyes and the finger
8 Gy single fraction nails. If the eyelids are involved, a lead internal eye shield
Orthovoltage can be used to the painful area plus a mar- is used. If 5 or 8 MeV electrons are used, Perspex is used to
gin of a few centimeters along the rib. reduce the depth of penetration. Skin in folds (e.g. axilla
and groin) is spared with this technique and may be
Hemibody radiotherapy for widespread deposits marked for separate treatment when skin erythema devel-
This is now rarely used since systemic treatment options ops. This can be minimized by positioning patients
have increased. carefully.
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Walter and Millers Textbook of Radiotherapy
CHEMOTHERAPY REGIMENS
AND TOXICITIES BEACOPP
Intensive first-line treatment for high-risk patients.
All cause myelosuppression and the risk of fatal neutrope- Bleomycin
nic sepsis, particularly the intravenous combination Etoposide
therapies, of which most cause total alopecia and the Adriamycin
risk of infertility, particularly in men. The problems of Cyclophosphamide
nausea and vomiting (particularly due to anthracyclines, Vincristine (Oncovin)
dacarbazine and mustine) have been transformed by Procarbazine
new antiemetics in the HT3 blocker class (ondansetron, Prednisolone
granisetron). Anthracyclines cause cardiomyopathy if a
high cumulative dose has to be given but this is rarely a
problem with first-line treatment. The vinca alkaloids Non-Hodgkins lymphoma
(vincristine, vinblastine) cause peripheral neuropathy Follicular grade 1 and 2 and marginal zone
and constipation. Bleomycin can rarely cause pulmonary
fibrosis which can be fatal. Oral chlorambucil alone is the Oral chlorambucil: 10 mg daily for 14 days every
least acutely toxic treatment used; it does not cause alope- 28 days 6
cia or much nausea but, like other alkylating agents Well tolerated with rare reports of serious toxicity but
(cyclophosphamide, melphalan, mustine), causes some myelotoxic.
irreversible toxicity to bone marrow and gonads.
R-COP (also known as R-CVP)
As R-CHOP see below, but without doxorubicin.
Hodgkins lymphoma
ABVD Mantle cell
Doxorubicin (Adriamycin) Days 1 and 15
25 mg/m2 i.v. FC
Bleomycin 10 000 units/m2 i.v. Days 1 and 15 Fludarabine
Vinblastine 6 mg/m2 i.v. Days 1 and 15 Cyclophosphamide
Dacarbazine 375 mg/m2 i.v. Days 1 and 15 Repeated every 28 days
Repeated every 28 days
Myelotoxic but well tolerated oral regimen without
Acute toxicity is marked (alopecia is usual, nausea, myelo- alopecia.
suppression, constipation, painful veins, pulmonary fibro-
sis from bleomycin which is fatal in 130%, highest in
elderly patients), but there is minimal risk of infertility or
Diffuse large B-cell, T-cell-rich, B cell,
leukaemia with ABVD, so this is standard treatment. follicular grade 3 (and for T-cell
lymphomas)
ChlVPP Use CHOP alone without rituximab.
2
Chlorambucil 6 mg/m (max. 10 mg) Days 114 R-CHOP
orally
Standard regimen; trials suggest adding etoposide or giving
Vinblastine 6 mg/m2 (max. 10 mg) i.v. Days 1 and 8
at 2-week rather then 3-week intervals, with GCSF. Alope-
Procarbazine 100 mg/m2 orally Days 114
cia, nausea, myelosuppression, peripheral neuropathy,
Prednisolone 40 mg orally Days 114
antibody reaction, steroid effects, cardiomyopathy.
Repeated every 28 days
Rituximab 375 mg/m2 Day 1
This is well tolerated but with 3% risk of later leukemogen- Cyclophosphamide 750 mg/m2 i.v. Day 1
esis, and infertility is induced in men, but less likely in Doxorubicin 50 mg/m2 i.v. Day 1
women. Only the vinblastine is intravenous and hair loss Vincristine 1.4 mg/m2 (max. 2mg) i.v. Day 1
is unusual. Used less commonly but may be considered Prednisolone 50 mg/m2 orally Days 15
if ABVD is deemed unsuitable. Repeated every 21 days (minimum six courses)
526
Chapter | 29 | Lymphoma and disease of bone marrow
FURTHER READING
Kyle RA, Rajkumar SV. Treatment Girinsky T, van der Maazen R, Specht L, radiation therapy effects in Hodgkins
of multiple myeloma: et al. Involved-node radiotherapy lymphoma. Acta Oncol
a comprehensive review. Clin (INRT) in patients with early Hodgkin 2003;42:589604.
Lymphoma Myeloma 2009;9:27888. lymphoma: concepts and guidelines. Kheng-Wei Y, Mikhaeel NG. Role of
Yahalom J. Radiation therapy after Radiother Oncol 2006;79:2707. radiotherapy in modern treatment of
R-CHOP for diffuse large B cell Yahalom J, Mauch P. The involved field is Hodgkins lymphoma. Adv Hematol
lymphoma: the gain remains. J Clin back: issues in delineating the 2011; Article ID 258797.
Oncol 2010;28:41057. radiation field in Hodgkins disease. Ganem G, Cartron G, Girinsky T, et al.
Herbst C, Rehan FA, Brillant C, Ann Oncol 2002;13(Suppl. 1):7983. Localised low-dose radiotherapy for
et al. Combined modality Press OW. Radioimmunotherapy for follicular lymphoma: history, clinical
treatment improves tumour control non-Hodgkins lymphomas: a results, mechanisms of action,
and overall survival in patients historical perspective. Semin Oncol and future outlooks. Int J Radiat Oncol
with early stage Hodgkins lymphoma: 2003;30(Suppl. 4):1021. Biol Phys 2010;78:97582.
a systematic review. Haematologia Gustavsson A, Osterman B, Cavallin- Hoppe RT. The indolent extranodal
(Budap) 2010;95:494500. Stahl E. A systematic overview of lymphomas: what is the role of
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Walter and Millers Textbook of Radiotherapy
radiation therapy? Haematol Meet Hallek M, Fischer K, Fingerle-Rowson G, review of ten years experience with
Rep 2009;3:104. et al. Addition of rituximab to new transplant concepts and new
Strauchen JA. Immunophenotypic and fludarabine and cyclophosphamide in therapeutic agents. Leukaemia
molecular studies in the diagnosis and patients with chronic lymphocytic 2006;20:166172.
classification of malignant lymphoma. leukaemia: a randomised, open-label, Bruker B. Translation of the
Cancer Invest 2004;22:13848. phase 3 trial. Lancet Philadelphia chromsosome into
Coiffier B, et al. CHOP chemotherapy 2010;376:116474. therapy for CML. Blood
plus rituximab compared with CHOP The diagnosis and management of 2008;112:480817.
alone in elderly patients with diffuse multiple myeloma, British Committee Younes et al. Brentuximab Vedotin
large B-cell lymphoma. N Engl J Med of Standards in Haematology; 2010. (SGN-35) for Relapsed CD30-Positive
2002;346:23542. Available online: http://www. Lymphomas. N Engl J Med
Salles G, Seymour JF, Offner F, bcshguidelines.com/. 2010;363:181221.
et al. Rituximab maintenance for 2 years Armitage JO. Early stage Hodgkins Burger JA. Inhibiting B-Cell Receptor
in patients with high tumour burden lymphoma. N Engl J Med Signaling Pathways in Chronic
follicular lymphoma responding to 2010;363:65362. Lymphocytic Leukaemia. Current
rituximab plus chemotherapy (PRIMA): Barrett AJ, Savan BN. Stem cell hematologic malignancy reports. Curr
a phase 3, randomised controlled trial. transplantation with reduced- Hematol Malig Rep 2011 Nov 22;
Lancet 2010;377:4251. intensity conditioning regimens: a [Epub ahead of print].
Figure evolve 29.1 Mantle field: shielding of spine away from sites Figure evolve 29.23 Orbital lymphoma:
shielding partly with multileaf of disease mass medial to globe, no bolus
collimators and partly using Figure evolve 29.12 Bilateral neck with Figure evolve 29.24 Orbital lymphoma:
customised lung blocks and spine sparing of salivary glands on right sagittal view of anterior wedged pair of
blocks (outlined in wire) where only supraclavicular nodes angled beams
Figure evolve 29.2 Modified mantle were involved Figure evolve 29.25 Nasal NK/T cell
field: post-chemotherapy, with Figure evolve 29.13 Modified left lymphoma: target volume 1 cm margin
lowered superior border where no high dogleg: palliative treatment Figure evolve 29.26 Nasal NK/T cell
neck nodes were involved encompassing disease along pelvic and lymphoma: 3-field plan
Figure evolve 29.3 Field in 29.2 with para-aortic node chain Figure evolve 29.27 Nasal NK/T cell
shielding using multileaf collimators Figure evolve 29.14 Right pelvic and lymphoma: volume and critical
Figure evolve 29.4 Diagrammatic inguinofemoral nodes structures contralateral eye and
examples of involved fields for Figure evolve 29.15 Anterior brainstem
combined-modality treatment of mediastinal residual lymphoma after Figure evolve 29.28 Nasal NK/T cell
Hodgkins lymphoma chemotherapy: anterior wedged pair of lymphoma: volume, lateral field and
Figure evolve 29.5 Disease throughout angled beams brainstem
cervical chain: whole right neck Figure evolve 29.16 Tonsil and adjacent Figure evolve 29.29 Nasal NK/T cell
including infraclavicular nodes nodes: lateral fields lymphoma: volume, lateral beam and
Figure evolve 29.6 Superior Figure evolve 29.17 Nasoparyngeal isodoses
mediastinum and right supraclavicular lymphoma: parallel opposed lateral Figure evolve 29.30 Whole brain and
fossa: including medial SCF on beams meninges down to C2/3 for ALL
opposite side Figure evolve 29.18 Nasopharyngeal Figure evolve 29.31 CT plan for ALL
Figure evolve 29.7 Submandibular lymphoma: lateral fields covering Figure evolve 29.32 A Perspex screen
nodes: shielding infraclavicular lung Waldeyers ring with compensators is wheeled
Figure evolve 29.8 Waldeyers ring and Figure evolve 29.19 Orbotal lymphoma alongside the patient
whole neck: lateral fields. See 29.9 for with anterior mass: axial view of Figure evolve 29.33 Patient with
lower neck sagittal beams and bolus dosimeters placed ready for treatment
Figure evolve 29.9 Anterior fields to Figure evolve 29.20 Orbital lymphoma: Figure evolve 29.34 Patient with
treat lower neck: matched to laterals on sagittal view of anterior wedged pair of screen in place
29.8, with central spinal shielding angled beams Figure evolve 29.35 Machine head and
Figure evolve 29.10 Lower para-aortic, Figure evolve 29.21 Orbital lymphoma: patient showing extended FSD
iliac and inguinal nodes: dog-leg outline view of volume and beam Figure evolve 29.36 Abdominal
shaped field arrangement plasmacytoma: 3-field plan
Figure evolve 29.11 Mediastinum and Figure evolve 29.22 Orbital lymphoma: Figure evolve 29.37 Plasmacytoma of
bilateral supraclavicular nodes: sparing 3D graphics petrous bone: lateral wedged pair of
salivary glands, and with partial angled beams
528
Chapter | 30 |
Tumours of the central nervous system
Neil G. Burnet, Kate E. Burton, Sarah J. Jefferies
530
Chapter | 30 | Tumours of the central nervous system
3%
Table 30.1 A simplified classification of the major
categories of brain tumour
15%
Intrinsic tumours (i.e. those arising within the brain
substance)
Glial tumours 15%
Astrocytoma
67%
Oligodendroglioma
Oligoastrocytoma
Glioblastoma (GBM) Grade I
Ependymoma Grade II
Medulloblastoma Grade III
Grade IV
Germinoma / teratoma
Lymphoma (primary CNS lymphoma PCNSL) Figure 30.2 Percentages of different grades of glioma. Grade
Extrinsic tumours of the brain covering IV glioma is glioblastoma.
Meningioma
Other tumours of tumours (58%) are gliomas (Figure 30.1). Of the glio-
Pituitary adenoma and craniopharyngioma mas, two-thirds are glioblastomas (Figure 30.2), making
Acoustic (vestibular) schwannoma this the most common type of primary CNS tumour in
Skull base chordoma and chondrosarcoma adults. Gliomas in general, and glioblastomas, in particu-
Cerebral metastases lar, are devastating tumours, and therefore consume much
of the energy and resources of the neuro-oncology unit.
Notes: Although gliomas represent the major diagnosis of primary
1. Glioblastoma used to be known as glioblastoma multiforme brain tumours, over a third of new referrals are for other
2. The glial tumours are divided into four grades: grade I and II tumour types, so appropriate attention also needs to be
together constitute low-grade gliomas (LGGs), while grade III and
directed towards those.
IV tumours together are the high-grade gliomas (HGGs). The term
anaplastic is equivalent to a grade of III. A grade IV glioma is a Gliomas are graded according to the World Health
GBM. Organization (WHO) 2000 classification, on a scale of
3. Grade I tumours are rare in adults, though they do occur. They I to IV, where IV is the most malignant. Grade I and
also appear in adult practice in patients treated as children who grade II gliomas together are termed low-grade gliomas.
have outgrown the paediatric services. Grade I tumours are more typical of childhood but occa-
4. A large number of other uncommon tumours also occur.
sionally occur in adults. Grade III and grade IV tumours
5. Medulloblastoma is predominantly a disease of childhood, but
does occasionally occur in adults (i.e. patients over 16). together constitute high-grade gliomas. Grade III tumours
may also be called anaplastic and grade IV gliomas are
known as glioblastomas.
Gliomas arise from astrocytes and oligodendrocytes,
cells which nourish and support neurons. Primary tumours
of neurons alone are extremely uncommon, though they
Meningioma 10% do exist (e.g. neurocytoma). There is a surprising large
range of very rare tumours within the brain, but apart from
those mentioned explicitly in Table 30.1, and described
Pituitary and Cranio 9%
below, their overall management and outcome can gener-
ally be inferred from the grade of the tumour.
The male to female ratio for gliomas is 1.4 to 1. Menin-
Acoustic 5% giomas are commoner in females than males, in the ratio
Glioma 58% Ependymoma 3% of 2:1, which is unusual in oncology. There are only
Lymphoma 2% two definite aetiological factors for the development of
brain tumours: exposure to ionizing radiation and genetic
Other 7% predisposition. Genetic syndromes include Li-Fraumeni
syndrome, neurofibromatosis types 1 and 2, Gorlins syn-
Metastases 6% drome and ataxia-telangiectasia. These syndromes may
account for 12% of brain tumours. They are normally eas-
Figure 30.1 Frequency of the main tumour types in 1300 new ily identifiable, and many of the cases present in child-
adult neuro-oncology referrals. Metastases are few, accounting hood. Other genetic factors may play a part but as yet are
for only 6% in this specialized neuro-oncology practice. ill understood. Mobile phones and electricity power lines
531
Walter and Millers Textbook of Radiotherapy
have been proposed as predisposing factors, but good evi- Central sulcus
dence exists that these do not influence risk.
Motor cortex Sensory cortex
Secondary CNS metastases may arise from primary
tumours at almost any site. However, certain cancers have Frontal lobe Parietal lobe
a propensity to metastasize to the brain. Lung cancer Occipital
accounts for 60% of metastases, followed by breast lobe
(15%). Other tumours causing metastases include kidney,
colon, melanoma, pancreas, and ovary. Metastases are usu-
ally multiple but occasionally can be solitary. The majority
(85%) develops in the cerebrum.
532
Chapter | 30 | Tumours of the central nervous system
Frontal lobe
Occipital lobe
Sphenoid sinus
Cerebellum
Pituitary
IV ventricle
Pons
Hard palate
Medulla
Odontoid peg
particular areas of the brain, for example the motor cortex, Lateral ventricle
can lead to some function being taken over by other areas,
provided that the rate of damage is slow. In the adult, this
can occur in only a modest way, but can explain why, in
some circumstances, patients do not lose all the neurologi-
cal function that would be expected.
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Walter and Millers Textbook of Radiotherapy
foramen of Munro, usually from infiltrative high-grade glioma, Specific focal neurological deficit
causing hydrocephalus in one or both lateral ventricles.
Communicating hydrocephalus can be caused directly CNS tumours may make their presence known by local dam-
by tumour, when extensive meningeal involvement occurs. age, leading to specific deficits dependent on the location of
This is almost always metastatic (most commonly from the tumour. For example, a meningioma affecting the motor
breast cancer), and it is rare. A commoner cause of commu- cortex will produce weakness and stiffness typically in a limb,
nicating hydrocephalus in neuro-oncology practice, is specifically depending on which part of the motor cortex is
blood in the CSF, resulting from surgery or a spontaneous affected. A glioblastoma affecting the frontal lobe produces
bleed directly from a tumour. Blood can occlude the pores intellectual, motivational and memory problems. In this
in the arachnoid granulations. Often this resolves sponta- way, symptoms and signs indicate the site of the tumour,
neously but, occasionally, a CSF shunt (such as a ventricu- which can be confirmed with imaging. Tumours arising in
loperitoneal (VP) shunt) must be inserted. Infection is also eloquent areas typically present earlier than those in silent
a cause, through the same mechanism. areas of the brain, simply because they produce symptoms
when they are smaller. Tumours which grow slowly, for
example meningioma, produce an insidious onset, with rel-
Anatomy of the skull and meninges atively mild symptoms and signs, despite often being surpris-
The skull itself is divided into three fossae. The frontal fossa ingly large when detected. Tumours which grow rapidly, and
contains the frontal lobe; the middle cranial fossa contains destructively, such as glioblastoma, produce symptoms and
the temporal lobe; the posterior cranial fossa contains the cer- signs which often appear to commence abruptly.
ebellum. The cerebellum is divided from the rest of the cranial Symptoms and signs relating to specific parts of the brain
contents by the tentorium cerebelli (tent), except for an aper- are as follows:
ture through which the brainstem passes. The two cerebral frontal lobe intellectual impairment and personality
hemispheres are divided by the falx cerebri. These two struc- change.
tures are composed of layers of tough meninges, and are parietal lobe sensory or visual inattention.
designed to damp movements of the brain which might oth- fronto-temporo-parietal speech disturbance,
erwise be damaging to the delicate brain substance. They are especially dysphasia
relatively rigid. The falx and tentorium cannot be infiltrated occipital lobe visual field defects.
by gliomas, and so present efficient barriers to their spread. brainstem cranial nerve defects, sensory or motor
Meningiomas, on the other hand, can spread along their sur- disturbance.
face, and their potential direction of spread can be appre- cerebellum loss of coordination of movement.
ciated by understanding this anatomy.
The meninges consist of three layers. The outer dura
Epileptic seizure
mater (usually known simply as dura) is a tough mem-
brane, which acts like a periosteum; it is the part visible Almost all CNS tumours can potentially cause epileptic
on imaging, and forms the falx and tent. Below and closely seizures (as can craniotomy to treat them). These can take a
applied to the dura is the arachnoid mater. Below this lies number of forms, including generalized grand mal
the pia mater, a thin delicate layer which covers every sur- seizures, Jacksonian motor seizures, sensory seizures, and
face and fold of the brain substance. In some places, there is petit mal absence attacks. Seizures are typically associated
a space (the subarachnoid space) between the arachnoid with slow-growing, low-grade gliomas, especially oligoden-
and pia, crossed by thin strands with a cobweb-like appear- drogliomas. Seizures will often bring a tumour to light before
ance (hence the origin of the name arachnoid). The dura other symptoms and signs and, for that reason, the presence of
lines the whole cranial cavity, including the skull base. In seizure is associated with a slightly improved survival in
some areas, the dura splits to form venous channels, such patients with high-grade glioma. Most patients are controlled
as the superior sagittal sinus, and the cavernous sinuses. It with simple anticonvulsant medication, but where this is
also forms two important folds, the tentorium cerebelli and problematic, the advice of a neurologist is valuable.
the falx cerebri, which are continuous with the dura cover-
ing the skull vault and skull base.
Raised intracranial pressure
Raised intracranial pressure (ICP) typically produces a triad
CLINICAL FEATURES PRESENTATION of symptoms: headaches, which are typically worse in the
morning; nausea and vomiting; and papilloedema (oedema
OF BRAIN TUMOURS of the optic disk). Raised intracranial pressure most com-
monly arises as the result of obstructive hydrocephalus,
Presenting symptoms and signs of CNS tumours are char- and is therefore particularly associated with tumours in the
acteristic; patients may present with one or more classes of posterior fossa. This can also be associated with drowsiness,
symptoms, as follows. mild confusion and sometimes with personality change.
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Chapter | 30 | Tumours of the central nervous system
Principles of neurosurgery
Performance status in the treatment
The acquisition of histological material to define the diag-
decision nosis is extremely important. However, in many cases,
Performance status is an important predictor of outcome, there is also a role for a more extended procedure to debulk
including survival, particularly for patients with glioma or remove the tumour, and relieve pressure effects (see
(Table 30.2). It also indicates how well the patient is sections on individual tumours). Surgical decompression
likely to tolerate treatment. This is an important factor when improves symptoms quickly, allows reduced steroid doses,
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Walter and Millers Textbook of Radiotherapy
and facilitates radiotherapy, especially in patients with The correct choice of MRI sequence must be made, in order
high-grade gliomas (HGGs). to optimize definition of the tumour. However, CT and MRI
Occasional HGGs grow with a cystic component to the are complementary. While MRI is in general the better
tumour. If fluid reaccumulates, then a small catheter can modality for showing tumour, CT is extremely useful to
be placed into the cyst and attached to a subcutaneous determine the extent of bone involvement, or the extent of
(Ommaya) reservoir. By inserting a needle through the a non-invasive tumour which is limited by bone. In the next
skin, fluid can be aspirated without the need for a further few years, additional imaging is likely to be incorporated
surgical procedure. into planning, especially for gliomas. This includes newer
Patients who present with, or develop, hydrocephalus MR sequences (such as diffusion weighted and diffusion ten-
may need a shunting procedure to redirect the flow of CSF. sor imaging), MR spectroscopy and PET (positron emission
In adults, this is usually done with a ventriculoperitoneal tomography) imaging. In some meningiomas that have
(VP) shunt. Some patients with obstructive hydrocephalus been completely resected, coregistration with the preopera-
can be successfully treated by a third ventriculostomy, avoid- tive MRI may be helpful in determining the location of the
ing the need for a shunt. In this procedure, a perforation is tumour and possible spread.
made in the floor of the third ventricle, allowing CSF to The definitions of gross tumour volume (GTV), clinical
escape, and circumventing the obstruction. target volume (CTV) and planning target volume (PTV)
as outlined in ICRU 83 should be used for planning
purposes. Imaging shows the extent of the GTV; historical
Principles of radiotherapy planning data are used to define a CTV margin around it, which is
typically the same in all patients with the same condition.
for CNS tumours
The PTV margin is designed to account for uncertainties in
The fundamental principles of radiotherapy (RT) planning planning and treatment, and has systematic (i.e. treatment
and treatment delivery apply to CNS tumours. These include preparation) and random (i.e. treatment delivery) ele-
accurate and reproducible immobilization, high quality ments. The margin should be added based on the recipe
imaging to localize the tumour and critical normal struc- formula outlined the British Institute of Radiology 2003
tures, three-dimensional conformal or intensity modulated report Geometric Uncertainties in Radiotherapy, and
planning, and high precision treatment delivery. incorporated into ICRU 83.
Immobilization devices include Perspex or thermoplastic Conformal radiotherapy should be considered standard
beam direction shells or, where a higher precision is required, practice, because this limits dose to normal tissues. There
a relocatable stereotactic head frame. The optimal position is reasonable evidence that this in turn reduces complica-
for the patient depends on the location of the tumour, and tions in patients treated for CNS tumours, by reducing the
on the immobilization devices available. A supine position volume of tissue, especially brain, receiving a high dose, or
is more comfortable for the patient. Using couch extensions, avoiding exposure to sensitive structures, such as the hypo-
such as an S frame or a relocatable stereotactic radiotherapy thalamus and pituitary gland (conformal avoidance). Eye
(SRT) head frame, allows treatment of posterior lesions with lens doses should be estimated with thermoluminescent
the patient supine. With a Perspex or thermoplastic shell, dosimetry (TLD) for future reference. On-treatment portal
patients with posterior lesions need to be treated prone, to films or images should be used to confirm positioning for
allow appropriate beam directions without collision with radical treatments.
the couch. The exception is for palliative RT, using parallel-
opposed lateral fields, where the patient can be positioned
supine. For craniospinal axis treatment, a prone treatment Normal tissue tolerance to radiotherapy
position allows palpation of the spine and accurate visualiza- Normal tissue tolerance is an important concept. It
tion of matching field junctions. There is no role for lateral embodies both the risk of a complication and also the
shells, which are unstable and uncomfortable. Shells should severity of its effect on the patient. The relevance also
be cut out to improve skin sparing. depends on the clinical setting: a higher risk of normal
Most planning is based on CT, because this delivers exact tissue damage might be accepted in a patient with a
patient geometry and position without distortion, and highly malignant tumour requiring a high RT dose who
because CT density is required for accurate dosimetry cal- has only a low chance of long-term survival, than is
culation. Preferably, intravenous contrast should be used reasonable in a patients with a benign tumour. The dose
because this enhances discrimination of the target. Although that is considered safe may therefore vary from one
this changes the CT numbers slightly, dosimetry is affected condition to another.
by 1% or less. In most circumstances, tumours are less well There is almost certainly a volume effect in normal
demonstrated on CT than on MRI, and MRI should be con- tissue tolerance of CNS structures, as in other parts of
sidered an essential modality for planning. Typically, MRI the body. This means that the larger the volume irradiated,
does not have to be performed in the treatment position, the lower the safe dose. The CNS is also particularly
provided suitable image coregistration software is available. sensitive to the dose per fraction, and many of the
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Chapter | 30 | Tumours of the central nervous system
dose-fractionation schedules used are designed to take whom surgery has relieved intracranial pressure, none
advantage of this. Many of the data on tolerance in the may be necessary. It is thus possible to reduce steroid doses
CNS are based on literature reports which predate the during a course of RT.
use of modern imaging, especially MRI. Tolerance doses Dexamethasone has important side effects, which can
are thus far from absolute. impact seriously on quality of life. These include increased
Tolerance of the brain itself (to avoid necrosis) is in the appetite, weight gain, muscle weakness, gastric irritation,
region of 5460 Gy in approximately 30 fractions, depend- and diabetes. Rarely, it causes psychosis which is very
ing on volume treated and dose per fraction. A volume distressing and difficult to manage. Patients should be
effect also exists for intellectual damage. Using 3D confor- managed with the minimum possible dose. For reduction,
mal RT, intellectual damage in adults is uncommon with the dose must be tailed off slowly, and not stopped
doses up to 54 Gy in 30 fractions. The brainstem is said abruptly. Patients should also be issued with a steroid card.
to have a slightly lower tolerance than brain substance,
approximately 54 Gy in 30 fractions (or 55 Gy in 33 frac- Principles of additional
tions). The optic nerves and chiasm are also thought to
supportive care
be more sensitive than brain parenchyma. For benign
tumours in this region, a dose of 45 Gy in 25 fractions It is important to think holistically about patients with CNS
to 50 Gy in 30 fractions should be safe, with a risk of blind- tumours. This includes biological, psychological, social
ness which is virtually zero. and cultural aspects of their care. This patient group is very
The pituitary gland and hypothalamus have a much lower diverse, with a wide range of diagnoses and prognosis, and
tolerance for hormonal dysfunction. There is probably little the problems experienced by the patients therefore vary
effect for doses under 2024 Gy, but adults in whom these greatly. Even patients with benign tumours may experience
structures receive 4060 Gy have a significant long-term risk major problems, even if these are not life threatening. For
of hypothalamicpituitary axis dysfunction. example, the seriousness of the condition is obvious in a
The lacrimal gland shows reduced tear output after doses patient with weakness due to GBM undertaking palliative
over about 20 Gy (similar to salivary glands). The lens of treatment. However, hearing loss due to vestibular schwan-
the eye should not develop cataract after doses less than 5 noma can also have a distressing impact on a young patient
6 Gy, spread out over 30 fractions. There is a 50% risk of cata- who needs to hear for childcare or work.
ract after a dose of 15 Gy. The middle and inner ears are also Supportive input may be valuable to a patient throughout
sensitive structures but in adults recover in most patients after their journey. Needs vary according to tumour type, and may
doses up to 60 Gy. The risk of permanent alopecia depends fluctuate throughout the patients journey, with treatment
on the dose to the hair follicles in the dermis. The risk is very or progression. Many patients benefit from practical and
low with doses below 1015 Gy, but 50% of patients will psychological support. The relevant support is often best
develop permanent alopecia after 43 Gy (in 30 fractions) developed by a specialist nurse, who will be part of most
to the scalp. This dose is difficult to estimate routinely because neuro-oncology teams. Key roles are liaison with the patient
the hair follicles normally fall within the build-up region. and family, other healthcare professionals and hospice
The spinal cord has a tolerance of approximately 50 Gy services, and provision of information from local or general
in 30 fractions (equivalent to 46 Gy at 2 Gy per fraction). resources, such as Cancer BACUP (http://www.cancerbacup.
This may be a conservative (i.e. safe) estimate and, in some org.uk/Home). For some patients, especially those with
circumstances, higher doses may be appropriate, such as for gliomas, financial benefits may be available.
GBM of the spinal cord.
Driving after a diagnosis
Principles of steroid therapy of CNS tumour
Steroids are used to treat oedema in the brain, caused by Many patients with primary CNS tumours are not allowed
tumour or surgery, so many patients attend the neuro- to drive following the diagnosis. This is because there is a
oncology clinic already taking a steroid such as dexametha- risk of seizure as the result of the tumour. There is also a
sone. A daily dose of dexamethasone (Dex) of 16 mg is con- small risk of seizure following craniotomy, whatever the
sidered the highest useful dose in most circumstances. This is underlying condition. In particular, patients with high-
a typical dose used perioperatively, and is usually reduced as grade gliomas have their driving licenses revoked for
quickly as possible. Patients on anticonvulsant drugs, which 2 years, timed from the completion of treatment.
increase the metabolism of dexamethasone, occasionally Decisions about licensing are made by the Driver and Vehi-
benefit from higher doses in the palliative setting. cle Licensing Authority (DVLA), though with information
In patients requiring RT where significant intracranial provided from the clinical teams. In general, the DVLA will
pressure remains, steroid is needed, and may need to be help patients to regain a license, and will provide an indivi-
increased during the course. However, there is no absolute dualized decision in unusual circumstances. The DVLA pro-
indication for steroids during radiotherapy. In patients in vides information on the guidelines for return of licenses for
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Walter and Millers Textbook of Radiotherapy
medical practitioners which can be obtained from the DVLA HGGs, especially GBMs, are efficient at spreading
website (www.DVLA.gov.uk). It is worth using this on-line through the brain, predominantly following white matter
facility, since the regulations do change from time to time. tracts (see above and Figure 30.4). Spread across the mid-
line, principally through the corpus callosum, is a major
route for invasion. This infiltration occurs at a microscopic
Individual tumour types level, and so currently cannot be imaged. The extent of
invasion varies between individuals. Despite the wide infil-
tration, HGGs typically recur at the primary site. There is
HIGH-GRADE GLIOMAS thus no survival advantage in irradiating the whole brain.
HGGs very rarely metastasize outside the CNS.
Patients present as described above. On CT and MRI, HGGs
Pathology and clinical features can be seen as space-occupying lesions with surrounding
oedema, causing mass effect. The gross tumour enhances with
Glioblastoma (GBM) is the commonest primary CNS
intravenous contrast. GBMs in particular have a heteroge-
tumour in adults (see Figure 30.2). GBMs and grade III glio-
neous enhancement in the gross tumour. This reflects their
mas are collectively known as high-grade gliomas (HGGs).
growth, with areas of necrosis within the tumour. The typical
The major problems with high-grade gliomas are:
GBM is shown in Figure 30.6. In patients with pressure effects,
1. significant damage to neurological function surgical decompression may improve symptoms quickly,
2. diffuse infiltration through the brain, often over quite allowing reduced steroid doses, and facilitating radiotherapy.
large distances
3. resistance to treatment, including both RT and
chemotherapy. Treatment
HGGs grow with an expanding, destructive process. Beyond Management options may be radical (curative), palliative,
the gross tumour, malignant cells infiltrate widely. The gross or active supportive care only (Table 30.3). The decision
tumour is surrounded by a zone of extensive oedema. Ste- depends on performance status, age and tumour location,
roid treatment reduces oedema, and may improve neurolog- as well as patient preference. Patients with poor neurologi-
ical function. However, there is no method to restore cal condition are unlikely to benefit from radical treatment,
function which has been lost as a result of the destruction while older patients tolerate both the neurological effects of
of neural tissue in the centre of the tumour. the tumour, and the treatment less well. For these patients
A B
Figure 30.6 (A) CT with contrast of a patient with a GBM, showing a contrast-enhancing mass with central necrosis and surrounding
oedema. (B) Lateral field, of a parallel-opposed pair of open laterals, for palliative RT for a patient with GBM. The GTV has been
outlined, and a PTV has been grown with a margin of 1.5 0.5 cm. Finally, the fields have been added, with an additional 0.8 cm
margin. The collimator has been rotated to follow approximately the radiological baseline, although the volume is above the eyes in
this case. The craniotomy can be seen, and gives approximate confirmation of the correct target localization.
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Chapter | 30 | Tumours of the central nervous system
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Walter and Millers Textbook of Radiotherapy
increases during the course, has a fluctuating pattern, and Palliative treatment
may be at its worst shortly after completion of radiother-
apy. Early delayed somnolence is rare in adults. Target volume and technique
Hair loss occurs in the entry portals and sometimes in the The patient should be immobilized in a beam direction
exit portals also, in about the third week after treatment shell. The intended beam arrangement is a parallel pair
starts. Hair washing has no effect on hair loss or scalp reac- of lateral-opposing fields. CT is used for planning purposes,
tions, provided it is carried out carefully. Using conformal to outline the GTV; apply a slightly smaller margin of
RT, scalp shielding can be used to protect some of the scalp, 1.5 0.5 cm for CTV PTV margins; no editing of the
without compromise to the underlying target volume. With CTV is necessary. The collimator should be rotated to follow
54 Gy, hair regrowth is almost normal in most patients; with approximately the radiological baseline, in order to avoid
60 Gy, at least some hair loss will be permanent. Erythema the eyes. If there is uncertainty in localizing the tumour,
and soreness of skin can occur, particularly if the pinna is use a CTV margin of 2.5 cm, as for radical RT. An additional
included in an entry port. Cutting the shell out reduces margin of around 0.8 cm is needed to allow for the field
the skin dose, and minimizes skin reactions. If the external size to cover the PTV adequately (see Figure 30.6). Fields
auditory canal is irradiated, this gets sore and crusted, and are placed using a virtual simulation tool.
the wax becomes more viscid and difficult to remove. If
the ear drum and middle ear are irradiated, then secretory Dose and energy
otitis media (glue ear) may result, but this usually settles 30 Gy in six fractions, treating three times per week, over
spontaneously. Inner ear damage is very uncommon. 2 weeks, with megavoltage photons.
In patients treated for HGG, headache and nausea are
uncommon. Seizures occasionally worsen during radio- Side effects
therapy. Dexamethasone is useful, and anticonvulsants
Acute tiredness occurs with palliative RT, and hair loss is inev-
should be reviewed.
itable, though occurs after completion of RT. Although some
regrowth occurs, hair does not return to normal. Erythema is
Late
mild, and headache and nausea are very uncommon. Due to
If the hypothalamus and pituitary have been irradiated, the poor prognosis, late side effects are rarely relevant.
hormone failure may occur after a minimum of 12 years.
Routine pituitary function tests are therefore appropriate in
Results of treatment
the few patients who are long-term survivors. Although the
most important late effect in the brain is radionecrosis, this The outlook for patients with HGG who receive palliative RT
is extremely uncommon since the advent of 3-dimensional is poor, with a median survival of only 140 days (just under
planning. 5 months) from first presentation in oncology. However, a
small number of patients survive for much longer, a few
remaining alive for over 2 years. Those patients deemed unfit
Deterioration during radiotherapy
for palliative RT have a median survival of only 6 weeks.
Some patients deteriorate during radiotherapy. This is usu-
ally due to increased oedema, presumably resulting from
tumour cell necrosis. It is usually treatable with an increase LOW-GRADE GLIOMAS
in dexamethasone dose. Occasionally, a cystic component
can enlarge, and warrants neurosurgical intervention, such
as aspiration and insertion of an Ommaya reservoir. Pathology and clinical features
A few patients deteriorate during radiotherapy due to Low-grade gliomas (LGGs) include those with WHO
tumour progression. In these cases, it is appropriate to grade I and II. Grade I tumours are rare in adults. LGGs
switch to palliative fractionation (see below), making an represent about 12% of the total number of cases referred
appropriate dose change according to the dose already to oncology (see Figures 30.1 and 30.2). Although LGGs
delivered, or to stop RT altogether. present in similar ways to other primary tumours, seizure
is a much more common presenting complaint than with
Results of treatment other tumours. Oligodendrogliomas (of grade II) are
The outlook is more favourable for grade III tumours, with particularly likely to present with epilepsy. Because of this
50% survival at 3 years, than for patients with GBM, for tendency to cause seizure, many patients with LGG are fol-
whom the figure is only 23%. Nevertheless, this small lowed up in neurology clinics. The course of the illness is
group of GBM patients is important. In a randomized trial extremely variable. Some LGGs appear never to progress,
of patients with GBM, the addition of oral temozolomide and others may take a decade or more to do so. However,
chemotherapy extended survival significantly: median some tumours show evidence of disease progression from
survival was extended from 12 months to 14.5, and 2-year the time of diagnosis. It is the patients with these tumours
survival increased from 10% to 26%. that are typically referred for an oncology opinion.
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Chapter | 30 | Tumours of the central nervous system
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Walter and Millers Textbook of Radiotherapy
needed to achieve dose homogeneity, especially for large ventricular system. It arises most often in the posterior
target volumes. TLD is recommended to estimate doses fossa, though it can be supratentorial. Typically, posterior
to the lens, and portal imaging to verify treatment set-up. fossa lesions present as the result of obstructive hydroceph-
alus. Imaging demonstrates a contrast-enhancing tumour
adjacent to the fourth ventricle but away from the midline.
Dose and energy There is surrounding oedema, and typically enlarged ven-
Single phase: 50.454 Gy in 2830 daily fractions over tricles above. Supratentorial ependymomas present in the
5.56 weeks, with 6 MV photons. same way as other cerebral primary tumours. On imaging,
There is some evidence to suggest that a lower dose of the appearances are very similar to HGG. Spread may occur
45 Gy in 20 fractions may be as effective. For patients with in the CSF, so MR imaging of the spine is necessary to stage
gliomatosis cerebri, a slightly smaller dose per fraction may the patient.
be helpful, and a dose of 55 Gy in 33 fractions is suitable.
Treatment
Side effects
The maximum possible surgical resection is an advantage
Acute and late effects are similar to HGG, particularly grade III before radiotherapy. There is no definite role for adjuvant
gliomas, for which the same dose is used. Seizures may worsen chemotherapy in adults. Although ependymoma can
during radiotherapy. Dexamethasone is useful, and anticon- spread through the CSF, there is good evidence that pro-
vulsants should be reviewed. Late hypothalamus and pituitary phylactic craniospinal RT confers no advantage.
dysfunction is an important issue in long-term follow up, par-
ticularly since the prognosis is much more favorable than
HGG. Most studies of intellectual function suggest little or Target volume
no detrimental effect from 54 Gy (in 30 fractions), over and The patient should be immobilized in the conventional
above that already caused by the tumour (and surgery). way, positioned either prone (in a two-piece shell), or
supine in an S frame, to allow for posterior beams. The
Results of treatment shell should be cut out for treatment. For posterior fossa
tumours, it is typical to consider the whole posterior fossa
The outcome of patients with LGG is very variable. How- as the CTV, similar to the phase 2 treatment for medullo-
ever, younger age, smaller tumours, and lack of neurologi- blastoma (Chapter 33). However, for lateralized tumours
cal deficit are prognostic for better outcome. In addition, it may be acceptable to outline the GTV as enhancing
the histological type also has an effect: oligodendroglioma tumour, and add a CTV margin of 1.52.5 cm. An appro-
histology has a better outlook than astrocytoma. Mixed priate PTV should be added. Supratentorial ependymomas
tumours have an intermediate outlook. should be treated along similar lines to HGG, using postop-
Many patients with neurological deficits from tumour erative MRI to define the GTV. The CTV requires a margin of
experience improvement, and this is a very important indi- 1.52.5 cm, grown isotropically, which can be edited along
cation to undertake RT. This also applies to gliomatosis the skull. An appropriate PTV should be added.
cerebri, despite the enormous volumes of brain affected.
In half of patients who have epilepsy, the frequency and
severity of seizures improves after radiotherapy. Technique
In the large European trial which evaluated the timing of In adults, the posterior fossa is best treated with a plan, typi-
RT, early radiotherapy delayed progression of LGG by cally using three non-coplanar fields. The standard arrange-
about 2 years. This increase in disease-free survival may ment is with two posterior oblique and one posterior beam.
be of value to patients. Median survival (i.e. 50% of This achieves the best conformation to the posterior fossa
patients alive) was around 7.5 years, irrespective of the target volume. Supratentorial tumours require individua-
timing of RT. Ten-year survival data from that trial are lized beam arrangements, as per HGGs.
not available yet, but from other series the survival at
10 year is in the range 4060%.
Dose and energy
Megavoltage x-rays of 6 MV or equivalent should be used.
EPENDYMOMA (INTRACRANIAL) Single phase: 55 Gy in 33 daily fractions, over 6.5 weeks.
An alternative is 54 Gy in 30 fractions, treating daily over
Pathology and clinical features 6 weeks.
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Chapter | 30 | Tumours of the central nervous system
Management principles
PRIMARY CNS LYMPHOMA
Biopsy is necessary to prove the diagnosis, but resection
should not be undertaken if a diagnosis of PCNSL is sus-
Pathology and clinical features pected, because it does not improve the prognosis and car-
ries a greater risk of neurological deficit. Steroids are
Primary central nervous system lymphoma (PCNSL) is
cytotoxic to lymphomas (as with peripheral lymphomas).
non-Hodgkins lymphoma arising in the brain, typically
Therefore, if dexamethasone is given for symptom relief
of high-grade B-cell type. The incidence of PCNSL is increas-
before a biopsy is performed, the lesion may disappear
ing, but is still uncommon (see Figure 30.1). It affects
temporarily. The inclusion of lymphoma in the radiologi-
patients of all ages, the incidence rising with age, and the
cal differential diagnosis thus provides an important con-
majority are over 60. Myelosuppression predisposes to
tribution to management.
the development of PCNSL, and this was one of the early
Although treatment strategies have evolved, the opti-
AIDS-defining diagnoses. Happily, this is now a rare com-
mum treatment remains unclear. Until about 20 years
plication of HIV.
ago, radiotherapy was the mainstay of treatment. Treat-
Presentation is the same as other primary tumours aris-
ment typically commenced with whole brain irradiation
ing within the brain substance, typically with headache,
(e.g. to a dose of 45 Gy in 25 fractions), followed by a
neurological deficit often including intellectual decline,
focal boost for localized disease (e.g. 910 Gy in five frac-
or seizure. B symptoms (see Chapter 29) are not a feature
tions). Treatment with radiotherapy alone is well toler-
of PCNSL. On imaging, typical appearances are of a
ated but, in historical series, most patients recurred
homogeneously-enhancing mass, often in a periventricu-
locally, with fatal consequences. Therefore, the addition
lar location (Figure 30.8). In approximately two-thirds of
of chemotherapy was investigated, a strategy that had
cases, PCNSL presents as a single mass; in one-third it is
proved effective in systemic non-Hodgkins lymphoma.
multifocal. The disease can spread within the brain, espe-
It became clear that combined chemoradiotherapy is
cially in the subependymal layer around the ventricular
superior to radiotherapy alone. However, a particular
system, but it is rare for it to metastasize outside the
problem is late neurotoxicity associated with the combi-
CNS. Metastases to the brain from peripheral lymphoma
nation of chemotherapy, especially methotrexate, with
are also rare.
radiotherapy. This occurs commonly, especially in older
people, and can be severely disabling or even fatal. Treat-
ment schedules with very intensive chemotherapy alone
were therefore developed, and can now be considered the
mainstay of treatment. Overall, it appears that RT
improves progression-free survival rates, but not overall
survival. However, the neurotoxicity is worse with the
combined treatment, affecting about half the patients
receiving combined chemo-RT compared to a quarter
treated with chemo alone. Since omitting RT does not
compromise survival, and reduces serious toxicity, radio-
therapy is now not recommended as part of the first
line treatment for PCNSL. RT may be used as a salvage
treatment.
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Walter and Millers Textbook of Radiotherapy
limits. Avoidance of high dose areas may reduce the risk and
severity of late neurotoxicity. GERMINOMA
For phase 2, a localized volume is treated, using a three-
field plan, or equivalent. The GTV is the pre-chemotherapy
enhancing disease seen on MRI. A margin of 12 cm should Clinical features and management
be allowed around this for the CTV, and the appropriate principles
PTV margin added.
Germinomas are rare in adults, but present like other primary
Dose and energy tumours. They frequently arise in the region of the pineal
gland, close to the (CSF) aqueduct (see Figure 30.5) and,
Phase 1: 45 Gy in 25 daily fractions, over 5 weeks.
therefore, the symptoms and signs of hydrocephalus are com-
Phase 2: 910 Gy in 5 daily fractions, over 1 week.
mon presenting features. They should be curable in almost
every case.
Multifocal disease Germinomas spread through the CSF, and therefore
Target volume and technique require RT to the whole craniospinal axis. The tumour
has a curious predilection to form metastatic deposits on
Treat the whole brain with a single phase, as per phase 1.
the optic chiasm. Different tumours show a wide range
Dose of growth rates, but a few grow extremely fast. This can lead
Single phase: 45 Gy in 25 daily fractions, over 5 weeks. to neurological deterioration taking place over days or even
hours. If a patient has metastatic spread to the optic chiasm,
Alternative lower dose single phase schedules have also rapid progression may threaten vision. Such deterioration
been used by some groups, even for localised disease: warrants urgent treatment, with radiotherapy. This type
Single phase: 30.639.6 Gy in 17 22 fractions, over of disease does not respond well to steroid treatment.
34 weeks 45 Gy in 30 daily fractions, over 6 weeks Therefore, occasionally, a few fractions of emergency radio-
therapy must be given urgently to treat neurological deteri-
oration, while the full plan is prepared.
Palliative radiotherapy In adults, the standard treatment for intracranial germi-
This may be necessary for a few patients with poor perfor- noma should be radiotherapy. The total dose is modest,
mance status. and the toxicity profile in adults is excellent, because
growth is complete. There is therefore no advantage in con-
Target volume and technique sidering an alternative strategy of reduced dose RT together
with chemotherapy, at least at the present time.
Immobilize and irradiate the whole brain with a single
phase, as per palliative RT for metastases. Treatment
Dose Target volume
A variety of dose schedules can be utilized: Phase 1 should treat the whole craniospinal axis, and this is
most effectively planned from CT. The technique is the
30 Gy in 10 fractions, treating daily, over 2 weeks
same as for paediatric craniospinal RT (see Chapter 33),
20 Gy in 5 fractions, treating daily, over 1 week
and requires careful attention to detail.
30 Gy in 6 fractions, treating on alternate days over
For phase 2, the primary site is treated to a higher dose.
2 weeks (as for HGG).
This should be localized using CT:MR coregistration,
and the imaging must be carried out before RT starts,
Results of treatment because the tumour is extremely radiosensitive and may
The major prognostic factors for better survival are youn- disappear within a few days of starting RT. The GTV is the
ger age, especially less than 60, excellent performance contrast-enhancing tumour. The CTV margin can be small,
status and chemotherapy. Suitability for chemotherapy e.g. 12 cm, grown isotropically. The PTV should be grown
is strongly determined by performance status. Localized from the CTV, with a standard margin, such as 0.5 cm.
disease, rather than a multifocal pattern, also carries a Any sites of metastatic disease can also be boosted in this
better prognosis. Long-term survival is poor, especially phase. Occasionally, the whole craniospinal axis must be
in patients over 60, who comprise the majority. In a series treated to the phase 2 dose (see below).
of unselected cases, the median survival was only
8 months, with a 5-year survival of 6%. However, in
Technique
patients under 60 with good performance status who Phase 1 as for paediatric craniospinal RT (see Chapter 33).
are treated intensively, the median survival should reach For phase 2, use an appropriate beam arrangement, usually
3 years, and the 5-year survival 2030%. with three conformal fields.
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Chapter | 30 | Tumours of the central nervous system
Dose and energy express progesterone receptors (PR), but not oestrogen
receptors (ER), and this may account for occasional reports
Phase 1: craniospinal axis: 25 Gy in 15 daily fractions in
of change during pregnancy or in patients using hormone
3 weeks, using megavoltage x-rays.
replacement therapy. More malignant tumours typically
Phase 2: 15 Gy in 9 fractions in 2 weeks, to boost the
become less well differentiated and lose this expression.
primary site and any sites of metastasis.
Meningiomas arise in the coverings of the brain, and so
If necessary, in the case of extensive metastatic spread, it is can occur at any intracranial site. However, the commonest
possible to treat the whole craniospinal axis to 40 Gy in 24 two sites are the vertex of the skull, and the greater wing of
fractions, provided that the full blood count is carefully the sphenoid bone. This is the ridge of bone which divides
monitored. If urgent RT is required while the craniospinal the anterior and middle cranial fossae. Tumours at the ver-
plan is being prepared, this can be done using a parallel tex can usually be fully resected. Those on the sphenoid
pair of lateral fields. A few fractions (e.g. 5 Gy in three frac- wing are resectable if they lie laterally. Medial sphenoid
tions) are normally sufficient to prevent clinical deteriora- wing tumours usually involve the cavernous sinus, which
tion. It is probably best, in adults, simply to consider this as normally precludes complete resection.
extra dose, added to the two phases described above. In the first instance, management depends on whether
surgical resection can be performed. In a neurosurgery prac-
Results of treatment tice, the majority of meningiomas are completely resectable
With good radiotherapy technique, the cure rate is almost and usually cured without the need for further treatment.
100%. This applies even if metastatic disease is present at In those which can only be partially resected, or are entirely
diagnosis. unresectable, RT can be considered. Even if the whole
meningioma cannot be removed, there may be advantage
in debulking to reduce the tumour size, provided it is not
MEDULLOBLASTOMA at the cost of neurological damage. Some meningiomas
grow so slowly that they appear to be static. These may
be managed conservatively.
The management of medulloblastoma in adults follows the Optic nerve meningiomas cause visual deterioration. These
general principles of this disease in children. However, there tumours are normally diagnosed entirely on imaging. In
is less need to reduce doses in adults who have mature brains these patients, surgery, including biopsy, can further damage
and are fully grown. Exactly the same meticulous attention vision. RT is effective in stabilizing the disease, and some
to detail of radiotherapy technique is needed. Survival patients experience an improvement in vision. RT is thus
advantage has been shown for the addition of chemotherapy the treatment of choice for optic nerve meningioma.
in children. This issue needs to be addressed in adults. The WHO grading of meningiomas is from grade I to III.
The management of paediatric medulloblastoma is Most tumours are of grade I and usually grow slowly. Grade
described in Chapter 33. II tumours, also known as atypical, may grow faster and
have a higher tendency to recur. Grade III tumours, also
Dose and energy (adults) known as malignant, are faster growing, more aggressive
Phase 1: craniospinal axis: 35 Gy in 21 daily fractions in in their extension, and more difficult to eradicate. Although
4 weeks, using megavoltage x-rays. not as fast growing as HGGs, malignant meningiomas may
Phase 2: 20 Gy in 12 fractions in 2.5 weeks. still change over weeks to months. On average, malignant
meningiomas occur in younger patients than the benign
variety.
MENINGIOMA Meningiomas can infiltrate along the meninges, and this
even applies to tumours known to be benign. They may also
infiltrate through the foramina and fissures of the skull base,
Pathology and clinical features
and these areas must be carefully reviewed when planning RT.
Patients with meningioma present with a mixture of symp- On imaging, tumours are of similar density to the sur-
toms and signs. Headache is common. As with other primary rounding brain. Sometimes they cause surrounding oedema.
tumours, meningiomas may also cause confusion and intel- With contrast they normally enhance vigorously and homo-
lectual impairment, resulting from compression of the fron- geneously (Figure 30.9). It is typical to have meningeal
tal lobes. Occasionally, patients may present with specific enhancement extending away from the site of a meningioma,
cranial nerve palsies, which is different from glial tumours. and this does not necessarily indicate tumour spread. Rather,
The majority of meningiomas arise sporadically. How- this tail is a useful diagnostic feature. Nevertheless, many
ever, they may be associated with previous radiation patients referred for an oncology opinion have a tumour with
treatment, for example cranial RT used for childhood leu- a more invasive pattern of growth, with demonstrable exten-
kaemia. Unusually in oncology, they are commoner in sion along adjacent meningeal layers. A rule of thumb to dis-
women than men (2:1). Benign meningiomas normally tinguish the reactive tail from infiltration is the thickness of
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Walter and Millers Textbook of Radiotherapy
Treatment Technique
Radiotherapy target volume Conformal RT or IMRT should be standard, typically using
The patient should be immobilized in a beam direction three or four non-coplanar beams. A field-in-field boost may
shell, cut out to maximize skin sparing. For small lesions be needed to achieve dose homogeneity, especially for large
where high precision is desired, a relocatable stereotactic target volumes. TLD is recommended to estimate doses to
head frame can be used. If resection has been carried out, the lens, and portal imaging to verify treatment set up.
then postoperative imaging is required. A current MRI scan
should be used for planning, coregistered with the planning Dose and energy
CT. Both modalities are helpful for target volume delineation. 5055 Gy in 3033 daily fractions over 66.5 weeks, with
MRI using a T1W sequence with gadolinium contrast pro- 6 MV photons.
duces optimal localization of the tumour. CT shows the limits
The dose may vary according to which critical structures are
of meningioma extension up to bone or, in uncommon
contained within the CTV and PTV. In some centres, a dose
cases where the tumour involves the bone, the extent of the
of 60 Gy is considered appropriate for malignant (grade III)
invasion. CT also shows the foramina and fissures of the skull,
tumours.
through which meningiomas can spread.
The gross tumour (GTV) is defined as the visible edge of
contrast enhancement on MRI, plus relevant skull bound- Side effects
aries. If resection has been carried out, coregistration with Acute and late effects relate to the location irradiated. Tired-
the preoperative MRI is very helpful. This shows the location ness does occur, even using small doses per fraction; it is,
of the tumour and therefore the meningeal surfaces into however, less marked than for patients treated for HGG.
which spread might occur. There is very little hard evidence Hair loss occurs in about the third week after treatment
for the size of the CTV margin that should be used. For an starts. Hair washing has no effect on hair loss or scalp reac-
individual tumour, its growth pattern suggests whether a tions, provided it is carried out carefully. Scalp shielding
small or large margin is needed. The most benign tumours can be used to protect some of the scalp, without compro-
grow as a slowly expanding mass, often relatively spherical mise to the underlying target volume. With 50 Gy, hair
in shape. In these cases, the CTV may be the same as the regrowth is almost always normal.
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Chapter | 30 | Tumours of the central nervous system
Erythema and soreness of skin are uncommon with 50 Gy Patients with malignant meningiomas (i.e. grade III) have a
in 30 fractions, though can occur with higher doses. Cutting worse outlook, with 5-year survival rates around 40%, that
the shell out reduces the skin dose, and hydrocortisone is about half the survival of patients with benign tumours.
cream 1% applied topically reduces itching. The pinna
and external auditory canal may be affected. If the external
canal receives a significant dose, the wax becomes viscid Pituitary tumours and
and sticky. If the ear drum and middle ear are irradiated, craniopharyngioma
then secretory otitis media (glue ear) may occur. This may
cause noises in the ears, especially bubbling, reduction of
hearing and, occasionally, difficulties with balance, but this
is usually temporary and settles spontaneously. If the eusta- PITUITARY TUMOURS
chian tube is treated, the same problem often occurs.
Occasional patients experience nausea, especially when
the brainstem is irradiated. This is usually manageable
Pathology and clinical features
with 5-HT3 antagonists. Patients occasionally require ster- Pituitary tumours are virtually always primary adenomas of
oids during treatment for meningioma. Headache is also the anterior pituitary gland itself. Other primary tumours
uncommon as an acute side effect. are exceedingly rare, and metastatic deposits involving the
In terms of late effects, if the hypothalamus and pituitary pituitary fossa, although well described, are uncommon.
have been irradiated, hormone failure may occur after 12 Pituitary adenomas can be divided into secretory tumours
years, so routine pituitary function tests are necessary dur- that produce excess hormone and non-secretory ones that
ing follow up. Intellectual function should not be affected, do not. Secretory adenomas most commonly produce an
over and above changes already caused by the tumour (and excess of a single hormone, usually growth hormone causing
surgery). In cases where high eye doses cannot be avoided, acromegaly, adrenocorticotrophic hormone (ACTH) which
such as optic nerve meningiomas, cataracts may develop causes Cushings disease, or prolactin leading to hyperpro-
(see above). lactinemia. Other hormone production is very uncommon.
Patients with secretory tumours usually present with the
effects of the excess hormone production, and a small
Results of treatment tumour confined to the pituitary fossa. In many cases, hor-
It is likely that RT improves the outcome in patients for mone levels can be controlled medically. However, surgery
whom surgery is either impossible or incomplete. The produces the quickest reduction of hormone levels in secret-
results of subtotal resection plus RT are equivalent to com- ing tumours, and is often curative. Radiotherapy can reduce
plete surgical excision, and may be safer for the patient. hormone levels, but often very slowly, over months or years,
Meningiomas grow slowly, so that follow up needs to be and is therefore not helpful as an acute treatment.
carried out over a long period, at least 1015 years. Non-secretory tumours typically present with symptoms
Age does not appear to be prognostic, and should not be and signs of optic chiasm compression. Occasionally, they
considered a bar to radical RT. Tumours which are larger, or present with pituitary failure, and are sometimes associated
of higher grade, have a higher chance of earlier relapse. In with headache. Surgical decompression results in immedi-
addition, it is likely that tumours with a high number of ate relief of pressure on the optic tract, and vision often
cells actively in the mitotic cycle have a higher probability improves by the time the patient wakes from the anaes-
of early relapse. thetic. Extension of tumour to the lateral walls of the pitui-
In general, meningiomas do not change in size after tary fossa and cavernous sinus cannot be removed
RT, although a few do shrink modestly. However, it is impor- surgically, and is a frequent site for residual tumour.
tant for the patient to understand that no change after treat- After complete removal, radiotherapy is usually not
ment represents a successful outcome. Neurological deficits, required. However, a proportion do recur, so adequate
such as cranial nerve palsies do not usually improve. The follow up is essential. The indications for radiotherapy
exception is with optic nerve meningiomas: about one-third are relative, and patients are best managed through a
of patients experience some improvement in vision, even if multidisciplinary team. The decision regarding RT in an
there is no change in the size of the lesion on imaging. individual patient is the result of weighing the pros and
Overall, control rates for patients with meningioma are cons of observation versus early RT. Indications in favor
good, though published results are quite variable. Survival of radiotherapy include extensive residual tumour, inva-
after surgery and RT for benign meningiomas (i.e. grades I sion of the cavernous sinuses laterally, uncontrolled ele-
and II) is around 8090% at 5 years, and 5080% at 10 years. vated hormone levels, and evidence of progression of
For patients with inoperable tumours treated with RT alone, tumour after surgery alone. Factors against radiotherapy
control rates are probably on the low end of these ranges. include normal pituitary function, and young age, because
Although these results are good, and much better than for of the risk of inducing a second tumour. Patient preference
patients with gliomas, there is room for improvement. is also important. If recurrence does occur in a patient
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Chapter | 30 | Tumours of the central nervous system
In all, half to three-quarters of patients require hormone Surgery achieves decompression and tissue for histologi-
replacement after surgery and RT. cal confirmation. Complete surgical removal is sometimes
The risk of late radiotherapy damage to the optic nerves possible for very small lesions. More commonly, the
should be negligible with a dose of 45 Gy in 25 fractions, tumours are large, complex and highly adherent to the brain,
prescribed to the isocentre. Therefore, if visual deteriora- so that attempts to remove every finger-like projection of the
tion occurs after RT, it is important to look for a cause other cyst wall can produce very substantial traction injury to the
than radiotherapy. Cataract should not occur with standard brain. In general terms, decompression and subtotal resec-
techniques. tion plus radiotherapy produces similar local control rates
Any radiotherapy treatment carries a risk of late second to radical surgery, with much less neurological morbidity.
tumour causation. In patients treated for pituitary adenoma, Radiotherapy is recommended for virtually all adult
the risk is roughly 1% per decade of follow up after patients. Patients normally have panhypopituitarism
treatment. Of the tumours caused, about half are benign, typ- already, so that this relative contraindication is absent.
ically meningioma, and about half are malignant, for exam- The recurrence rates following surgery alone, even after
ple glioblastoma or sarcoma. Because the risk is cumulative apparently complete removal, are high. Since the recur-
with time, this is especially important in younger patients. rence can increase neurological deficits, which are often
found in patients with this disease already, the risk and
consequences of recurrence greatly outweigh the risks from
Results of treatment
RT. In children, where delay of RT may in itself be an advan-
Postoperative radiotherapy produces very high rates of con- tage, this balance is slightly different.
trol. Overall, tumour control rates should be around 95%
at 10 years and 90% at 20 years. However, control of hor-
Treatment
mone secretion is poorer, with only 6080% achieving
control of hypersecretion. Target volume
The patient should be immobilized in a beam direction
shell, in a comfortable, neutral position. A relocatable ste-
CRANIOPHARYNGIOMA
reotactic frame may also be used. CT planning should be
used, with coregistered MRI (T1WGd). In some circum-
Pathology and clinical features stances, coregistration with the preoperative MRI may also
be helpful as a guide to the GTV.
This is a rare tumour which predominates in children but RT for craniopharyngioma is more difficult to plan than for
can occur in adults. In adults, it typically presents with symp- pituitary adenoma. The tumour is very adherent at both a
toms and signs related to raised intracranial pressure, com- macroscopic and microscopic level, and all parts of the brain
pression of the optic chiasm and optic nerves, or reduction with which the original tumour was in contact need to be irra-
in pituitary hormone secretion. When these tumours are diated. However, resection decompresses the tumour and
very extensive, pressure on the frontal lobes or involvement reduces the mass effect, so shifting the anatomy. Thus, neither
of the hypothalamus can cause behavioural disturbance. In preoperative nor postoperative imaging exactly represents the
children, it may present with other manifestations of damage location of the target, so that the internal anatomy of the brain
to the hypothalamus, including precocious puberty. must also be considered in the planning.
Craniopharyngiomas are thought to arise from cells There are usually some solid or cystic remnants follow-
derived from the embryological structure known as Rathkes ing surgery, which can be demonstrated with MRI; these
pouch, which extends from the embryonic pharynx to form represent the GTV. The CTV should contain the following:
the anterior pituitary gland. Craniopharyngiomas are nor- any postoperative gross tumour; the surface of the preop-
mally cystic, with a thin wall, and may have some more solid erative gross tumour; and a margin for any uncertainty in
components. The craniopharyngioma itself is lined by epi- localizing either of these two volumes. It is reasonable for
thelium (reflecting its origin), which produces the cyst fluid. the CTV to follow any shift of the brain following decom-
At both a macroscopic and a microscopic level, the wall of pression, based on the anatomy. The PTV margin should
the cyst projects into spaces in the surface of the brain, to be grown isotropically, depending on the immobilization
which it can be strongly adherent. method used.
On CT, flecks of calcification are often seen. On MRI, the As noted above, the optic nerves, chiasm and tracts,
cyst has almost unique signal characteristics, being neither should be outlined, so that the dose distribution and the
those of CSF nor brain; the cyst wall is normally well shown DVHs for these structures can be reviewed.
on the T1W sequence and enhances with gadolinium
contrast. When opened surgically, thick viscous fluid is
often seen, with the macroscopic appearances of machine
Technique
oil and containing microscopic cholesterol crystals. This A three-field conformal plan is usual, as per pituitary ade-
accounts for the MRI appearances of the cyst fluid. noma. If the target is large or irregular, a non-coplanar plan
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Walter and Millers Textbook of Radiotherapy
may be useful. TLD measurements of the eye doses should Results of treatment
be made.
Radiotherapy following surgery produces high rates of con-
trol, around 8590% at 10 years, and 80% at 20 years. Lim-
Dose and energy
ited surgery plus radiotherapy produces local control rates
5055 Gy in 3033 daily fractions over 6 weeks, with as good as those from radical surgery, with lower neurolog-
megavoltage x-rays. ical morbidity.
As noted above, there is a small advantage from using high
energy (i.e. 1015 MV) x-rays to reduce temporal lobe doses
because these tumours are located centrally within the skull. VESTIBULAR (ACOUSTIC)
SCHWANNOMA
Side effects
Side effects are similar to those for pituitary adenoma. In the
Pathology and clinical features
occasional patient with a very large craniopharyngioma, hair
loss may be significant, but should regrow. Ear symptoms Strictly speaking, the correct term for this tumour is vestibu-
(as above) may occur, but this relates to the exactly how lar schwannoma, though the older term, acoustic neuroma,
far posteriorly and inferiorly the PTV extends. is still commonly used. These tumours represent a small
For patients already taking hydrocortisone replacement, proportion of patients referred for an opinion regarding
it is sensible to increase the dose, as noted above. Most RT (Figure 30.10). They are a common cause of unilateral
patients with craniopharyngioma already have complete deafness, with a population incidence in the range 0.52
loss of hypothalamicpituitary axis hormones. per 100 000 per year. Patients commonly experience tinni-
The major difference in side effects compared to pituitary tus, despite losing hearing, and this is an additional present-
adenoma is the small but important risk of visual de- ing symptom. Rarely, a vestibular schwannoma can be large
terioration during RT. The cystic component of a cranio- enough at presentation to compress the brainstem, causing
pharyngioma may refill with fluid at a variable period disturbance of balance. Some are associated with the genetic
after surgery, and cause compression of the optic chiasm. condition of neurofibromatosis type 2 (NF-2), which often
Re-accumulation of cyst fluid is unrelated to RT itself, presents with bilateral vestibular schwannomas.
but may occur coincidentally during the postoperative A multidisciplinary approach is desirable for the man-
phase when RT is being given. If visual deterioration occurs, agement of patients with vestibular schwannoma. This
urgent MRI is needed. If cyst recurrence is confirmed, group of patients is almost unique in having a choice of
urgent neurosurgical referral for operation should be made, treatment options, though the decision may not be simple.
to try to preserve vision. Patients with NF-2 may have other tumours in addition
The risk of late radiotherapy damage to the optic nerves to bilateral schwannomas, and their care is extremely
should be very small with a dose of 50 Gy in 30 fractions, complex.
prescribed to the isocentre. The risk of second tumour for- Small tumours can be managed with a watch, wait and
mation is similar to patients with pituitary adenoma, but rescan policy, and some stabilize spontaneously for long
this risk is very much less than the risk of recurrence of periods of time. Active treatment is only required with
the craniopharyngioma if RT is not given. disease progression. Small and medium-sized tumours
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Chapter | 30 | Tumours of the central nervous system
are well treated surgically, with very low rates of facial It is helpful to outline the pituitary so that a low dose
nerve damage. They are also well treated with both frac- can be confirmed. The cochlea is bound to lie within the
tionated stereotactic radiotherapy (FSRT) and stereotactic PTV so that the dose is predictable without it being out-
radiosurgery (SRS). SRS can be performed using a lined. The eyes, specifically the lenses, should be outlined,
Gamma Knife or linac-based X-knife. Large tumours, to ensure that the tolerance dose is not exceeded, for exam-
with significant brainstem compression, usually require ple, by the exit dose from the posterior oblique beam. The
surgical resection. However, very large tumours may be ipsilateral parotid gland can also be outlined for the same
too big to resect safely, and therefore are considered for reason.
radiotherapy. For these patients, FSRT is the appropriate
technique. Technique
Surgery is an excellent treatment, provided complete
excision is achieved without undue disability. Most cases, A three-field conformal plan is usual, using anterior oblique
though not all, are cured. Some surgical units prefer a and posterior oblique wedged fields and a lateral field, with
translabyrinthine approach, because it provides a safer coplanar or non-coplanar disposition depending on the
approach for preservation of the facial nerve, but this is exact target shape. Small volumes may also be treated with
at the expense of irreversible hearing loss. It is therefore multiple arcs.
relatively more attractive to patients who are already deaf.
For some patients, brainstem (cochlear) implants are Dose and energy
possible.
50 Gy in 30 daily fractions over 6 weeks, with 6 MV
Radiotherapy has excellent efficacy and low morbidity.
photons.
Rates of local control appear similar for both surgery and
RT, using either FSRT or SRS. Surgery has the attraction Some centres have used higher doses, in the range
of removing the tumour and avoiding the small risk of 5457.6 Gy, in 1.8 Gy fractions. Some hypofractionated
radiotherapy-related second tumour risk, but has the disad- schedules have also been designed, using lower doses in
vantages of a small operative mortality, protracted rehabil- 12 fractions only. These doses exceed brainstem tolerance
itation, a risk of facial nerve damage, and hearing loss and are only suitable for small lesions. Preservation of
depending on the surgical approach. Radiotherapy has cranial nerve function may be better with the slightly
the attraction of avoiding a major surgical procedure, has lower dose (50 Gy), but this needs to be formally evalu-
a lower rate of serious morbidity (and mortality) and prob- ated. The variation in local control with dose also needs
ably a lower rate of facial nerve damage, at the expense of investigation.
the tumour remaining in situ. Patient preference must be Although the hearing preservation rate is lower in NF
considered, and this group of patients is typically very well patients, a lower dose is not recommended lest the tumour
informed. Nevertheless, the decision may not be easy. control rates are reduced.
Treatment
Side effects
Here, only the technique for FSRT will be described; SRS is a Acute side effects include hair loss in the field entry
highly specialized technique, which should be studied in portals, and there may be mild erythema of the skin.
more specific texts. The skin within the external auditory meatus may also
become irritated and, in the longer term, the wax may
Target volume become thicker and more tenacious. Some patients expe-
The patient should be immobilized in a beam direction rience mild nausea, which is easily controlled with simple
shell or relocatable stereotactic frame. Radiotherapy antiemetics. A proportion of patients also experience
should be fully conformal, based on CT planning with some disturbance of balance, due to vestibulocochlear
coregistered T1WGd MRI (see Figure 30.10). The irritation. This resolves after RT, though this may take
tumour is not well shown on CT, but the internal auditory several weeks.
meatus (IAM) can be visualized. On MRI, the tumour is Important late effects include consideration of hearing
obvious, and extension into the IAM is obvious. Accuracy preservation and cranial nerve function. Hearing preserva-
of the CT:MRI coregistration can be reviewed by compar- tion rates are in the region of 75% with both FSRT and SRS
ing the bony canal of the IAM on CT with tumour exten- but also depend on tumour size in SRS series. Preservation
sion into the canal on MRI. An accuracy of better than of some useful hearing may be higher, and has been sug-
1 mm should be achievable. gested to be as high as 90% in FSRT series. Patients with
The GTV is the enhancing edge of the tumour seen on NF-2 have a higher risk of losing hearing, with a preserva-
MRI. Provided the coregistration accuracy is high, no tion rate of only 60%. Both FSRT and SRS series report
CTV margin is required. The PTV should be grown isotro- facial neuropathy risks in around 1%, and trigeminal
pically with an appropriate margin. symptoms in 13% of patients. However, the risks are
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Walter and Millers Textbook of Radiotherapy
dose-related and may be lower than this with the sug- UK patients have been referred abroad under the proton
gested dose above. Oversees Programme.
There is a risk of late second tumour following RT, most
relevant in younger patients. By analogy with the data from Target volume
pituitary patients, and considering the small, lateralized
The whole of the preoperative volume should be included
volume, this is expected to be rather less than 1% per
in phase 1. For phase 2, a smaller volume should be
decade after treatment.
boosted, corresponding to residual, imageable tumour or
to the likely site of microscopic disease. Both pre- and post-
Results of treatment operative imaging using CT and MRI are valuable. CT
shows bone erosion, while MR demonstrates tumour itself.
Local control rates after fractionated stereotactic radio- If the brainstem and spinal cord are close by, then it is
therapy (FSRT) or stereotactic radiosurgery (SRS) are often appropriate to add a planning organ at risk volume
excellent, with approximately 95% tumour control at (PRV) around these structures.
5 years. This is equivalent to microsurgery results,
though a direct comparison has never been attempted. Technique
Thus, radiotherapy has excellent efficacy as well as low
morbidity. In order to minimize the PTV margin, and reduce dose to
normal tissues, a relocatable stereotactic head frame is
recommended, where possible. Patients whose tumours
extend below the skull base require a beam direction shell.
CHORDOMA AND CHONDROSARCOMA Individualized IMRT planning is required, in order to
OF THE SKULL BASE achieve high target doses without exceeding normal tissue
tolerance, which might be life threatening. Each case
should be considered individually.
Pathology and clinical features
These are rare tumours, but they present particular man- Dose and energy
agement problems. Chordomas and chondrosarcomas Chordoma
are distinct pathological entities. However, they share High doses are possible with image guided IMRT:
common features, and can be considered together. They
70 Gy in 39 fractions over 8 weeks
are difficult to resect, and require very high doses of Sometimes a 2 phase approach can be used: 5055 Gy
RT to achieve local control. Both types of tumour can
followed by 1520 Gy. Slightly higher doses can be used
metastasize. for residual extracranial disease
Chordomas are twice as common as chondrosarcomas.
They arise from remnants of the notochord, an embryo- Chondrosarcoma
logical structure which elicits formation of the CNS. They 65 Gy in 39 fractions over 8 weeks
may arise in the skull base, typically near but not in the Even higher doses are given using protons (abroad).
midline, and along the whole length of the spine. The
Any plan needs to take into consideration the proximity of
skull base, upper cervical spine and the sacrum are the
critical normal tissues.
most common locations. The distinction between a low
skull base chordoma and an upper cervical tumour is
often blurred. Chondrosarcomas also occur in the skull Results of treatment
base, arising from bony or cartilaginous elements. These
tumours usually present with pain, headache or cranial Excellent surgery has a profound effect on outcome. Thus,
nerve palsies. these cases are best treated in specialist centres including a
skull base surgical team.
Local control is the most important problem. Chondro-
sarcomas can be controlled in over 8090% of cases, and
Treatment
metastasize very rarely. Chordomas are less well con-
Both tumur types require resection, which should aim to trolled, with local control rates of only 4080%. Of those
remove as much tumour as possible, and introduce space chordomas that recur, local failure is the major problem,
between tumour and brain stem. Because of their location, occurring in 95% of patients, but metastatic disease is
surgery is challenging and typically it is difficult to remove found in 20%. This can be manifest as widespread dissem-
all tumour from the deep aspect. Radiotherapy should fol- ination, or involvement of regional lymph nodes. No
low, but there is evidence that doses of at least 65 Gy are effective treatment is available for patients who recur.
required. These have been treated very successfully outside The best results are reported following RT with protons
the UK with proton or carbon ion radiotherapy. Since 2008 or light ions.
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Chapter | 30 | Tumours of the central nervous system
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Walter and Millers Textbook of Radiotherapy
A B
Figure 30.11 (A) CT of a patient showing multiple cerebral metastases from non-small cell lung cancer, surrounded by oedema.
Three deposits are seen in the left hemisphere, and another single lesion is visible in the right cerebral hemisphere, posteriorly.
Oedema is seen around each deposit. (B) Field for whole brain irradiation (WBI), showing adequate coverage around the skull,
including at the skull base. The collimator angle allows sparing of dose to the eyes and pharynx.
554
Chapter | 30 | Tumours of the central nervous system
disease, to guide systemic treatment, and inform prognosis. bones through which the cranial nerves pass, the field
It is usually appropriate for the patient to be managed by should extend from the outer canthus down and back to
the relevant site-specific team. As well as palliative radio- the posterior edge of the foramen magnum. This will cover
therapy, chemotherapy and hormonal therapy may be cranial nerves IIXII.
helpful.
A few patients have a solitary metastasis, are fit with no Dose and energy
active disease outside the brain, and have a reasonable dis- Megavoltage x-rays are preferable. If orthovoltage x-rays
ease-free interval (e.g. 1 year) since completion of primary must be used, then the head should be packed round with
treatment. These patients may warrant more aggressive bolus material to approximate a tissue-equivalent cube, and
treatment, involving surgical resection or stereotactic radio- a 10% dose reduction should be made to allow for the
surgery (SRS). Both surgical resection and SRS improve higher relative biological efficiency (RBE) of orthovoltage
local control within the brain. Both can be followed by compared to megavoltage x-rays.
whole brain irradiation (WBI), which treats micrometa- A variety of dose schedules is available:
static disease and has been shown to improve control in
30 Gy in 10 fractions, treating daily, over 2 weeks
the remainder of the brain. Surgical resection is particularly
20 Gy in 5 fractions, treating daily, over 1 week
useful for patients with posterior fossa tumours causing
12 Gy in 2 fractions, treating on consecutive days or up
hydrocephalus. Where SRS is to be used, it should be
to 1 week apart.
given before WBI, to ensure that the lesion is visible on
imaging.
Side effects
Some patients may be in sufficiently poor general condi-
tion that even simple palliative radiotherapy may not Side effects are the same as for palliative RT for HGG.
be of value. For meningeal disease, i.e. carcinomatous men-
ingitis, in addition to palliative radiotherapy, intrathecal
Palliative stereotactic radiosurgery (SRS)
methotrexate may be of symptomatic benefit.
Target volume and technique
Treatment SRS can be carried out using a skull fixation frame or a relo-
catable stereotactic head frame. To use a relocatable head
Palliative radiotherapy treatment frame successfully, the patient must have good teeth and
Target volume and technique normal neurological function. MRI demonstrates the
tumour optimally, and should be electronically coregis-
tered with the localization planning CT. The simplest sys-
Whole brain irradiation (WBI)
tems use circular applicators, to treat spherical targets.
The patient should ideally be immobilized in a beam direc- Happily, metastases usually form an approximately spheri-
tion shell. At the least, the head should be immobilized cal shape. The applicator with the appropriate diameter is
using tape or bolus bags around the head. The whole brain chosen to cover the metastasis. Multiple non-coplanar,
should be treated, both cerebrum and cerebellum, since non-opposed arcs are normally used, starting and finishing
part of the objective is to treat micrometastases. to avoid entry or exit through the eyes. IMRT can also be
The standard beam arrangement is a parallel pair of used. An upper size limit of 3 cm diameter is usual.
lateral-opposing fields. These can be applied from simula- The target may be the edge of the gross tumour or an
tor or CT imaging using a virtual simulator tool. The col- additional margin of 23 mm to allow for set-up inaccura-
limator should be rotated to follow approximately the cies. However, the patient position can be verified before
radiological baseline, in order to avoid the eyes. Sufficient treatment proceeds, and treating only the gross tumour
margin should be allowed, first for patient movement or minimizes acute side effects.
day-to-day variation in positioning (i.e. a PTV margin)
and, secondly, to allow an adequate field size to treat Dose and energy
the whole brain effectively (see Figure 30.11).
The prescription is normally made to the 90% isodose line,
If it is impossible to simulate, then simple landmarks can
which is placed around the edge of the target. Some centres
be used. The inferior border of the lateral field can follow a
prescribe to the 50% isodose.
line between the lateral edge of the superior orbital ridge to
the notch below the tragus of the ear. Clearance of the scalp Dose: 1624 Gy in 1 fraction, at 90% isodose.
by 1 cm at the other three edges will be sufficient. It is advisable to give steroids to cover the SRS, such as dexa-
methasone 16 mg starting 24 hours before treatment, for
Skull base irradiation 24 hours after, then tailing off over 34 days.
The beam arrangement is also a parallel pair of lateral- In some centres, a higher WBI is used in patients with
opposing fields, applied from simulator or CT. Under solitary metastases receiving SRS, such as 40 Gy in 20
normal circumstances, when it is necessary to treat the fractions over 4 weeks.
555
Walter and Millers Textbook of Radiotherapy
FURTHER READING
General management issues Jansen EP, Dewit LG, van Herk M, Estall V, Treece SJ, Jena R, Jefferies SJ,
Burnet NG, Bulusu VR, Jefferies SJ. Bartelink H. Target volumes in Burton KE, Parker RA, Burnet NG.
Management of primary brain radiotherapy for high-grade Pattern of relapse after fractionated
tumours. In: Booth S, Bruera E, editors. malignant glioma of the brain. external beam radiotherapy for
Palliative care consultations in primary Radiother Oncol 2000;56: meningioma: experience from
and metastatic brain tumours. Oxford 1516. Addenbrookes Hospital. Clin Oncol
University Press; 2004. Stupp R, Hegi ME, Mason WP, van den 2009;21(10):74552.
Bent MJ, Taphoorn MJ, Janzer RC, Minniti G, Amelio D, Amichetti M,
Specifics of radiotherapy Ludwin SK, Allgeier A, Fisher B, Salvati M, Muni R, Bozzao A,
planning for CNS tumours Belanger K, Hau P, Brandes AA, Lanzetta G, Scarpino S, Arcella A,
Burnet NG, Thomas SJ, Burton KE, Gijtenbeek J, Marosi C, Vecht CJ, Enrici RM. Patterns of failure and
Jefferies SJ. Defining the tumour Mokhtari K, Wesseling P, Villa S, comparison of different target
and target volumes for Eisenhauer E, Gorlia T, Weller M, volume delineations in patients
radiotherapy. Cancer Imaging Lacombe D, Cairncross JG, with glioblastoma treated with
2004;4:19. Mirimanoff RO. European conformal radiotherapy plus
Burnet NG, Jefferies SJ, Benson RJ, Organisation for Research and concomitant and adjuvant
Hunt DP, Treasure FP. Years of life lost Treatment of Cancer Brain Tumour temozolomide. Radiother Oncol
(YLL) from cancer is an important and Radiation Oncology Groups; 2010;97(3):37781.
measure of population burden and National Cancer Institute of Canada Potluri S, Jefferies SJ, Jena R, Harris F,
should be considered when allocating Clinical Trials Group. Effects of Burton KE, Prevost AT, Burnet NG.
research funds. Br J Cancer 2005;92: radiotherapy with concomitant and Residual post-operative tumour
24155. adjuvant temozolomide versus volume predicts outcome after high
radiotherapy alone on survival in dose radiotherapy for Chordoma and
Burton KE, Thomas SJ, Whitney D,
glioblastoma in a randomised phase Chondrosarcoma of the skull base and
Routsis DS, Benson RJ, Burnet NG.
III study: 5-year analysis of the spine. Clin Oncol 2011;23
Accuracy of a relocatable stereotactic
EORTC-NCIC trial. Lancet Oncol (3):199208.
radiotherapy head frame evaluated by
2009;10(5):45966. Thiel E, Korfel A, Martus P, Kanz L,
use of a depth helmet. Clin Oncol
2002;14:319. The Royal College of Radiologists . Griesinger F, Rauch M, Roth A,
Imaging for oncology. BFCO(04)2. Hertenstein B, von Toll T,
Combs SE, Volk S, Schulz-Ertner D,
The Royal College of Radiologists; Hundsberger T, Mergenthaler HG,
Huber PE, Thilmann C, Debus J.
2004. Leithauser M, Birnbaum T, Fischer L,
Management of acoustic neuromas
with fractionated stereotactic van den Bent MJ, Afra D, Jahnke K, Herrlinger U, Plasswilm L,
radiotherapy (FSRT): long-term de Witte O, et al. EORTC Radiotherapy Nagele T, Pietsch T, Bamberg M,
results in 106 patients treated in a and Brain Tumour Groups and the UK Weller M. High-dose methotrexate
single institution. Int J Radiat Oncol Medical Research Council. Long-term with or without whole brain
Biol Phys 2005;63:7581. efficacy of early versus delayed radiotherapy for primary CNS
radiotherapy for low- lymphoma (G-PCNSL-SG-1): a
Hodson DJ, Bowles KM, Cooke LJ, et al.
grade astrocytoma and phase 3, randomised, non-inferiority
Primary central nervous system
oligodendroglioma in adults: trial. Lancet Oncol 2010;11
lymphoma: a single-centre experience
the EORTC 22845 randomised (11):103647.
of 55 unselected cases. Clin Oncol
trial. Lancet 2005;366:98590.
2005;17:18591.
556
Chapter | 31 |
Eye and orbit
Adrian Harnett
nerves, the IIIrd, IVth and VIth. The VIth cranial nerve 3. Intraocular
supplies the lateral rectus muscle which moves the eyeball a. Melanoma (choroidal and iris)
laterally. The medial, superior and inferior recti elevate, b. Retinoblastoma.
depress and move the eyeball inward, while the inferior
oblique moves the eyeball upward and outward. All these
four muscles are supplied by the IIIrd cranial nerve. The RADIATION AND OCULAR MORBIDITY
superior oblique which moves the eye downward and out-
ward is supplied by the IVth cranial nerve.
The lens
The membrane lining the inner surface of the eyelids is
the conjunctiva which courses over the anterior surface The eye contains structures that are both very radiosensitive
of the globe, extending to the corneoscleral junction. Tears and radioresistant. One of the most sensitive tissues in the
are secreted by minor lacrimal glands situated on mainly body is the lens. Cataracts have been reported at doses as
the lower eyelid and can be supplemented by the lacrimal low as 2 Gy. However, it should be remembered that they
gland situated in the upper lateral part of the orbit. They invariably occur over the age of 70 and are associated with
drain into the nose through the nasolacrimal duct. various common diseases, such as diabetes, and medica-
tions, such as steroids. The appearance and region of the
cataract can help in deciding their causation. Radiation cat-
aracts are caused by damage to cells in the anterior central
PATHOLOGY
area of the lens, which then start to form a cataract at the
back of the lens centrally. The total dose, energy of radia-
Benign tion, volume of the lens, health of the eye and concomitant
disease are all factors that play a part in cataract formation.
Dysthyroid eye disease and reactive When high doses are given with b-irradiation eye plaques,
lymphoid hyperplasia usually for treatment of posterior choroidal melanomas,
The pathology of both these conditions is poorly cataracts often will not occur because of the rapid fall off
understood. of dose (as opposed to the historical use of cobalt plaques).
After external beam radiotherapy, fractionated doses of
over 10 Gy are likely to cause detectable lens opacities, usu-
Malignant ally occurring within 23 years of radiotherapy. Figure 31.1
shows a radiation cataract. Treatment of a cataract is by sur-
Primary
gical removal, although if the eye is dry (most commonly as
Secondary/metastatic
a result of radiotherapy), this may adversely affect the suc-
Tumours can be classified as arising from the skin and cess of surgery.
adnexia, orbit or intraocularly. Basal cell carcinomas
(BCC) and squamous cell carcinomas (SCCs) are skin
tumours commonly arising on the face, especially around
the eye and lower eye lid. In contrast, lacrimal gland and
nasolacrimal duct tumours are rare, as are orbital tumours.
Rhabdomyosarcoma of the orbit is a tumour of childhood.
It is usually embryonal and is discussed in further detail in
Chapter 33. Intraocular tumours are rare with retinoblas-
toma occurring in the very young and melanoma in adults.
The choroid is the commonest site in the eye for metastatic
disease.
Primary tumours of the eye and orbit are listed below:
1. Skin and adnexal
a. Basal cell carcinoma (BCC)
b. Squamous cell carcinoma (SCC)
c. Lacrimal gland
d. Nasolacrimal duct
e. Miscellaneous
2. Orbital tumours
a. Lymphoma
b. Melanoma (conjunctival)
c. Rhabdomyosarcoma
d. Optic nerve glioma Figure 31.1 Radiation cataract.
558
Chapter | 31 | Eye and orbit
The sclera and retina reduced due to build-up and skin sparing. Tear production
is from the minor lacrimal glands mainly located on the
The sclera, on the other hand, is radioresistant because it is lower eyelid and supplemented by the major lacrimal gland
avascular and can tolerate doses of up to 100 Gy by radio- in the upper lateral part of the orbit anteriorly. This should
active eye plaques to a small area. Above this dose there be shielded in radiotherapy planning in an attempt to pre-
is a risk of necrosis. The retina can tolerate doses of serve tear production as much as possible. It is reduced
50 Gy but, above this, retinal damage is manifest by hae- above 30 Gy and patients may require hypomellose eye
morrhages, exudates and atrophy. Radiation atrophy and drops (artificial tears) above this dose and lacrilube. Doses
post-subcapsular cataract are shown in Figures 31.2 and of 50 Gy and above result in more serious problems.
31.3. The macula is the most sensitive area of the retina Stenosis or occlusion of the nasolacrimal duct due to a
and doses here should be minimized or avoided if possi- tumour adjacent to the inner canthus will result in a
ble when using radioactive eye plaques. Similarly, as the weeping eye (epiphora). There is evidence that this does
dose increases above 50 Gy, there is an increasing likeli- not happen due to radiotherapy alone if it is carefully frac-
hood of optic atrophy. tionated and the tumour has not comprised the function
of the duct already. A dose of 45 Gy in 10 fractions on a
The cornea and lacrimal apparatus superficial unit (100 kV) is the minimum fractionation
recommended. Figures 31.4 (before radiotherapy) and
These structures usually tolerate doses of up to 50 Gy well, 31.5 (after radiotherapy) illustrate a basal cell carcinoma
depending on radiotherapy technique, energy, fractionation in this region treated with superficial radiotherapy.
and attention to good eye care. It will result in erythema of
both skin and conjunctiva, local irritation and lacrimation.
If megavoltage radiotherapy is used, these reactions will be
Figure 31.2 Radiation atrophy. Figure 31.4 Basal cell carcinoma pre-radiotherapy.
Figure 31.3 Radiation atrophy and postsubcapsular cataract. Figure 31.5 Basal cell carcinoma post-radiotherapy 4 months
later.
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Walter and Millers Textbook of Radiotherapy
PRINCIPLES OF IRRADIATION
560
Chapter | 31 | Eye and orbit
Figure 31.8 Dosimetric plan of dysthyroid eye disease. decompression carried out. The daily dose should be
increased after the first dose to 1.73 Gy per day to a total
dose of 20 Gy in 12 fractions over 16 days. For reactive lym-
phoid hyperplasia, the standard dose is 30 Gy in 15 frac-
tions over 19 days.
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Walter and Millers Textbook of Radiotherapy
Figure 31.11 Extensive basal cell carcinoma. Figure 31.12 Angiosarcoma of forehead.
radiotherapy should not occur if it is reasonably fractio- evolve 31.14 for the right posterior olique field. A point
nated and the nasolacrimal duct is not stenosed by the dose for the left (contralateral) lens is shown.
tumour. An internal eyeshield should be inserted for each
treatment when the treated area is right next to the eye or
involving the lower eyelid. Lymphoma
Lacrimal gland and nasolacrimal duct carcinomas are rare,
locally invasive and difficult to treat. Involvement due to Pathology
lymphoma must be excluded. Each case must be considered Ocular lymphoma may be localized and the sole site of dis-
on its merits and discussed with the ophthalmic surgeon and ease or a manifestation of widespread involvement. The
oncologist in order that the most appropriate treatment is former is more likely to be due to low-grade lymphoma
selected, either surgery or high dose radical radiotherapy. and is very rarely bilateral, whereas high grade frequently
As in other sites, rare primary tumours can occur involves other sites.
around the eye. Figure 31.12 is one such example of an
angiosarcoma arising on the forehead in an elderly retired
fisherman. Note the characteristic appearance of a cystic Clinical features
red/purple lesion. They respond rapidly to radiotherapy
but, despite high doses, also recur locally and regionally. Presentation may be due to a typically discrete erythema-
tous conjunctival lesion (Figure 31.15), minor eye discom-
fort, a mass most often involving the major lacrimal gland,
Tumours arising from adjacent ptyosis, chemosis, diplopia, exophthalmos and a red eye
structures (Figure 31.16). Symptoms and signs of more widespread
involvement can be present.
Other tumours can invade directly into the orbit and cause
extensive destruction. One example is a maxillary sinus
squamous carcinoma (see Figure evolve 31.6 ). Radio-
therapy was planned with a three-field technique with fields
Diagnosis and investigation
one and two blocked medially for the contralateral eye and A tissue diagnosis may have been obtained from either a
field three blocked posteriorly to shield the brain (Figure lymph node biopsy if the patient has lymphadenopathy,
evolve 31.13 ). Bolus was used as shown and the red occasionally from bone marrow examination or from the
outline shows the GTV and light blue shows the PTV. Note ocular site. Access to a posterior orbital mass is difficult even
the course of the contralateral optic nerve has been outlined. when the mass is relatively large. The usual staging proce-
All fields were conformal, which is illustrated in Figure dures for lymphoma should be performed including
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Chapter | 31 | Eye and orbit
Figure 31.15 Conjunctival lymphoma pre-radiotherapy. Figure 31.17 Conjunctival lymphoma post-radiotherapy.
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Walter and Millers Textbook of Radiotherapy
Natural history
Melanomas of the eye are often detected when they are very
small and may measure under 5 mm at their base and
Figure 31.20 Conjunctival melanoma visible as a poorly Figure 31.23 Choroidal melanoma seen on indirect
demarcated lesion. ophthalmoscopy.
564
Chapter | 31 | Eye and orbit
1 mm in height. They grow slowly and so initial treatment on cell division and is thus referred to as a tumour suppres-
may be observation in order to confirm the diagnosis. sor gene. When it is lost from chromosome 13, it leads to
Some patients present with metastases, particularly involv- uncontrolled cell replication and tumour formation.
ing the liver. Others develop metastatic disease up to 15
years later and, not surprisingly, the risk increases with Clinical features
the size of the ocular tumour at presentation. Patients with
anterior placed tumours in the uveal tract are at higher risk Parents or family may notice a white reflex in the pupil,
than those with posterior choroidal melanomas. which usually indicates a large tumour, or a squint and dif-
ficulty in fixation. Extension into the orbit or perforation of
the globe are very unusual but very serious with respect to
Treatment prognosis as these patients are incurable. In advanced dis-
The mainstay of treatment of conjunctival and iris melano- ease, rarely seen in patients in Europe at initial presenta-
mas is local excision. Rarely, radioactive eye plaques are tion, metastases may occur to the central nervous system
used as primary treatment or post-surgery. Due to the size and the bone marrow.
of the tumour, enucleation may be the only option.
There are more treatment options for choroid and ciliary Diagnosis and investigation
body tumours. Historically, enucleation has been the stan-
Retinoblastoma is exceptional with respect to oncological
dard treatment but more conservative treatment using
management in that a biopsy for confirmation of the diagno-
radioactive eye plaques, originally with cobalt-60 but
sis is never performed and, indeed, contraindicated because
now superseded by ruthinium or iodine, has been used
of the high risk of spread of tumour cells outside the globe.
for a long time. Studies have therefore shown that eye pres-
Therefore, the diagnosis is a clinical one made in specialized
ervation has not adversely affected survival. Indeed, it was
centres with great expertise in retinoblastoma and character-
even considered by some to improve survival by possibly
ized by appearances on bilateral indirect binocular ophthal-
an immunoprotective mechanism.
moscopy under general anesthetic. Even when enucleation is
It is unclear whether the dose to the base or apex of the
performed for a large tumour and/or a non-seeing eye, pre-
tumour is important. Most centres prescribe a dose to the
vious biopsy should not have been carried out.
apex of 10 000 cGy (100 Gy). Retreatment has been car-
ried out but it is advised that the total dose to the choroid
does not exceed 100 000 cGy. Otherwise the risk of severe Staging
complications including vitreous hemorrhage and perfora- The best known staging system is the Reese-Ellsworth clas-
tion of the globe becomes unacceptable. sification. It is mainly based on tumour size, grouped into
For medium-sized tumours, local resection can be per- small (<4 disk diameters (DD)), medium (410 DD) and
formed under hypotensive anesthesia. This is often supple- large (>10 DD). A disk diameter is just under one centime-
mented with insertion of a radioactive plaque at the end of ter. Tumour height is important for decisions about mode
the procedure and removal several days later, depending on of treatment but is usually governed by base diameter. The
the activity of the plaque and the dose prescribed. classification also takes into account whether the tumour is
Unfortunately, very occasionally patients present with solitary or multiple, tumour location with respect to the
very extensive, neglected tumours (Figure evolve 31.24 ). macula, optic disk and anterior to the equator, vitreous
Obviously, the treatment options in these situations are seedling and retinal detachment. Late stage disease includes
very limited. Radiotherapy has been used and, as in the optic nerve and extrascleral extension.
figure, shows a response with regression of the extensive
tumour. High fractionated doses have to be used, either
with weekly fractions of 6 Gy or daily treatment to 60 Gy Treatment
or more over 6 weeks, as employed in this patient. Treatment options are surgery, which includes local ther-
Chemotherapy is not particularly active in metastatic apy including photocoagulation, cryotherapy, radioactive
uveal melanoma. The regimens employed are those simi- eye plaques and removal of the eye (enucleation), external
larly used in melanoma arising from the skin. beam radiotherapy and chemotherapy. Historically, enu-
cleation was the treatment for retinoblastoma and still
should be carried out for large tumours, tumours uncon-
Retinoblastoma
trolled by more conservative measures and in eyes with lit-
Retinoblastoma is a rare tumour occurring in the very tle hope of vision. However, when both eyes are affected by
young, usually occurring in children under the age of 2. a combination of large tumours and/or poor vision, an
It arises from primitive cells in the retina and may occur attempt is often made to try to preserve the less advanced
as either an inherited or sporadic case. In the hereditary eye and therefore some vision.
form, often both eyes are affected. It is due to an abnormal Small tumours can usually be treated by focal treatment
gene on chromosome 13, the Rb gene, which is a control with photocoagulation, cryotherapy or a combination of
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Walter and Millers Textbook of Radiotherapy
the two and useful vision preserved. Cryotherapy is a attempt to preserve vision in a young child, or thirdly,
method of freezing the tumour but can only be used in by using external beam radiotherapy and increasing the
more anteriorly placed tumours. Tumours that are larger risk of second malignancy when alternative treatment would
or lie adjacent to the macula or optic disk are treated with have been more appropriate. Patients with bilateral retino-
a radioactive plaque, although some vision may be lost. blastoma have a 50% incidence of developing a second
Some plaques are designed with cut outs to reduce the dose malignancy within 50 years of treatment of retinoblastoma.
on the margin next to the disk or optic nerve in order to pre- It is therefore important in patients who present with no
serve vision if possible. Historically, cobalt-60 plaques were prospect of useful vision to sacrifice the eye and perform
used, but gamma radiation frequently caused ocular mor- enucleation. Referral for prosthetic replacement should
bidity including cataract and radioprotection was a prob- all be part of postoperative care and this will have to be
lem. It has therefore been replaced by ruthenium-106 ongoing as the young child grows.
and iodine-125 plaques, both of which are beta emitters Many posteriorly placed tumours can be controlled by
and therefore not so penetrating. They are sutured onto conservative management and useful vision maintained,
the back of the globe overlying the tumour, its position out- but this will depend on the size and position of the tumour
lined by transillumination. A dose of 40 Gy is given over (or tumours), and the treatment given. When tumour
24 days, depending on the activity of the plaque at time extends outside the eye, or there is metastatic disease, mor-
of use, and prescribed to the apex of the tumour which tality is very high. Fortunately, these situations are
has been measured by ultrasound. The maximum height uncommon.
of the tumour for treatment with radioactive eye plaque
is 4 mm. The diameter of the plaque is most frequently
15 mm, although 20 mm plaques are occasionally used. Metastases
For larger tumours and multiple tumours, radiotherapy
is no longer commonly used because of the risk of carcino- Pathology and clinical features
genesis. There are very accurate radiotherapy techniques Secondary deposits to the eye via the blood stream are com-
employing a contact lens system on the front of the eye mon but often not clinically evident or recognized. The
and acting as a reference point in order to bring in a lateral most frequent site is the vascular choroid leading to retinal
beam behind the front of the eye. This enables the whole of detachment. Therefore, presentation may be an oncologi-
the retina to be treated but still avoids the radiosensitive cal emergency due to sudden loss of vision. It usually occurs
anterior structures in the eye. A dose of 40 Gy in 20 frac- in patients known to have malignancy, especially from
tions over 4 weeks is the standard dose, requiring a daily breast and lung cancer. Other tumours which less fre-
anesthetic for the child immobilized in a beam directional quently metastasize are urogenital and upper gastrointesti-
shell. Very occasionally, whole eye radiotherapy is required nal tumours. They usually indicate widespread metastatic
for large more anteriorly placed tumours or following enu- disease and, consequently, a poor prognosis, except in
cleation for extrascleral extension. some breast cancer patients. Patients may have brain metas-
Chemotherapy used to be employed only for palliation tases as well. If full fundal examination is carried out,
but, over the last 10 years, this has changed due to the appre- asymptomatic metastases are not infrequently found, often
ciation of the risk of developing second primary tumours in involving the contralateral eye. Choroidal metastases have
hereditary retinoblastoma. External beam radiotherapy, pre- a characteristic appearance, with a yellow raised honey-
viously often used as primary treatment, increases the risk of comb lesion (Figure 31.25).
second malignancies further, particularly in children under
the age of 1. As a result, chemotherapy has been moved for-
ward and used in earlier stage disease with chemoreductive
protocols using drugs such as carboplatin, etoposide and
vincristine (CEV). The number of courses depends on the
extent of disease and response, but chemoreduction will
make many eyes amenable to local treatment with photoco-
agulation or cryotherapy. Indeed, the treatments may be
used concurrently with chemotherapy.
Prognosis
The outlook for patients with retinoblastoma is excellent
with over 95% cured. This prognosis should not be compro-
mised by inexperienced management, either by biopsy of
the tumour which may lead to disasterous sequelae, by
performing conservative management with a large tumour
(usually because it involves their better seeing eye) in an Figure 31.25 Choroidal metastasis from carcinoma of breast.
566
Chapter | 31 | Eye and orbit
Figure 31.27 Anterior chamber metastasis from carcinoma of Figure 31.30 CT scan showing extensive prostatic metastatic
lung pre-radiotherapy. deposit.
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Walter and Millers Textbook of Radiotherapy
bilateral and so both eyes should be treated using parallel- which shows a dosimetric plan for a large renal metastasis.
opposed lateral fields. For more extensive lesions, field The globe was displaced medially.
arrangements depend on the individual cases, but are usu- A dose of 20 Gy in five daily fractions over one
ally single direct or parallel opposed. Occasionally, a pair of week with megavoltage radiotherapy is usually most
wedged fields is used, as shown in Figure evolve 31.31 appropriate.
FURTHER READING
Shields JA. Diagnosis and management ButterworthHeineman; (1991). management of retinoblastoma. Arch
of ocular tumours. Saunders and Co; p. 36178. Ophthal 2004;122:72935.
1988. Pizzo P, et al. Principles and practice Kingston JE, Hungerford JL,
Harnett AN, Hungerford JL. Ocular of paediatric oncology. 4th ed. Madreperla SA, et al. Results of
morbidity to radiotherapy. In: Williams and Wilkins Lippincott; combined chemotherapy and
Plowman PN, McElwain TJ, 2002. radiotherapy for advanced intraocular
Meadows A, editor. Complications Shields CL, Mashayekhi A, Demirci H, retinoblastoma. Arch Ophthal
of cancer management. et al. Practical approach to 1996;114:133943.
Figure evolve 31.6 Dosimetric plan for Figure evolve 31.14 Beams eye view Figure evolve 31.24 Orbital malignant
an advanced orbital tumour showing the conformal right posterior melanoma, pre- and post-radiotherapy
Figure evolve 31.13 Dosimetric three- olique field and point dose for the left Figure evolve 31.31 Dosimetric plan of
field plan with the course of the lens an extensive renal metastasis
contralateral optic nerve shown
568
Chapter | 32 |
Sarcomas
Martin Robinson, Paul Symonds, Mike Sokal
570
Chapter | 32 | Sarcomas
Clinical features
Approximately 40% of soft tissue sarcomas occur in the
upper and lower limbs. Of these, about 75% occur at or
above the knee. Ten percent of sarcomas arise in the upper
half of the body. Of the sarcomas of the trunk, 10% occur in
the retroperitoneum and 20% in the chest or abdominal
wall. Presentation with locally advanced disease is com-
mon, particularly with intra-abdominal sarcomas, which
may reach a very large size.
The history is usually of a painless lump developing over
a few weeks or months and occasionally over years. Pain
may occur from pressure on local structures, e.g. nerves
and joints. Occasionally, non-metastatic effects are seen
(e.g. hypoglyacemia in malignant fibrous histiocytoma).
Diagnosis and staging Figure 32.1 MRI scan showing soft tissue sarcoma with central
necrosis in the hamstring compartment of the thigh.
Important features of local examination for limb or truncal (Courtesy of Dr L Turnbull, MRI Unit, Sheffield.)
sarcomas is the position of the lesion superficial or deep to
the fascia at the primary tumour site and any involvement
of bone, vascular or neural invasion. Regional nodes, better multiplanar versatility in planning surgery and radio-
although uncommonly involved, should be palpated. therapy. CT can be helpful in exclusion of cortical erosion of
A biopsy is required. In 90% of cases, adequate histology bone. CT and MRI are also useful in confirming any
can be achieved by needle core biopsy. Where an incisional subsequent local recurrence, but are not currently used
biopsy is required, care should be taken to make the inci- for routine follow up. CT of the thorax is advisable if chest
sion longitudinal so that any subsequent radical surgery radiography is normal and radical therapy is contemplated,
or postoperative radiation fields can include it. This is par- since it may demonstrate small-volume lung metastases
ticularly important where preservation of limb function is a (Figure evolve 32.5 ). The staging system commonly
major consideration. Appropriate siting of the biopsy is adopted includes grade, size, and presence/absence of
vital if the probability of local control is to be maximized. metastases (Tables 32.2 & 32.3).
The biopsy should ideally be carried out by the surgeon
who will undertake the definitive resection. There is other-
wise the risk of tumour spillage, particularly after
Management
unplanned attempts to remove deep-seated lesions. If com- A multidisciplinary approach (MDT) is required since sur-
puted tomography (CT)-guided biopsy is needed, for gery, radiotherapy and chemotherapy may all have a role to
example for impalpable deep-seated lesions, there is also play, depending on the stage, site, grade and size of the
potential for needle track contamination. Close liaison tumour. A dedicated sarcoma MDT allows treatment to
with the surgeon and clinical oncologist is needed to plan be carefully coordinated and minimizes the number of sur-
the best route of biopsy. Specialist pathology review is gical procedures necessary. Correct procedures for biopsy,
essential in view of the complexity of these tumours and imaging and exclusion of metastatic disease are essential.
the need for careful assessment of the tumour margins. Historically, amputation was the main treatment for limb
A full blood count, liver function tests, chest radiograph, sarcomas but, in the 1970s, it was appreciated that radio-
plain radiographs of the tumour-bearing region therapy and less radical surgery could provide comparable
(Figure 32.1) and liver ultrasound are the initial investiga- results. Limb-sparing surgery with postoperative radiother-
tions. CT and magnetic resonance imaging (MRI) (Figures apy achieved the same survival as amputation, albeit with a
evolve 32.232.4 ) scanning are important in defining slightly higher local recurrence rate. In the past, sarcomas
the local extent and operability of the tumour. MRI is the were regarded as relatively radioresistant tumours. It is
imaging modality of choice for limb sarcomas since it pro- now known that they are relatively radiosensitive, compa-
vides good contrast between the tumour and adjoining rable to breast cancer.
normal tissues with particular regard to the tumours rela- Local control while maximizing the probability of con-
tionship with the neurovascular bundle. It also provides serving limb function and long-term survival is of vital
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Walter and Millers Textbook of Radiotherapy
T1 5 cms
T1a Superficial
T1b Deep
Anterior superior
T2 >5 cms iliac spine
Tensor fasciae latae
T2a Superficial
T2b Deep
M1 Distant metastases
Vastus medialis
importance. For extremity limb sarcomas, 90% local con-
trol at 5 years should be the standard. The management
of soft tissue sarcomas is controversial. In part, this Patella
reflects the limited number of randomized trials in this
heterogeneous group of tumours. The relative rarity of
non-extremity sarcomas makes the design of and recruit-
ment to large randomized trials difficult. Few would dis-
pute the primary role of radical surgery. If the surgical Figure 32.6 Compartmentectomy. The diagram illustrates the
resection margins are clear, the 5-year local control for wide surgical excision of soft tissue situated, in this case, in the
limb sarcomas is of the order of 90%. If the margins are rectus femoris.
involved, this falls to 6080%. Involved margins are an (Reproduced with permission from Souhami & Tobias, Cancer and its
independent risk factor for local recurrence. The extent Management, Blackwells, 1986.)
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Chapter | 32 | Sarcomas
Adjuvant therapy can be done by varying the proton energy or by the use of
wax compensators to alter the size of the Bragg peak and
For low-grade tumours less than 5 cm in size which have
consequently the volume of tissue which is subsequently
been widely excised with clear surgical margins, no further
irradiated.
therapy is necessary in most cases. The same applies follow-
Not all sites are suitable for radical radiotherapy. Pelvic,
ing an amputation. However, postoperative radiotherapy is
thoracic or abdominal sarcomas present particular difficul-
indicated in the following circumstances to reduce the
ties because of the morbidity that would be caused by wide-
probability of local recurrence (see above):
field irradiation, dose-limiting critical structures (e.g. the
limb-conserving or limited surgery (see below) spinal cord). Placement of spacers in the abdominal cavity
gross residual tumour or inadequate excision margins may be used to displace small bowel out of the high dose
grade 2 or 3 histology radiation field (Figures evolve 32.7 and 32.8 ).
tumours 5 cm or more in any dimension plus most
tumours deep to the fascia
virtually all tumours in the head and neck (because of Limb-conserving surgery
the impossibility of adequate excision). If limb-conserving surgery is undertaken (i.e. removal of
after surgery for recurrent sarcoma if not previously the tumour mass with narrower excision margins), postop-
irradiated. erative radiotherapy is given to sterilize microscopic resid-
Postoperative radiotherapy conventionally is with exter- ual disease. In this way, a functional limb with a satisfactory
nal beam (photons or electrons), although postoperative cosmetic result can be achieved. Conservative surgery is
brachytherapy with iridium-192 (4245 Gy over 46 contraindicated where high-dose radiotherapy is poorly
days) had a high 5-year local control rate of 90% in a ran- tolerated (see below).
domized trial compared to 65% for high- but not low-
grade lesions. There are no randomized trials comparing
Timing of radiotherapy
brachytherapy with external beam irradiation. Brachy-
therapy should only be carried out in specialist units Preoperative radiotherapy has the advantage that the
undertaking a substantial number of procedures. The rea- tumour is well oxygenated and intact. It may also allow
son for the ineffectiveness of brachytherapy in low-grade coverage by smaller radiation fields and use of lower doses
tumours is not clear. One possibility is that the long cell without reducing local control. These advantages have to
cycle in low-grade tumours may result in cells not entering be balanced against the disadvantages of difficulties in
the radiosensitive phase of the cell cycle during the period interpreting pathology following irradiation and an
of brachytherapy. Retroperitoneal sarcomas require increase in risk of wound complications. Retrospective
special mention. They are often huge, causing dramatic series of preoperative radiotherapy are subject to selection
distortion of the patients contour but rarely present as bias but have suggested that preoperative radiotherapy may
an emergency. Such cases should therefore always be be of value in lesions >5 cm. A recent randomized Cana-
discussed in the sarcoma MDT. The tumours are often dian trial comparing preoperative and postoperative radio-
dedifferentiated liposarcomas and as such have a very therapy was stopped because of increased wound
characteristic CT scan appearance. In these circumstances, complications in the preoperative arm. However, final limb
preoperative biopsy may be eschewed, but if there is any function was still better in the preoperative group. Sites
radiological doubt, biopsy is mandated. where preoperative radiotherapy may be considered within
Surgery may require removal of many organs, spleen, the constraints of normal tissue tolerance are the head and
one kidney, tail or body of pancreas or segments of large neck (paranasal sinuses, skull base, cheek and face), retro-
and/or small bowel. The placement of surgical clips around peritoneum, and extremity tumours.
narrowly excised tumour areas can guide the clinical oncol-
ogist. The dose of post-operative radiotherapy is necessarily
Primary radical radiotherapy
limited and >50 Gy is unlikely to be achievable. Recently,
interest has been rekindled in the use of pre-operative RT, Radical radiotherapy alone is indicated for patients unfit
with very large fields being applied to a dose of 50 Gy for surgery but otherwise in reasonable general condition,
in 1.82.0 Gy fractions. This has been made possible with those who refuse surgery or where the anatomical site pre-
the use of IMRT to spare radiosensitive organs such as kid- cludes it (e.g. retroperitoneum). Preoperative neoadjuvant
ney and spinal cord. An EORTC trial is recruiting now ran- radiotherapy is recommended for very large sarcomas.
domising to surgery alone or preoperative radiotherapy
followed by radical resection 46 weeks later.
Contraindications to radical radiotherapy
Protons are being used in clinical trials. Protons have a
similar relative biological effectiveness (RBE) to photons. The high doses of radiotherapy required for sarcoma are
The advantage of protons is a reduction of dose to critical poorly tolerated by highly stressed areas of the lower limb,
structures, such as the spinal cord or underlying bone. This e.g. Achilles tendon, or in the ribs where pathological
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Walter and Millers Textbook of Radiotherapy
fractures may occur. Radical radiotherapy to the Achilles ten- the treatment volume, while limiting the dose to normal tis-
don is inadvisable, especially in young and active patients, sues which may affect function and cosmesis. Intensity
since rupture may occur. modulated radiotherapy (IMRT) may have a role in the irra-
diation of sites where minimization of dose to critical struc-
tures is particularly important, such as the skull base or the
Target volume
abdomen.
Definition of the target volume requires information from
the surgeon, pathologist and radiologist. The surgeon
should be encouraged to place radiopaque clips at the mar- Technique
gins of the resection. The pathologist should comment on This will vary with the site of the tumour. For the limbs and
the adequacy of the resection. Very often, it is necessary to retroperitoneum, a parallel-opposed pair of fields, often
ask the surgeon to carry out a further excision before post- wedged, will provide a satisfactory dose distribution in
operative radiotherapy is undertaken. The radiotherapist most cases. In the shoulder region, tangential fields may
needs to discuss with the radiologist the position of the be needed to reduce the volume of lung irradiated. Tangen-
tumour, local extent and any residual disease as seen on tial fields are also appropriate for superficial trunk lesions
CT and MRI. to spare the bowel. For tumours in the buttock, a direct pos-
Most sarcomas tend to spread in the axial plane of the terior field and two wedged lateral fields will reduce the
limb (major fascial planes, bone and interosseous mem- dose to the rectum. In the head and neck, the principles
branes). For this reason, the margins of the radiation field of planning and respect for the tolerance of critical struc-
must be generous in the craniocaudal directions. In the tures, such as the spinal cord, are the same as for squamous
transverse plane, there can be greater confidence that local carcinoma of the head and neck. Target volumes tend to be
structures are not breached and field margins can be tighter. smaller than below the clavicles and so higher doses can
For non-extremity lesions, the orientation of the fields often be delivered with acceptable morbidity. Computer
should follow the planes of the local musculature, while planning is essential to obtain a homogeneous distribution
including the local fascial planes. of dose within the target volume.
For the purposes of planning, the gross tumour volume Stability of the limb is best assisted by a shell and appro-
(GTV) should be defined, with a margin around it to priately positioned bolus bags. Bolus can be applied to the
include the tissues at risk of microscopic involvement, to scar to ensure it receives the maximum dose to minimize
create the clinical tumour volume (CTV). In practice, the the risk of scar recurrence but this is not the practice of
GTV is defined radiologically on CT or MRI. Whether or all oncologists. The application of bolus to the scar is not
not the peritumoural oedema should be included in the recommended in the current UK VORTEX trial. Sagittal
GTV is unclear (it is not known if the oedema contains lasers are especially useful in lining up the limbs.
tumour cells). Including the peritumoural oedema will sig- Care is taken to avoid irradiating the whole circumfer-
nificantly increase the CTV in most cases. Until we know ence of a limb to reduce the likelihood of lymphedema
whether or not peritumoural oedema contains tumour as a late complication. This is achieved by adjusting the
cells, its inclusion within the CTV is not recommended. width of the field to leave a longitudinal strip of unirradi-
In theory, the target volume should vary with the grade of ated tissue outside the target volume. In the proximal part
the tumour. For well-differentiated (grade 1) tumours a 5 cm of the limb, especially in the thigh, this strip occupies a
margin above and below the site of the original tumour is large proportion of the limb (Figures evolve 32.932.11 ).
adequate. For moderately and poorly differentiated tumours When the retroperitoneum is irradiated, part or the
(grades 2 and 3), a 10 cm margin maybe considered. How- whole of one kidney may need to be included in the target
ever, in practice, the fields would be so large that radiother- volume. Shielding of the other kidney by lead blocks on the
apy may be considered inadvisable. The margins required anterior and posterior fields may be necessary, depending
are another uncertainty in sarcoma radiotherapy. The target upon the site of the tumour (Figure evolve 32.12 ).
volume has traditionally been reduced later in the treatment
(see below) to include the length of the scar with a margin of
security at either end of 2 cm for boosting with electrons. Dose and fractionation
Whether this field reduction is necessary for completely There is little information on total dose and response in
excised tumours is the subject of a current UK study (VOR- sarcomas. Most centres tend to give 50 Gy to a wide
TEX Volume of Radiotherapy for Extremity Sarcomas). volume, shrinking to a final boost of 1016 Gy. There is
Where there is macroscopic residual disease, the volume limited information on the relationship between total
cannot be reduced in the same way as when the excision dose and response. However, fraction sizes should be kept
margins are clear. In this situation, a 5 cm margin around small (1.82 Gy) to minimize the risks of late damage to
the tumour is sustained throughout treatment. normal tissue. Hypofractionated and hyperfractionated
Three-dimensional treatment planning where available schedules have shown no advantage over conventional
can assist in the delivery of a homogeneous dose throughout fractionation.
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Chapter | 32 | Sarcomas
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Walter and Millers Textbook of Radiotherapy
Pathology
Osteosarcoma is commonest near the knee in the metaphy-
sis of the distal femur or proximal tibia. In the elderly, its
distribution matches Pagets disease.
Macroscopically, the tumour is usually haemorrhagic. It
expands the bone, destroying both the cortex and the
medulla. The periosteum is frequently raised giving rise
to the radiological features of Codmans triangle where
the raised periosteum meets the cortex. Extension into
the soft tissue follows. A
Blood-borne metastases to the lungs occur early. Bone
metastases, though less frequent, also occur. Microscopically,
there are malignant osteoblasts laying down small pieces of
irregular osteoid tissue. There is a variety of histological
576
Chapter | 32 | Sarcomas
liver function tests and chest radiograph (for lung metas- Chemotherapy
tases) are required.
Adjuvant and neoadjuvant chemotherapy are an important
A CT or MRI scan is necessary if surgery is contemplated,
part of the treatment of osteogenic sarcoma. Initial chemo-
to assess the involvement of the medullary cavity and the
therapy allows treatment to be instituted early, can shrink
extent of soft tissue involvement. CT is also helpful in asses-
the primary tumour, any obvious metastases as well as
sing whether the capsule of a limb joint has been breached.
obliterating micrometastases. Undoubtedly, neoadjuvant
An isotope bone scan may show increased uptake at the site
chemotherapy has reduced the rate of amputation in this
of the tumour, in the adjacent bone (due to increased vas-
disease. Moreover, chemotherapy has reduced the fre-
cularity), in bone metastases and in bone-forming metas-
quency of pulmonary metastases which used to occur in
tases in soft tissues. A biopsy should be carried out to
80% of cases. Although only about 10% of inoperable
confirm the diagnosis. It is important that the position of
tumours are rendered operable by neoadjuvant chemother-
the biopsy is chosen so that the whole biopsy scar can be
apy, in many more cases, surgery is much easier owing to
excised with the tumour to include potentially surgically-
the reduction of the tumour allowing for the insertion of
contaminated tissue along the track of the biopsy. The ini-
an endoprosthesis and sparing of the limb. The effective
tial biopsy for histological confirmation and, in cases of
agents are doxorubicin (Adriamycin) and cisplatin and
high clinical and radiological suspicion, so-called clear-
methotrexate. A good response to neoadjuvant chemother-
ance biopsies to assess the distance of spread along the
apy is an independent good prognostic factor and the
bone shaft, should be performed as the first procedure with
degree of viable tumour at surgery is related to ultimate
a view to subsequent limb-sparing surgery. Ideally, both
survival. In the current EURAMOS1 Trial, patients are ran-
biopsy and definitive surgery should be performed by the
domized after two cycles of cisplatin, doxorubicin, metho-
same surgical team. The endoprosthesis has to be planned
trexate or surgery to four further cycles depending on the
several weeks ahead of limb-sparing surgery.
amount of tumour cell kill defined histologically.
Osteogenic sarcoma is often fatal owing to spread to the
lungs, therefore, patients should have a CT scan of lungs
prior to any local therapy. Surgery
There has been an increasing trend since the early 1980s to
Treatment conserve limb function as far as possible and avoid ampu-
The management of osteosarcoma requires a multidisci- tation. Limb preservation involves removing the tumour
plinary approach including orthopaedic surgeon, oncolo- and replacing the bone defect with a custom-made artificial
gist, pathologist and physiotherapist. prosthesis (Figure 32.15). Careful preoperative assessment
Hamstring
transfer
T Gastrocnemius
transfer
II III
I
SKELETAL MOTOR AND SOFT
TUMOUR RESECTION RECONSTRUCTION TISSUE RECONSTRUCTION
577
Walter and Millers Textbook of Radiotherapy
is necessary and referral to a specialist centre (Birmingham Palliative radiotherapy of primary tumour
and London in the UK) is essential. To obtain adequate
margins, the prosthesis incorporates an artificial joint as Technique
well as femoral and tibial components. Resections of pelvic A parallel-opposed pair of fields is suitable for limb
primaries and replacing the bony defects with bone allo- primaries.
graft or autografts are a major challenge.
Contraindications to limb conservation are: Dose and energy
1. extensive soft tissue infiltration 30 Gy in 10 daily fractions over 2 weeks (46 MV photons
2. invasion of neurovascular bundles or cobalt-60).
3. involvement of the ankle joint.
Similar principles apply to the upper limb.
Radical radiotherapy
Resection of lung metastases Technique
Lung metastases are occasionally isolated and, in the This will vary with the site of the primary. For tumours
absence of metastases elsewhere, surgical resection should arising in a vertebra, a posterior oblique wedged pair
be considered. Results are best if lung metastases develop (Figure 32.16) with or without an unwedged direct poste-
after a long disease-free interval. Surgery is contraindicated rior field provides a satisfactory dose distribution. For the
if there is pleural involvement. A 5-year survival of up to ilium, parallel-opposed fields suffice.
30% has been reported following resection of pulmonary
metastasis. Dose and energy
Megavoltage is required. The choice of dose will be deter-
Radiotherapy mined by critical organ tolerance. In the spine above L2,
it will be limited by spinal cord tolerance to 47.5 Gy in
The indications for radiotherapy are:
25 daily fractions over 5 weeks. In the iliac bone, the dose
1. use postoperatively where surgical margins are delivered is limited by small bowel tolerance to a central
involved tumour dose of 45 Gy in 25 daily fractions over 5 weeks.
2. palliation of pain from the primary tumour in the
presence of metastatic disease or of bony metastases
3. radical treatment of inoperable sites (e.g. skull,
Results of treatment
vertebrae, ilium and sacrum). However, proximity of The survival of osteosarcoma has improved with the devel-
critical structures, such as the spinal cord, often limits opment of more effective adjuvant chemotherapy. Average
the dose that can be delivered. survival is 60% at 3 years. Osteoblastic and telangiectatic
90
Lung Lung
30
L R
ANT
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Chapter | 32 | Sarcomas
Ewings sarcoma
Ewings sarcoma is the second most common primary
bone tumour. In the UK, its incidence is 0.6 per million.
The peak age is between 10 and 15 years. It is slightly com-
moner in males.
Pathology
Ewings sarcoma probably arises from connective tissue
within the bone marrow. The commonest sites in order
of frequency are the pelvis, femur, tibia, fibula, rib, scapula,
vertebra and humerus. In contrast to osteogenic sarcoma, a
higher proportion of these tumours occur in the flat bones
of the trunk. About 40% occur in the axial skeleton. Micro-
scopically, there are sheets of uniform undifferentiated,
small, deeply-staining round cells. The tumour needs to
be distinguished from other small-round-cell tumours,
including non-Hodgkins lymphoma, Hodgkins disease,
neuroblastoma and metastatic carcinoma. Ninety percent Figure 32.17 Plain radiograph of the femur showing typical
of tumours have 11:22 chromosome translation. appearance of Ewings sarcoma of bone.
There is local spread along the marrow cavity causing (Courtesy of Dr R Nakielny, Sheffield.)
bone destruction. However, the epiphyseal plates are rarely
breached. Blood-borne spread is early and common. About
Clinical features
50% will have lung metastases and 40% bone metastases
and/or widespread bone marrow infiltration at presenta- Presentation is usually with a rapidly developing and
tion. Lymph node metastases are uncommon (less than painful swelling. Neurological symptoms may accompany
10%). Spread to the CNS may occur, usually late in the this if there is nerve compression. Fever occurs in about
course of the disease. 30% of patients.
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Walter and Millers Textbook of Radiotherapy
Target volume
Unlike osteogenic sarcomas, Ewings sarcomas are radio- Surgery
sensitive. Radiotherapy is indicated if the surgical excision Surgery should be as radical as possible, hopefully with
margins are narrow. limb preservation but, occasionally, mandating amputa-
It is not usually possible to deliver a radical dose uni- tion as the definitive operation. The same surgical princi-
formly to the whole bone unless it is very small, because ples as described in the section for osteosarcoma apply
of toxicity to normal tissue. For this reason, a shrinking field equally to Ewings tumours. The likelihood of local tumour
approach is adopted with two consecutive phases based on control is less if the primary tumour is large (9 cm or more).
the pretreatment volume. The initial volume is the tumour In these circumstances, unless the soft tissue component is
and a 5 cm margin of adjacent tissue. In long bones, an unir- very substantial, radical surgical removal of the whole bone
radiated strip of normal tissue containing lymphatics out- (e.g. rib or fibula) is advised.
side the tumour-bearing area is left, if possible, to reduce Where radical surgery to a limb would cause major
the risk of lymphedema as a late complication. In the second functional impairment, a conservative approach, as in
phase, the volume is reduced to encompass the primary osteogenic sarcoma, can be adopted. A customized artifi-
tumour with a 2 cm margin of normal tissue. cial prosthesis can be inserted at the end of the resected
long bone. However, amputation may be preferable for
Technique proximal tibial or distal femoral tumours in growing
The choice of technique will vary with the site of the pri- children because of reduced bone growth in the affected
mary. For the limbs, a parallel-opposed wedged pair of limb following local radiotherapy. The latter may give rise
fields usually suffices. A shrinking field technique is used to limbs of unequal length and therefore a permanent
for limb tumours. For pelvic primaries, it may be possible handicap.
surgically to displace the bowel out of the radiation field,
by inserting an absorbable mesh or a spacer. For rib pri-
maries, electrons of appropriate energy may be used to
Results of treatment
diminish the dose to the underlying lung. The outcome is better for patients with tumours of the
peripheral rather than central skeleton. Up to 90%
Dose and energy disease-free survival for peripheral tumours and 65% for
central (axial) tumours has been achieved. Overall 5-year
A high local dose (of the order of 5060 Gy conventionally
survival (and probably cure) is about 50%. Local recur-
fractionated) to the bulk of the tumour must be delivered at
rence occurs in about 1015% of long bone primaries
megavoltage, using photons or electrons as appropriate.
and 2530% of pelvic tumours. The higher recurrence rate
Patients should be included in nationally agreed protocols.
in the pelvis is probably due to the larger tumour size and
The following regimen is illustrative:
the difficulty of irradiating the tumour homogeneously
Phase 1: 39.6 Gy in 22 daily fractions over 30 days (46 MV without damaging surrounding normal tissues.
photons).
Phase 2: 13.6 Gy in 8 daily fractions of 1.8 Gy over 10 days
(46MV photons). Chondrosarcoma
Chondrosarcomas are malignant tumours of cartilage.
Acute and late reactions
They may arise in benign enchondromas or be malignant
These are the same as for soft tissue sarcoma. from the start. Adults aged 3050 are affected. The com-
monest sites in order of frequency are the pelvis (50%),
Palliative radiotherapy femur, humerus and scapula.
Macroscopically, the tumour is bulky, lobulated and
Whole lung irradiation is useful in relieving cough and dys- semitranslucent. Microscopically, it is a sarcoma contain-
ponea from lung metastases. ing cartilage. Differentiation is variable. Poorly-differen-
tiated tumours (mesenchymal chondrosarcomas) behave
Technique more aggressively. In the well-differentiated form, spread
A parallel-opposed pair of fields encompassing both lung is slow locally. Blood-borne metastases occur late to the
fields is used. lungs.
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Chapter | 32 | Sarcomas
Clinical features very useful in osteogenic sarcoma, particularly for the mes-
enchymal subtypes. However, the increase in overall sur-
Presentation is usually with a slowly progressive painless
vival following chemotherapy is small.
swelling which eventually becomes painful.
Results of treatment
Diagnosis and investigation
Five-year survival is about 50% over the age of 21 years
A biopsy is required. Plain radiography shows bone destruc-
but falls to 35% under that age. Younger patients tend to
tion and commonly abnormal flecks of calcification. MRI
have tumours in the pelvis, where radical surgery is more
scanning (Figure 32.18) helps define the local extent.
difficult than in long bones. They also have more poorly-
differentiated tumours which metastasize more frequently.
Treatment
Radical surgery is the treatment of choice. Limb preserva- Spindle cell sarcomas
tion may be possible. It is a very radioresistant tumour.
An exception is chondrosarcomas of the facial bones and These include malignant fibrous histiocytoma (MFH),
the base of skull, where a combination of surgery and angiosarcoma and sarcomas NOS (not otherwise stated).
radiotherapy offer long-term control. Radiotherapy has They occur later (3060 years of age) than osteosarcoma.
only a palliative role for the relief of local symptoms, such Origin is both in the diaphysis and the metaphysis from
as pain, and relatively high doses are required even for the periosteum or the medullary cavity. Any bone may
palliative effect. be affected. Microscopically, there is variable collagen
formation. Spread from the periosteum is to the soft tissues
more than bone, and within the medullary cavity for
Radiotherapy endosteal tumours.
Technique
A parallel-opposed wedged pair of fields is suitable for the Clinical features
long bones. A three-field technique for pelvic tumours
Pain and swelling are the main features.
using anterior and posterior wedged fields with an open lat-
eral field may limit the dose to the bowel.
Dose and energy Diagnosis and investigations
60 Gy in 30 daily fractions over 6 weeks at megavoltage Plain radiography may show an area of bone similar in
(46 MV photons). appearance to a bone infarct. A bone biopsy is necessary.
Chemotherapy
Treatment
By and large, chondrosarcomas are chemoresistant, al-
Local excision is the treatment of choice with limb preserva-
though there has been a renewal of interest in chemo-
tion if possible. Amputation may be necessary. Radiother-
therapy recently using the same agents that have been
apy is only of palliative value. Adjuvant chemotherapy
similar to that for osteogenic sarcoma is being evaluated.
Results of treatment
The prognosis is poor, with 5-year survival about 25%.
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Walter and Millers Textbook of Radiotherapy
by a combination of analgesics and local radiotherapy can Plain radiographs of the symptomatic area may show the
be achieved in most cases. deposits (osteolytic or osteosclerotic or both) or a patho-
logical fracture. However, a metastasis in a vertebral body
has to have reached a size of about 2 cm before it will be
Clinical features and investigation
visible on a radiograph.
The usual presentation is with pain due to pressure on A radioisotope bone scan is helpful in detecting bone
the periosteum or on nerve roots as they emerge from metastases too small to be visible on plain radiographs
the spinal canal (Figure 32.19). Early diagnosis is impor- and to detect deposits elsewhere in the skeleton. Multiple
tant before bone destruction has advanced so far as to bone metastases are common, predominantly in the spine,
cause pathological fracture (Figure 32.20) or spinal cord ribs, pelvis and upper femur. CT scanning of areas of the
compression. spine and sacrum where plain radiographs and bone scan
are equivocal or normal may show bone destruction. If
there is no known primary site, a CT-guided biopsy may
be necessary.
Treatment
The treatment of bone metastases includes analgesics,
Collapsed
vertebra
radiotherapy, bisphosphonates and, occasionally, sur-
gery. Treatment is aimed at relieving pain as simply and
quickly as possible. Patients should always be given ade-
Erosions by
secondary
quate analgesia escalating from paracetamol through
growth non-steroidals, mild and then stronger opiates. The choice
of treatment will depend on the site of the pain, its sever-
ity, complications, such as spinal cord compression or
pathological fracture, the presence of hypercalcaemia,
the underlying tumour and the general condition of the
Figure 32.19 Diagrammatic radiological appearances of patient.
normal vertebral column and secondary deposits from cancer Numerous randomized clinical trials have shown that a
(e.g. breast). single fraction of 810 Gy is as effective for relieving pain as
a regimen of 30 Gy in 10 fractions when analgesic effect is
measured at 6 weeks after treatment. The duration of pain
relief after a single fraction is not known, but it is very easy
to repeat the treatment. Depending on the site of the
tumour, up to 80% of patients have a marked diminution
of pain following a single radiation fraction and up to 50%
have complete pain relief (Figure 32.21). There is an argu-
ment for giving higher doses (up to 40 Gy in 15 fractions) to
a select group of patients. This may include young women
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Chapter | 32 | Sarcomas
with a solitary bone metastasis from breast cancer, espe- If there is evidence of spinal cord compression, surgical
cially when there has been a long disease-free interval. Sim- decompression of the cord may be necessary prior to frac-
ilarly, patients with a solitary metastasis from a renal or tionated radiotherapy. Steroids should be given to patients
thyroid carcinoma may gain durable palliation from a with pain from nerve root infiltration and spinal cord
higher dose. Single fields are usually adequate for vertebral, compression.
sacral and rib deposits. Obese patients with lumbar metas- Some patients are too unwell for even single fractions of
tasis should be treated with parallel-opposed fields. Kilo- radiotherapy. Their pain should be controlled medically.
voltage radiation offers practical treatment advantages in
the treatment of cervical spine lesions. Patients can be trea-
Hemibody irradiation
ted sitting in a chair, which is very useful if the neck is pain-
ful or the patient is wearing a supportive collar. As the If there are widespread painful bone metastases and the
absorbtion of kilovoltage x-rays in bone is greater than tumour is relatively radiosensitive (e.g. myeloma and
megavoltage, the exit dose is small with less mucositis. Sim- prostate cancer), hemibody irradiation in a single fraction
ilarly, rib lesions can easily be treated using 300 kV x-rays. can be considered. Typically, single doses of 6 Gy are
Parallel-opposed fields are usually used for tumours in the given to the upper and 8 Gy to the lower body. Doses
pelvis, long bones and the base of skull. Usually, field sizes greater than 6 Gy can induce an acute pulmonary reaction
are generous, particularly in the spine. Fields usually and pulmonary oedema. Radiation-induced nausea and
include the uninvolved vertebra above and below the target vomiting can be suppressed by steroids such as dexa-
lesions. In the treatment of long bone metastases, margins methasone and 5HT3 antagonists (granisetron and
of 35 cm are added beyond visible lesions to deal with ondansetron).
occult disease.
Bisphosphonates
These drugs, usually given intravenously every 3 weeks, are
Pathological fracture
effective by preventing further osteoclastic resorption of
If there is a pathological fracture of a long bone, an ortho- bone. Pain relief is durable. The main side effect is hypocal-
paedic opinion should be sought on the feasibility of reduc- caemia. They are licensed for use long-term in multiple
ing and stabilizing the fracture. Pinning a fracture usually myeloma and breast cancer. Studies are ongoing into their
provides prompt pain relief and a return to mobility. role in metastatic prostate cancer.
FURTHER READING
Suit H, Spiro I. Radiation as a therapeutic Price P, Hoskin PJ, Easton D. Prospective tumours in pediatric patients:
modality in sarcomas of the soft randomised trial of single and outcome and prognostic factors.
tissue. Hematol Oncol Clin North Am multifraction radiotherapy in the Int J Radiat Oncol Biol Phys
1995;9:7336. treatment of painful bone metastases. 2004;60:8308.
Tierney JF, Stewart LA, Parmar MK. Radiother Oncol 1986;6:24755. Aksnes LH, Hall KS, Folleraas S, et al.
Adjuvant chemotherapy for localised La TH, Meyers PA, Wexler LH, et al. Management of high grade bone
resectable soft tissue sarcoma of Radiation therapy for Ewings sarcoma over two decades: the
adults: meta-analysis of individual sarcoma: results from Memorial Norwegian Radium Hospital
patients data. Lancet Sloan-Kettering in the modern era. experience. Acta Oncol
1997;350:164754. Int J Radiat Oncol Biol Phys 2006;45:3846.
Van Geel AN, Pastorino U, Jauch KW, 2006;64:54450. DeLaney TF, Trofimov AV, Engelsman M,
et al. Surgical treatment of lung European Society for Medical Oncology. Suit HD. Advanced-technology
metastases: the EORTC soft tissue ESMO minimum clinical radiation therapy in the management
and bone sarcoma group study recommendations for diagnosis, of bone and soft tissue sarcomas.
of 255 patients. Cancer treatment and follow-up of Ewings Cancer Control 2005;12:2735.
1996;77:67582. sarcoma of bone. Ann Oncol 2005; Souhami RL, Craft AW, van der Eijken JW,
OSullivan B, Ward I, Haycock T, et al. 16(Suppl. 1):1734. et al. Randomised trial of two
Techniques to modulate radiotherapy Krasin MJ, Rodriguez-Galindo C, regimens of chemotherapy in
toxicity and outcome in soft tissue Billups CA, et al. Definitive irradiation operable osteosarcoma: a study of the
sarcoma. Curr Opin Oncol in multidisciplinary management of European Osteosarcoma intergroup.
2003;4:45364. localized Ewing sarcoma family of Lancet 1997;350:9117.
583
Walter and Millers Textbook of Radiotherapy
Figure evolve 32.2 T2 weighted MRI Figure evolve 32.5 CT scan of the thorax Figure evolve 32.10 3D conformal CT
showing a well defined, encapsulated, demonstrating a sub-pleural radiotherapy plan demonstrating a
high signal mass lesion in the posterior metastases in the right lower lobe from vacuum bag immobilising the
compartment of the distal left thigh. a soft tissue sarcoma treatment leg and elevating it away
Histology was consistent with a high Figure evolve 32.7 A large ossified mass from the contra-lateral leg
grade soft tissue sarcoma in the right pelvic wall with a Figure evolve 32.11 3D conformal CT
Figure evolve 32.3 A plain X-ray significant soft tissue component. radiotherapy plan for the patient in
showing soft tissue swelling on the Histology was consistent with Ewings Fig 32.10. The patients contra-lateral
medial aspect of the lower left thigh. Sarcoma leg was elevated to move it away from
The patient had a previous knee Figure evolve 32.8 The post operative, the treatment beams
replacement. Further investigations radiotherapy planning CT scan for the Figure evolve 32.12 A large
confirmed a high grade soft tissue patient in figure 32.7. A spacer has retroperitoneal soft tissue sarcoma
sarcoma been put in at surgery to help move the compressing the inferior vena cava.
Figure evolve 32.4 MRI scan showing a small bowel away from the Histology was consistent with a
large, heterogeneous, dumb bell radiotherapy field leiomyosarcoma
shaped mass passing through the Figure evolve 32.9 3D conformal CT Figure evolve 32.13 An expansile lesion
sciatic notch in the right side of the radiotherapy plan for a superficial, in the metaphysic of the distal right
pelvis. Histology confirmed a large high grade sarcoma. Note the humerus in a 20 year old female.
malignant peripheral nerve sheath immobilisation technique and the Histology was consistent with
tumour corridor of normal tissue osteosarcoma
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Chapter | 33 |
Paediatric oncology
Roger E. Taylor
Osteosarcoma 595
CHAPTER CONTENTS
Central nervous system tumours 595
Introduction 585 Long-term effects of radiotherapy
Toxicity of radiotherapy for children 587 for CNS tumours 595
Acute morbidity 587 Chemotherapy for CNS tumours 596
Subacute effects 587 Low-grade astrocytoma 596
Liver 587 High-grade astrocytoma (HGG) 597
Lung 587 Brainstem glioma 597
Central nervous system 587 Ependymoma 597
Long-term effects 587 Medulloblastoma/PNET 597
Bone growth 587 Studies of altered fractionation for
Central nervous system 587 medulloblastoma/PNET 598
Kidney 588 Craniospinal radiotherapy (CSRT) 598
Endocrine 588 Intracranial germ cell tumours 599
Reproductive 588 Management of germinoma 599
Tolerance of critical organs to radiotherapy 588 Craniopharyngioma 599
Chemotherapy/radiotherapy interactions 588 Proton therapy for paediatric tumours 599
Radiotherapy quality assurance (QA) 588 Conclusions 600
Leukaemia 589 Further reading 600
Total body irradiation (TBI) 590
Indications for BMT/TBI in children 590
Morbidity of TBI 590 INTRODUCTION
Hodgkins disease 590
Non-Hodgkins lymphoma (NHL) 591 Cancer in childhood is uncommon. In the UK, approxi-
Neuroblastoma 591 mately 1500 children below the age of 15 develop cancer
MIBG therapy for neuroblastoma 591 each year. Approximately one individual child in 500 will
develop cancer before the age of 15. The range of childhood
Wilms tumour (nephroblastoma) 591 cancers is very different from that seen in the adult popula-
Rhabdomyosarcoma 592 tion. Table 33.1 summarizes data on relative incidence of
Ewings sarcoma/peripheral primitive the various tumour types from the US Surveillance, Epide-
neuroectodermal tumour (PPNET) 594 miology and End Results (SEER) programme.
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It is essential for all radiotherapy departments to deliver brain radiotherapy may be employed for patients who pres-
the highest possible standard of radiotherapy for all ent with CNS involvement (Figure evolve 33.1 ). Patients
patients including children. Many radiotherapy depart- are immobilized in a head shell and treated with lateral-
ments have adopted quality systems. opposed 46 MV megavoltage fields which may be centred
In a number of studies, particularly those employing cra- on outer canthus to minimize divergence into the contra-
niospinal radiotherapy for medulloblastoma, the accuracy lateral lens. Shielding will cover the face, dentition, nasal
of delivery of radiotherapy has impacted upon tumour con- structures and lenses. The clinical target volume (CTV)
trol and patient survival. In many North American paedia- includes the intracranial meninges extending inferiorly to
tric multicentre studies, radiotherapy quality, including the lower border of the second or third cervical vertebra.
beam data, dose prescription, planning and verification Great care is taken to include the cribriform fossa, temporal
films are reviewed centrally in the Quality Assurance lobe and base of skull. Although the lens is shielded, as
Review Centre (QARC) situated in Providence, Rhode much of the posterior orbit as possible is included as
Island. In the majority of European studies, QA is not as ocular relapses occasionally occur. The CTV is localized
well organized. Ideally, review of radiotherapy simulator with lateral simulator radiographs or, more recently, com-
or verification films by study coordinators should be suffi- puted tomography (CT) simulation. The prescribed dose in
ciently fast to provide feedback early in the course of radio- current UK protocols is 24 Gy in 15 fractions of
therapy so that the treatment plan can be modified if 1.6 Gy daily.
necessary. The electronic transmission of planning films Boys who suffer a testicular relapse are treated with
and associated clinical data can facilitate this process. This testicular radiotherapy (Figure 33.2). The technique
is logistically difficult but has been achieved in the USA employed is an anterior field, generally electrons or ortho-
for radiotherapy administered to children treated within voltage (200300 kV). The CTV includes both testes, scro-
POG, CCG and more recently COG trials. In Europe, where tum and inguinal canal superlaterally as far as the deep
funding for these activities is more problematic, this has inguinal ring with shielding of non-target skin and peri-
been achieved in Germany for radiotherapy for Ewings neum. The prescribed dose is 24 Gy in 12 fractions of
sarcoma. 2.0 Gy daily.
As for adults, children with ANNL are treated with
intensive multidrug chemotherapy, which can achieve
LEUKAEMIA a survival rate of 60%. Bone marrow transplantation
(BMT) is frequently employed for children who have an
HLA-matched sibling. A survival rate of 65% can be
The improvement in survival of children with acute lym-
achieved for children in first complete remission treated
phoblastic leukaemia (ALL) was one of the early successes
with BMT as consolidation therapy for acute myeloid
of paediatric oncology. Currently, more than 70% are long-
leukaemia.
term survivors. The leukaemias account for the most fre-
quent group of paediatric malignancies. Approximately
80% have ALL and 20% acute non-lymphoblastic leukae-
mia (ANLL), usually acute myeloid leukaemia (AML) or
rarely chronic myeloid leukaemia (CML).
Current treatment for ALL is stratified according to risk
status based on presenting white count and cytogenetic
profile. The four phases of treatment are:
1. remission induction, usually with vincristine,
corticosteroids and asparaginase
2. intensification with multidrug combinations. The
number of intensification modules is dependent upon
risk status at presentation
3. CNS prophylaxis with intrathecal methotrexate.
Cranial radiotherapy is no longer employed except for
patients presenting with CNS involvement by
leukaemia
4. maintenance, usually based on a continuous low dose
antimetabolite drug such as 6-thioguanine, with a total
duration of therapy of approximately 2 years.
During the 1960s and 1970s, the routine use of prophylac- Shaded areas = position of shielding
tic whole brain radiotherapy and intrathecal methotrexate
reduced the risk of CNS relapse to less than 10%. Whole Figure 33.2 Diagram of field for testicular radiotherapy.
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Walter and Millers Textbook of Radiotherapy
Total body irradiation (TBI) 6 weeks after TBI. Long-term effects of TBI include impaired
growth due to a direct effect from irradiation of epiphyses
TBI is an important technique used together usually with and also as a growth hormone deficiency. There is also a risk
high dose cyclophosphamide (Cyclo-TBI) as the condition- of cataract, hypothyroidism and, in some studies, the possi-
ing regimen prior to BMT for adults and children. Bone bility of renal impairment. TBI is generally not considered
marrow donors for BMT are generally HLA-matched sib- for children under the age of 2 and, instead, a conditioning
lings. However, increasingly, volunteer unrelated donors regimen with two drugs, busulfan and cyclophosphamide
from donor panels donate marrow, resulting in a signifi- (Bu-Cy), is generally employed.
cant increase in the number of patients for whom BMT
can be considered.
Techniques for TBI have evolved in different depart- HODGKINS DISEASE
ments, generally depending on availability of treatment
facilities. Modern linear accelerator design and field sizes Hodgkins disease spans the older paediatric age range,
allow the use of large anterior and posterior fields. TBI through the adolescent and young adult age ranges. The
dosimetry is usually based on in vivo measurements. overall survival rate for children with Hodgkins disease
As an example of a TBI technique, the Leeds technique is is approximately 90% and an important aim is to main-
described. The patient lies in the lateral position in an evac- tain this good overall survival rate while reducing
uated polystyrene immobilization bag. Hands are placed long-term treatment effects. These include orthopaedic
under chin to provide lung compensation (Figure long-term effects of radiotherapy, such as impaired bone
evolve 33.3 ). Dosimetry is determined using in-vivo growth resulting from direct irradiation of the epiphyses,
measurements performed at a test dose of 0.2 Gy for each and also infertility from alkylating agents and procarba-
field. For such a large and complex target volume, it is not zine. Wide field radiotherapy, such as the mantle tech-
feasible to adhere to the ICRU 50 guidelines of a range nique, has been avoided in children for several decades.
of 5% to 7%, and a range of 10% to 10% is more In the UK, single modality therapy has been generally
realistic. The standard TBI dose for children in the UK is used. Children aged 10 or older with disease high in the
14.4 Gy in eight fractions of 1.8 Gy twice daily with a min- neck will generally receive involved field radiotherapy.
imum interfraction interval of 6 hours. The dose prescribed is 35 Gy in 20 fractions. Both sides
For children with ALL, many centres advise a cranial boost of the neck are irradiated to avoid asymmetric cervical
in addition to the TBI with the aim of reducing the risk spine growth, and the clavicles are shielded (Figure
of CNS relapse. Planning for the cranial boost is the same evolve 33.4 ). With this approach, approximately 70%
as for prophylactic cranial irradiation. Unlike the use of of children with stage I disease will remain disease free.
the standard TBI dose, policies for the cranial boost vary However, approximately 30% relapse, generally with dis-
between individual centres. A typical regimen for the cranial ease outside the irradiated area, and require chemother-
boost would be 5.4 Gy in three daily fractions. apy. For children aged less than 10 and for those with
more extensive disease including all stages IIIV and chil-
dren with stage I disease low in the neck, chemotherapy
Indications for BMT/TBI in children
is used. The current CCLG regimen employs alternating
In the current UK Medical Research Council (MRC) Study, cycles of chlorambucil, vinblastine, procarbazine and
children with AML are selected for BMT and TBI based on prednisolone (ChlVPP) with Adriamycin, bleomycin, vin-
risk status at presentation. Those with an HLA-matched sib- cristine and dacarbazine (ABVD).
ling are selected for BMT if they fall into the intermediate or Many North American and European protocols employ
high-risk category, whereas those with low-risk disease, i.e. low intensity chemotherapy and low-dose involved
those with chromosome mutations t(8;21), t(15;17) or Inv field radiotherapy with the aim of avoiding infertility and
16 do well with standard chemotherapy. Children with ALL serious orthopaedic effect. In the UK, the question of
selected for BMT and TBI include relapsed patients and adopting more widespread use of combined modality ther-
those presenting with features indicating a high risk of apy is under discussion. Also, positron emission tomogra-
failure with standard chemotherapy. Other conditions con- phy (PET) scanning following chemotherapy may have the
sidered for BMT where TBI is sometimes employed include potential for selecting patients who require consolidation
severe aplastic anaemia, thalassaemia and immunodefi- radiotherapy. Those who are PET positive may require
ciency syndromes. radiotherapy, whereas those who are PET negative may
not require radiotherapy following chemotherapy. The role
of PET scanning in this setting requires further evaluation.
Morbidity of TBI The management of adolescents with Hodgkins disease
Acute effects include nausea and lethargy during TBI, muco- is an example of where local and national collaboration
sitis, diarrhea, erythema and parotitis in the first few with adult oncology groups is important in order to pro-
weeks following treatment and somnolence approximately vide age-related treatment protocols.
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Walter and Millers Textbook of Radiotherapy
IV Haematogenous metastases
V Bilateral disease
592
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Walter and Millers Textbook of Radiotherapy
have a high risk of recurrence and now routinely receive National Groups (Euro-EWING 99) study. Chemotherapy
radiotherapy in recent European protocols. is commenced with VIDE (vincristine, ifosfamide, doxoru-
Planning of radiotherapy requires meticulous attention bicin and etoposide). Patients are then stratified according
to detail, avoiding excessive field sizes, particularly in the to primary tumour volume. For patients with small
head and neck region. tumours (<200 ml), and those with a good histological
Brachytherapy may be considered for a few highly response to VIDE chemotherapy, treatment continues with
selected children with RMS, usually with limited tumours doxorubicin and vincristine and a randomization to either
arising in the head and neck, vagina, bladder or prostate. cyclophosphamide or ifosfamide. For those with a poor
However, in the UK, the main area where brachytherapy histological response, there is a randomization between
has been successfully employed has been for the treat- conventional chemotherapy or high dose chemotherapy
ment of primary RMS arising in the vaginal vault. Brachy- with busulfan and melphalan.
therapy can provide a means of local tumour control with Local tumour control is important and the decision as to
reduced morbidity compared with external beam RT. whether surgery, radiotherapy or a combination of both
However, for a child to be suitable for brachytherapy, should be employed demands careful multidisciplinary
the tumour must be sufficiently localized in order to discussion. In previous series of patients treated in Europe,
achieve local control with a small planning target volume survival has been better following local treatment with sur-
(PTV) suitable for brachytherapy rather than a larger vol- gery (with or without preoperative or postoperative radio-
ume suitable for only external beam radiotherapy (typi- therapy), compared with radiotherapy alone. However,
cally 23 cm). If brachytherapy is being considered for these series are confounded by selection bias with patients
a genitourinary tract primary, discussion between oncol- with smaller tumours selected for surgery and many
ogists and surgeons at an early stage is essential followed patients with very large or inoperable pelvic tumours
by a joint examination under anaesthetic (EUA). Both selected for radiotherapy alone.
low dose rate and high dose rate afterloading brachyther- Planning of radiotherapy for Ewings sarcoma or PPNET
apy techniques have been used with equal success. Most is technically challenging. Multidisciplinary radiotherapy
young children require sedation or general anaesthetic planning involving radiologists, physicists, specialist ther-
during treatment. apy radiographers and mould room technicians is impor-
tant at the outset. Three-dimensional planning may be
employed in order to achieve a uniform dose within the tar-
EWINGS SARCOMA/PERIPHERAL get volume, which is frequently large and adjacent to criti-
PRIMITIVE NEUROECTODERMAL cal organs.
Radiotherapy technique will depend upon the tumour
TUMOUR (PPNET) site and anatomy. Individualized, generally multiple fields
are used in order to deliver homogeneous irradiation to the
Ewings sarcoma of bone is predominantly a disease of ado- PTV and to minimize dose to non-target tissues and organs
lescents, having its peak incidence in the early teenage at risk (Figure 33.10).
years. Survival rates of between 55 and 65% are reported.
Approximately 60% of primary tumours occur in the long
bones of the limbs, and 40% in the flat bones of the ribs,
vertebrae or spine. Significant soft tissue extension is com- 2
mon. Peripheral primitive neuroectodermal tumour
(PPNET), previously referred to as soft tissue Ewings sar-
coma has become increasingly recognized in the last two DVH-VOL 3
decades. One of the first subtypes of PPNET to be described 5
100 95
90
was the Askin tumour of the chest wall. The majority of 30
Ewings sarcomas of bone share with PPNET a chromo- 100 Norm
somal translocation, t(11;22) (q24;q12). In recent years, +
10 105
Ewings sarcoma and PPNET have generally been treated Max
according to common protocols.
Managing children with Ewings sarcoma and PPNET
requires a multidisciplinary team approach. Initial
treatment is with systemic chemotherapy which treats mac-
roscopic tumour and any subclinical metastases. Appropri- 1
ate use of local therapy, either surgical resection,
radiotherapy, or a combination of both modalities is also
necessary. Patients in the UK are currently entered into Figure 33.10 CT plan of radiotherapy for pelvic Ewings
the European Ewings Tumour Working Initiative of sarcoma.
594
Chapter | 33 | Paediatric oncology
When planning the CTV, phase 1 includes the gross regimen is the combination of cisplatin and doxorubicin,
tumour volume (GTV) prior to chemotherapy and/or sur- although there is evidence that high dose methotrexate
gery if feasible with a minimum margin of 35 cm for may further improve outcome. The European Osteosar-
extremity primaries and 2 cm for trunk or head and neck coma Intergroup (EOI) randomized study comparing six
primaries. For a second phase, a margin of 2 cm is cycles of cisplatin and doxorubicin given either every 3
employed. Immobilization is dependent upon primary weeks or every 2 weeks using granulocyte colony stimulat-
tumour site and anatomy. For limbs, an immobilization ing factor (GCSF) to accelerate recovery of the blood count
device, such as an evacuated polystyrene bag, may be use- has recently closed. Early results suggest no significant dif-
ful. The CTV and PTV are localized on a planning CT ference in outcome.
scan. The prescribed doses are, for phase 1 and postoperative Radiotherapy has only a minor role in the management of
volume: 44.8 Gy in fractions of 1.82.0 Gy and, for phase 2, osteosarcoma. However, it is probably not as radioresistant
for macroscopic disease: 9.6 Gy in fractions of 1.82.0 Gy. as previously thought. In selected patients, after insertion
Selected patients may benefit from a higher dose, up to of an endoprosthesis, postoperative radiotherapy may be
64 Gy if this can be delivered without undue toxicity. How- employed for those felt to be at a high risk of local recurrence,
ever, patients selected for definitive radiotherapy frequently i.e. those with tumour at a resection margin. Radiotherapy
have large tumours, and dose may be limited by organ tox- is sometimes employed for the treatment of an unresect-
icity, and thus a dose of 64 Gy is generally difficult to able tumour, such as a spinal vertebral or extensive pelvic
achieve. For postoperative radiotherapy, the prescribed primary tumour. In these cases, the dose has to be as high
dose depends on the extent of surgery and histological as normal tissues will tolerate, i.e. 60 Gy if possible. Radio-
response of the primary to initial chemotherapy. Following therapy can be employed for the local palliation of metas-
intralesional surgery or marginal surgery with poor histo- tases, using a relatively high dose, e.g. 40 Gy in 15 fractions.
logical response to chemotherapy (>10% residual tumour
cells), 54.4 Gy is prescribed. For marginal surgery with
good histological response (<10% residual tumour cells) CENTRAL NERVOUS SYSTEM TUMOURS
or wide surgery with poor histological response, 44.8 Gy
is prescribed. For patients who present with pulmonary
Tumours of the central nervous system (CNS) account for
metastases, whole lung RT is employed, 15 Gy for patients
approximately 2025% of malignant childhood tumours.
aged less than 14 and 18 Gy for those aged over 14. These
Approximately 350 children develop CNS tumours each year
doses are subject to homogeneity correction for reduced
in the UK. However, individual tumour types are uncommon
attenuation in lung.
and experience in the management of each type is limited.
Care has to be taken when combining chemotherapy
In contrast to most other paediatric malignancies, the use
and radiotherapy to avoid excessive morbidity from en-
of chemotherapy has not yet resulted in significant improve-
hanced radiation reactions. Actinomycin-D is not given
ments in survival for the majority of children with CNS
during radiotherapy and anthracyclines, such as doxorubicin
tumours. The overall 5-year survival rate is approximately
and epirubicin, are omitted if there is a significant amount of
50%, inferior to that reported for many other childrens
bowel or mucosa in the treated volume. Patients requiring
tumours. The burdens of survivorship are high and the
radical radiotherapy involving the spinal cord or significant
majority of survivors experience sequelae from either the
radiotherapy to the lungs should not receive busulfan.
tumour or therapy or, very frequently, a combination of both.
Children with CNS tumours and their families are
managed by specialized paediatric neuro-oncology multi-
OSTEOSARCOMA disciplinary teams. The UK intercollegiate publication
Guidance for Services for Children and Young People with
Brain and Spinal Tumours describes the elements of a com-
Osteosarcoma is the most frequent bone tumour of child-
prehensive multidisciplinary service.
hood, with the majority arising in teenagers. The lower
Radiotherapy for children with CNS tumours is techni-
femur and upper tibia are the most frequent primary sites,
cally challenging. Many children require craniospinal
with approximately 65% developing around the knee. Less
radiotherapy, which is one of the most complex techniques
frequent sites include the humerus, fibula, sacrum, spine,
employed in most oncology departments.
mandible and pelvis. Prior to the advent of effective chemo-
therapy, approximately 80% of patients died because of
progression of lung metastases. Currently, a survival rate Long-term effects of radiotherapy
of approximately 55% can be achieved with the use of for CNS tumours
intensive adjuvant chemotherapy. The majority of primary
tumours can be resected and the affected bone replaced by Of greatest concern are the long-term neuropsychological
a titanium endoprosthesis, thus avoiding the need for an effects of radiotherapy to the CNS, particularly for very
amputation. The most frequently employed chemotherapy young children. Other factors include direct and indirect
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Walter and Millers Textbook of Radiotherapy
effects of the tumour itself and also the effects of surgery. the risk of the procedure (i.e. visual deterioration) out-
One of the most important factors which increases the risk weighs the risk of an incorrect diagnosis.
and severity of long-term neuropsychological sequelae is During the last 10 years, North American and European
young age at diagnosis. For children aged less than 3 years collaborative group studies have attempted to standardize
at diagnosis, radiotherapy is delayed if possible by the use the management of children with LGG. The International
of chemotherapy. Society of Paediatric Oncology (SIOP) series of studies
Children receiving craniospinal radiotherapy will experi- has defined a strategy for managing these tumours. Follow-
ence spinal shortening as a direct effect of irradiation of the ing initial maximal surgical resection, patients undergo a
spine. period of observation. Patients with clinical or radiological
For many children, the hypothalamic/pituitary axis has evidence of progression, those with severe symptoms or
to be included in the irradiated volume. This often results threat to vision receive non-surgical treatment.
in growth hormone deficiency, but other endocrine defi- In the recently opened European SIOP study, those over
ciencies such as thyrotrophin-releasing hormone (TRH) the age of 7 years are treated by radiotherapy. Those aged
or adrenocorticotrophic hormone (ACTH) deficiency 7 or under receive chemotherapy with the aim of delaying
may occur. TRH deficiency is relatively easily managed by radiotherapy. It is hoped that by employing this strategy
thyroid hormone replacement, but ACTH deficiency may for younger children the long-term neuropsychological
require life-long steroid replacement therapy, which may effects of radiotherapy may be lessened by the delay. Using
be problematic. the drug combination of carboplatin and vincristine, the
majority of children with LGG can achieve either a response,
Chemotherapy for CNS tumours or stabilization of previously progressive tumour. In the cur-
rent SIOP study, patients are randomized to receive initial
Chemotherapy does not yet have an established role for the chemotherapy with either carboplatin and vincristine, or
majority of paediatric CNS tumours. Secreting intracranial this drug combination with the addition of etoposide. The
germ cell tumours are routinely treated with chemother- aim of this study will be to assess whether the addition of
apy. Adjuvant chemotherapy improves the outcome for etoposide can reduce the risk of tumour progression within
standard risk medulloblastoma compared with radiother- the first few months of chemotherapy, which was a signifi-
apy alone. The use of chemotherapy can delay the need cant problem in the previous SIOP LGG study. The total
for radiotherapy for very young children, particularly those duration of chemotherapy is 18 months. Patients who are
with low-grade astrocytoma and probably ependymoma. treated initially with chemotherapy and who experience
However, in most cases, the use of chemotherapy is evalu- progression will receive radiotherapy, and vice versa. For
ated within the context of a clinical trial. patients who present with spinal cord primary low-grade
glioma, the management policy will be similar.
Low-grade astrocytoma Radiotherapy for low-grade gliomas is based on a careful
imaging for target volume definition (Figure evolve 33.11
Low-grade astrocytomas (LGG) comprise the most fre- ). The technique will depend upon tumour site and anat-
quent group of childrens CNS tumours (see Table 31.1). omy. Individualized multiple fields in order to deliver
The most frequent histological types are WHO grade I homogeneous RT to the PTV and to minimize dose to
(pilocytic) or grade II (usually fibrillary), with other vari- non-target tissues and OARs. The CTV includes the GTV
eties, such as ganglioglioma and oligodendroglioma, much and, in the case of surgical resection, any brain tissue pre-
less frequent. The presence of neurofibromatosis type I viously surrounding the tumour with a margin in potential
(NF1) predisposes to the development of these tumours. areas of spread of 0.5 cm. Patients are immobilized supine
It is now clear that LGG may undergo long periods of qui- or prone depending upon anatomy, generally in a Perspex
escence even when not completely resected. It is now also head shell. The extent of GTV is localized using T2 or flair
clear that low-grade gliomas are more chemosensitive than images on the MRI scan. Ideally, CT/MRI fusion should be
previously thought. Following treatment of LGG, the 5-year employed. The radiotherapy dose is specified to the ICRU
survival rate is relatively high at approximately 8085%, reference point. In international studies, the prescribed
but late relapse is not uncommon. dose is 54 Gy in 30 fractions of 1.8 Gy daily. For patients
Initial treatment is usually with surgical resection, which with a spinal cord primary requiring radiotherapy, the dose
should be as complete as is considered safe. This is usually is 50.4 Gy in 28 fractions of 1.8 Gy.
more straightforward for tumours arising in the cerebel- Three-dimensional conformal planning can reduce the
lum, where complete resection is usually feasible, com- amount of normal brain within the irradiated volume,
pared with those arising from the optic tract or optic and has the potential for reducing long-term effects, an
chiasm. Because of the considerable risk of surgery in this important priority for this group of patients who have a
area, tumours with typical features on magnetic resonance high chance of long-term survival. In future, it is planned
imaging (MRI) scanning of a hypothalamic/optic tract to assess the impact of radiotherapy parameters on long-
astrocytoma are not necessarily biopsied, as many consider term intellectual and functional outcome.
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accuracy contributes to the chances of cure of medullo- have a tendency for subependymal spread, which has to be
blastoma and other PNETs. It is essential to avoid areas taken into account when planning the boost volume. A
of underdose at field junctions and partially shielding margin of 2 cm around the gross tumour volume should
of any part of the intracranial or spinal meninges. The be employed. For non-germinomatous tumours, the progno-
moving junction between abutting fields is a safety mea- sis is worse. Initial treatment is with platinum-containing
sure, which reduces the risk of underdose or overdose in chemotherapy followed by radiotherapy, either focal for loca-
the cervical spinal cord if a systematic error develops lized non-metastatic tumours or CSRT for those with lepto-
during CSRT. meningeal meningeal metastases. For secreting GCT, the
When planning the posterior fossa boost for medul- total radiotherapy dose is 54 Gy to the primary tumour, with
loblastoma, it is generally accepted that the CTV should 30 Gy CSRT for patients with leptomeningeal metastases.
encompass the meninges of the entire posterior fossa,
because of the risk of infiltration of the meninges adja-
cent to the primary tumour. It has been standard to Craniopharyngioma
employ a standard field arrangement, with a parallel- These account for approximately 510% of intracranial
opposed pair of fields. However, to avoid a higher dose tumours in childhood. These are predominantly cystic
in the neck, it is usually necessary to employ wedges as tumours which arise in the suprasellar area from remnants
tissue compensators. In many centres, the posterior fossa of Rathkes pouch. Although considered histologically
boost volume is planned using a posterior oblique field benign, they are often associated with considerable
arrangement which can reduce the radiation dose to the morbidity. They are associated with pituitary deficiencies,
inner ears. including diabetes insipidus and disturbances of hypo-
CSRT techniques are continuing to evolve, and need to thalamic function such as obesity. They are frequently adher-
incorporate technical developments in radiotherapy ent to adjacent structures within the CNS. There is a
immobilization, planning and treatment delivery. For the significant risk of involvement of the optic chiasm with a risk
posterior fossa boost, it is possible to employ three- of visual impairment or blindness. Small cranipharyngio-
dimensional conformal planning to reduce the radiation mas may be amenable to complete surgical excision if this
dose to non-target structures, such as the hypothalamus can be achieved without a risk of damage to the optic chi-
and middle ear. Virtual simulation has been used to define asm. An alternative approach is to consider partial or subto-
the target volume for CSRT in critical areas such as the crib- tal excision of the tumour with postoperative radiotherapy.
riform fossa (see Figure evolve 33.14 ). The margin for CTV around the GTV is generally approxi-
mately 0.5 cm, with a dose of 5055 Gy in a fraction size
Intracranial germ cell tumours of 1.671.8 Gy. With either complete resection or partial
resection and postoperative radiotherapy, long-term local
Intracranial germ cell tumours (GCT) account for approxi- control rates of approximately 80% can be achieved.
mately 30% of paediatric GCTs and arise in the suprasellar
or pineal regions. Germinomas are the histological coun- Proton therapy for paediatric tumours
terpart of testicular seminoma and may arise in either
the suprasellar or pineal regions. Non-germinomatous germ Proton therapy has been available for several decades in
cell tumours, also known as secreting germ cell tumours, are selected centres, mainly in North America. There is now
the histological equivalent of testicular non-seminomatous increasing interest in developing centres in Europe. How-
germ cell tumours. They generally arise in the pineal region ever, in the UK, there is no proton facility of sufficient
and may secrete alpha-fetoprotein (AFP) and/or human energy to deliver therapy for deep-seated tumours such as
chorionic gonadotrophin (HCG). those of the CNS or skull base. In recent years, there has
been increasing interest in the potential role for proton
therapy in the management of paediatric tumours. The
Management of germinoma modulated Bragg peak can deliver homogeneous irradia-
In common with testicular seminoma, germinomas are tion to the target volume while reducing the magnitude
very radiosensitive. The traditional view has been that and/or extent of the low dose area beyond. This may
CSRT should be employed because of the risk of leptome- be clinically relevant for long-term effects in children. For
ningeal metastases and, with this approach, more than several decades, proton therapy has had an established role
90% of germinomas are cured. However, as with testicu- in the treatment of adults with skull base chordomas and
lar seminoma, there has been a gradual reduction in chondrosarcomas. This role has now been extended to the
both the CSRT dose and the dose used for the boost to treatment of children. In addition, planning studies have
the primary tumour in an attempt to minimize long-term demonstrated the potential for improving the therapeutic
effects. In the current SIOP protocol, the CSRT dose is 24 Gy ratio for radiotherapy for tumours either within or adjacent
in 15 fractions of 1.6 Gy and the boost dose to the primary is a to the CNS and by achieving a uniform dose within the
further 16 Gy in 10 daily fractions of 1.6 Gy. Germinomas target volume, while potentially minimizing the severity of
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Walter and Millers Textbook of Radiotherapy
neuropsychological sequelae. In several North American families. Thus, management needs to be family-centred
proton therapy centres, the role of proton therapy for as well as patient-centred. Although cure rates for the
craniospinal radiotherapy is under investigation. majority of childhood cancers have continued to improve
over the last decade, this has frequently been achieved with
increased intensity of chemotherapy. Compared with adult
CONCLUSIONS radiation oncology practice, when planning radiotherapy
for children, consideration of the long-term effects of
Paediatric oncology management continues to present treatment is always of paramount importance. With the
many challenges and radiotherapy plays an important role increasing use of concurrent combined modality therapy,
in the treatment of many of these children. They require the including intensive chemotherapy, constant vigilance for
highest standard of radiotherapy planning and delivery, interactions between chemotherapy and radiotherapy is
incorporating modern technical developments. Children required. Therapeutic developments initially investigated
present with a wide variety of malignancies which pose in adults, such as hyperfractionation, also require investiga-
many different problems for patients themselves and their tion for childhood cancers.
FURTHER READING
Malpas J, editor. Cancer in children. controversies. 2nd ed. Chapman & brain and spinal tumours. Royal
Br Med Bull 1996;52(4):67181. Hall; 1997. College of Paediatrics and Child
Pizzo PA, Poplack DG. Principles and Halperin EC, Constine LS, Tarbell NJ, Health; 1997.
practice of pediatric oncology. 4th ed. Kun LE. Pediatric radiation oncology. Walker DA, Perilongo G, Punt JAG,
Lippincott, Williams and Wilkins; 3rd ed. Raven Press; 1999. Taylor RE. Brain and spinal tumours
2002. Royal College of Paediatrics and Child of childhood. Arnold; 2004.
Pinkerton CR, Plowman PN. Paediatric Health. Guidance for services for Wallace H, Green D. Late effects of
oncology clinical practice and children and young people with childhood cancer. Arnold; 2004.
Figure evolve 33.1 Simulator film of Figure evolve 33.6 Wilms tumour flank Figure evolve 33.12 Sagittal view of a
whole brain field for ALL CNS radiotherapy typical pontine glioma
prophylaxis Figure evolve 33.8 Whole lung Figure evolve 33.13 Diffuse pontine
Figure evolve 33.3 TBI technique radiotherapy glioma R/T
Figure evolve 33.4 Neck irradiation for Figure evolve 33.11 Series-Imaging for Figure evolve 33.14 Series craniospinal
Hodgkins disease. low-grade glioma RT planning radiotherapy field arrangement
600
Chapter | 34 |
Care of patients during radiotherapy
Cathy Meredith, Lorraine Webster
Table 34.1 Radiation Therapy Oncology Group grading of acute skin reactions
No visible Faint or dull Tender or bright erythema with/ Patchy moist desquamation; Confluent moist
change erythema without dry desquamation moderate oedema desquamation; pitting
oedema
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Chapter | 34 | Care of patients during radiotherapy
Table 34.2 Recommendations for reducing irritants to Table 34.3 Characteristics of skin-care products
irradiated skin during a course of radiotherapy for each stage of radiation skin reactions
Sun Protect from direct sun exposure: cover No change in skin No intervention required.
exposure with clothing or shade area. Stress that risk (RTOG0) Aqueous cream if desired ( n.b.
from sun exposure is lifelong and following this will not prevent or delay
radiotherapy a sun block should always be skin reaction
used if exposure unavoidable
Faint or dull erythema Aqueous cream applied to skin
Mechanical Minimize friction: wash or shower gently; (RTOG 1) within the treatment field - may
irritants avoid using a washcloth; pat dry with a soothe and moisturise skin
soft, clean towel; wear loose fitting,
soft clothing Tender or bright Aqueous cream may soothe
Avoid shaving or shave causing as little erythema and moisturise skin, relieve
trauma to skin as possible- suggest electric (RTOG 2a) itching Hydrocortisone cream
shaver can be used sparingly for up to
Avoid scratching one week, skin to be reviewed
Avoid rubbing vigorously and massaging and documented daily
Avoid use of adhesive tape in treatment
Patchy moist Dressings should be non
field
desquamation adhesive
Chemical Use mild soap (un-perfumed) and rinse (RTOG 2b) Hydrogel and non adhesive
irritants thoroughly dressings, soft polymer
Apply only recommended products- check dressings, hydrocolloid dressings
with treatment centre. Any topical cream
Moist desquamation Dressings should be non
or lotion to be used at room temperature
(Pitting oedema) adhesive
Avoid perfume, aftershave, deodorant
(RTOG 3) Hydrogel dressings, hydrocolloid
Use mild detergent to wash clothing
dressings, anti microbial
Thermal Use tepid water dressings, polyurethane foam
irritants Avoid exposure to temperature extremes dressings
Avoid application of ice packs or heat (e.g.
heating pad, hot water bottles, sun lamp)
The nutritional status of patients may be adversely affected
by not only their disease but by the impact of their radio-
event requires a knowledge of the more general wound therapy. Treatment-induced toxicities such as dry mouth,
care literature. It is important that advice and treatment mucositis, dysphagia, nausea, vomiting, diarrhoea and
given to patients is evidence based and that advice such tenesmus can all impact negatively on nutritional status
as no washing is now seen as inappropriate. Sadly this and, ultimately, upon the quality of life of patients. In addi-
remains an area which lacks robust evidence from the lit- tion, when patients are referred for radiotherapy they may
erature, which in turn, creates challenges when making already have undergone surgical intervention, chemother-
recommendations, Table 34.3 provides some small detail apy or both and they may also be receiving concomitant
of skin-care products which can be utilized. treatment that could exacerbate further their nutritional
Other sources which may be useful include published status. These factors and the possibility that food intake
national skin-care guidelines [7]. When moist desquama- may be modified during radiotherapy makes it essential
tion becomes infected or infection is suspected, use of a sil- that sound nutritional advice and support is available.
ver or iodine based antimicrobial dressing may be used. Although radiotherapy will not have a significant adverse
Care should be taken to ensure the dressing is designed impact on the nutritional status of all patients, they still
to prevent silver being absorbed by the wound (check require sufficient nutrition to support tissue repair. Patients
manufacturers information) and the dressing should be often have coexisting medical and social conditions that
removed daily before treatment. can affect nutritional status and it is important that these
are recognized and their impact incorporated into nutri-
tional planning.
NUTRITION There are particular areas where side effects of treatment
commonly jeopardize nutritional status, e.g. head and
Guidance on nutritional status and diet for patients under- neck, oesophagus, colorectal and pelvis/abdomen. It has
going radiotherapy can impact positively on patients if been suggested that these patients and others require to
it is undertaken in a routine and evidence-based manner. be screened to identify those who need a more in depth
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Walter and Millers Textbook of Radiotherapy
nutritional assessment. A study by Ravasco et al [8] has lethargy and being overwhelmed by events. Patients should
demonstrated the benefits that can be gained when early be advised that, although their treatment may cause tired-
intervention and proper assessment of nutritional status ness, they should try to get enough rest and sleep and try to
and requirements is undertaken alongside early nutritional continue some of their daily activities. This and even some
counselling and monitoring of diet. gentle exercise can help to achieve a healthy balance and
Advice to patients should, wherever possible, have an can prevent patients ending up in a fatigue/lethargy cycle.
evidence base and will be dependent upon the area being Macmillan Cancer Support have recently been proactive
treated, the regimen employed and a myriad of other fac- in disseminating information, underpinned by research,
tors. Treatment and advice to patients should therefore promoting the advantages of exercise in helping alleviate
be tailored to suit their needs. However, it is essential that side effects, fatigue and depression as well as overall health
initial assessment of all patients is carried out, in order that benefits.
appropriate action can be taken at a time when any condi-
tion can be more easily dealt with. Identifying the reason
for the impaired nutrition is pivotal to its adequate treat-
ment and, although dieticians are the key professionals, PSYCHOSOCIAL ISSUES
this is the responsibility of the multidisciplinary team.
Patients should be sign posted to existing good quality It is crucial to remember that patients do not exist with a
sources of information. particular illness in isolation and that the dynamics of
family and social relationships that may or may not exist
within their own supportive networks may influence the
NAUSEA, VOMITING AND DIARRHOEA content, context and ability to offer the desired or needed
care. In short, the patient should rarely be considered in
isolation and due thought and support should also be
There is little doubt that the above can cause a significant
given to the needs of close family and carers, as they will
threat to the comfort and well being of patients and thus
also experience many similar feelings to those of our
affect quality of life. It is important that patients are moni-
patients. The family is an extended agent of patient care
tored for the development of such side effects, that their
and a cancer illness can have a profound effect not only
severity is assessed and appropriate treatment instigated.
on patients but on their relatives and, indeed, the process
Side effects such as dehydration and weight loss as a con-
of a patient informing relatives of their illness can be
sequence of diarrhoea are to be avoided and, although some
traumatic for all concerned.
patients may find it difficult to discuss, a comprehensive
Many patients and carers experience a range of psy-
assessment of the condition is essential in order that the
chological and emotional challenges as a result of their
appropriate pharmacological therapy can be made available.
diagnosis and subsequent treatment effects. Research sug-
Loperamide (Imodium) is a frequently used standby in the
gests that the prevalence of long-term psychological distress
treatment of diarrhoea. Codeine phosphate is especially use-
in cancer patients ranges from 20 to 66% [9]. In addition,
ful if diarrhoea is associated with colicky abdominal pain.
there are also the practical implications of illness, and a
In relation to the prevention of nausea and vomiting,
patient and their family may have difficulties in terms
granisetron 2 mg orally an hour before radiotherapy can
of their financial and employment status, as well as dis-
be a very good prophylaxis even for wide field radiotherapy
ruption caused by changes in their role and the family
and is much more effective than old antiemetics such
dynamics.
as metoclopramide.
For the patient coming to terms with a cancer diagnosis, it
has become helpful to think of their emotional adjustment
as a series of different emotional stages. Barraclough [10]
FATIGUE describes patients initially experiencing shock, numbness
or disbelief, often with the bad news seeming too much
One of the most common symptoms experienced by cancer to take in. This usually short-term denial is then followed
patients is fatigue although, not until recently, has it begun by distress as the reality of the situation becomes clear and
to be given the attention it deserves. It is a multidimen- is often associated with anger, anxiety, protest and bargain-
sional phenomenon which makes it difficult to describe. ing. This phase often lasts a number of weeks and can be
It has been attributed to both the illness, cancer-related followed by sadness and depression again taking several
fatigue and, as it develops, the term radiotherapy-related weeks before gradual movement to adjustment and accep-
fatigue is used. The evidence to support a relationship tance, taking weeks and even months.
between radiotherapy and fatigue is difficult to isolate Although this is a useful guide to apply to many situa-
but what is known is that it can and does adversely affect tions associated with loss of any kind, it is important
patients quality of life. Patients can describe fatigue in to caution against using it as a simple sequential model
many ways, describing feelings of tiredness, exhaustion, of what every patient (and their carers) will experience.
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Chapter | 34 | Care of patients during radiotherapy
Individual characteristics
personality, coping style and defenses
Age in relation to life cycle Acceptance / Mastery What family, friends and other
related biological, personal and Fear / Anxiety support structures are available
social life goals when illness occurs to the person at this time
Helplessness / Hopelessness
Although many will react with some of the above emo- and meaningful health outcomes. The benefits of effective
tions, we should not expect all to be initially shocked communication between healthcare professionals and
by a diagnosis and then work through all the stages to a patients include improvements in treatment compliance
final acceptance. Often there are more individual emotions and satisfaction with their care and decision making as well
and they may not occur in any clear order, or may overlap as overall improvement in their psychosocial adjustment.
or may be gone through more than once, particularly in an In addition, it is important to highlight that a major effect
illness that has remissions and relapses or a series of of poor communication is dissatisfaction. When patients
progressive deteriorations. Heightened anxiety and inten- are dissatisfied and feel unable to speak freely, it has a negative
sity of these emotions will occur most strongly at diagnosis, effect on the likelihood that they will offer and seek the infor-
during treatment episodes and at times of recurrence and mation necessary for a good informative exchange. The resul-
in terminal phase. tant effect of this is that the accurate exchange of information
A summary of some of the common responses and influ- will be limited.
encing factors is illustrated in Figure 34.1, which aims to It must therefore be acknowledged that good communi-
illustrate the dynamic that emotional adjustment changes cation is essential to allow patients and their carers to be
through time, and is affected by many different factors involved with decisions about their care. Patients and carers
which will be highly individualized for each patient. These place a lot of importance on face-to face communication
reactions do not occur in any particular order and are par- with healthcare professionals and is the usual way informa-
ticular to the individual who may move in and out of the tion is given at crucial points in the patients illness and treat-
different responses as the stimuli change. ment pathway. Indeed, the NHS cancer plan [11] cites that a
willingness to listen and explain is considered by patients
to be one of the essential attributes of a health professional.
COMMUNICATION In addition, effective communication is central to the
identification of an individuals specific needs and the
There is compelling evidence demonstrating that good, provision of appropriate information and psychosocial
patient-centred communication is associated with important support. Healthcare professionals also need to be sensitive
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Walter and Millers Textbook of Radiotherapy
to particular needs of each person in terms of awareness of time and that this needs to be judged at the level of the indi-
issues of age, gender, culture and socioeconomic status. vidual patient and carer need and should be assessed on an
Good communication also involves more than just ongoing basis throughout the patient pathway. For exam-
being able to use the right words for a particular situation. ple, a persons desire for information at the time of diag-
It also requires an ability to listen and hear the person, and nosis may be very different at a time of relapse. Thus, the
engage with them both emotionally and psychologically. challenge is that it is vital that any information given is
While all professionals involved in cancer care are increas- appropriate to an individuals personal needs and circum-
ingly aware of the need to interact effectively with patients, stances, therefore, when and how we communicate this
many feel inadequately trained in the various aspects of information is crucial.
communication. There is also growing expectation from
patients and their families that good communication is an
essential component of their cancer treatment and care CONSENT
and it therefore becomes an important focus for all health
professionals to judge whether they have addressed an
The NHS Plan [12] pledges that consent must be sought
individual patient or carers communication and indeed
from all NHS patients. Both English and Scottish law
information needs within any consultation or interaction.
state that before you examine, treat or care for competent
adult patients you must obtain their consent. The Depart-
ment of Healths Reference Guide to the consent process
INFORMATION offers a comprehensive summary of the law on consent
and offers help on frequently asked questions for both
It is now widely accepted that seeking information is one health professionals and patients (available at www.doh.
strategy that many people use to help them cope with gov.uk/consent). This provides a comprehensive guide
the challenges that a cancer diagnosis brings. The consen- and is usually well supplemented by individual health
sus would appear to be that the provision of appropriate, providers producing their own guidelines for use at a local
timely and honest information can make them feel more level.
in control of their situation and can therefore be a key With respect to the issue of competence, as a general
element for many people in managing the experience of guide, the professional seeking consent should consider
cancer. In addition, there is evidence that the psychological the question of whether a patient can understand and
distress in patients with serious illness is less when they weigh up the information needed to make the required
think that they have received adequate information. decision. It is also important to bear in mind that, if a
It is therefore important that any healthcare profes- patient reaches a decision that appears unexpected, it
sional working with cancer patients should be attuned to may not indicate incompetence, but rather a need for
the fact that patients are unlikely to have retained all the further information or explanation.
relevant information, particularly after one consultation. Thus, information giving is pivotal to underpinning a
Hence, there is a need to assess this accurately and consis- morally and ethically sound consent process. In essence,
tently repeat and reinforce this at subsequent consultations informed consent requires that patients have had their
and visits for treatments. treatment options and procedures explained in a way that
Regardless of the amount of information retained, they can understand and, as patients are increasingly
because patients tend to remember what they have been involved in their own healthcare, they need possession of
told first, rather than subsequent information, it can be the facts, including risks and benefits, to enable them
difficult to undo any wrong perception and understand- to make decisions about their own treatment and care.
ing of the patient and their carers in relation to this. It is This is important at all stages in the process but, particu-
therefore vital that there is consistency in explaining diag- larly, at times when stages of illness and treatment options
nosis, prognosis, treatment and effects. Consequently, it is change. Indeed, the law regards giving and obtaining con-
exceptionally important that this is given accurately and sent to be a process, not a one-off event and, therefore,
not contradicted at a later date, by the same person or must be valued as crucial in the treatment of cancer where
another member of the team. different treatment options, such as further chemotherapy
However, it should be acknowledged that this remains and radiotherapy, are required in the disease trajectory.
an area of many challenges and tensions for all involved It is also important to be aware that any patient may
in working with patients with cancer for several reasons. change their mind and withdraw consent at any time and
While research has demonstrated that a majority of people this is applicable not only to those in clinical trials. As a
want to be informed about all aspects of their disease and general guidance point, if in any doubt, always check that
treatment, there is a responsibility also to be sensitive to the patient still consents to treatment.
the minority who do not. It is also important to acknowl- With respect to explaining particular benefits and risks
edge that patients information needs will change through associated with treatment to patients, these will relate
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Chapter | 34 | Care of patients during radiotherapy
specifically to site and stage of disease as well as treatment Patients need to be supported to find coping mechan-
intent and planned rationale. For example, whether radio- isms during their illness and the spiritual dimension
therapy is being combined with chemotherapy will affect may help in this process. There is a recognition that
not only outcome but early and late effects of treatment, meeting spiritual need is important and policies to develop
as will whether the patient has had previous surgery. While and implement spiritual care in our centres are now
the current Department of Health Guidelines state that being advised. A study by Murray et al [13] concluded that
patients should be advised on substantial or unusual risks spiritual issues were significant for many patients in their
of treatment, the detail of these for site-specific conditions last year of life and their carers and that many health
are beyond the remit of this chapter. However, it is worth professionals lack the necessary time and skills to uncover
noting that many cancer centres now include specific and address such issues.
details of both acute and late effects of treatment for spe- Addressing patients spirituality can be a challenge but
cific cancers as an essential element in the consent process communicating at this level can be a positive experience
and this level of written detail can aid the professional for healthcare professionals as well as patients.
seeking consent. In addition, it allows the patient to have
time to reflect on many of the effects discussed and to give
due consideration prior to actually consenting to treat- COMPLEMENTARY THERAPIES
ment. The important message to get across to patients is
one that should be balanced. That yes, indeed, radio-
Complementary therapies do not offer patients an alter-
therapy does carry risks (and these should be explained
native approach to established treatments such as surgery,
individually for each patient and their related cancer)
chemotherapy and radiotherapy but, as the name suggests,
but must always be weighed up against the risks of not
are designed to complement existing treatments. These
having any treatment at all. It should also be emphasized
therapies are diverse and varied and include self-help
that, generally, the long-term risks tend to be rare and
approaches, such as relaxation, meditation, visual thera-
affect a very small number of people and that, generally,
pies and touch therapies, such as aromatherapy, massage
the benefits of radiotherapy treatment far outweigh the
and reflexology, as well as more established practices of
possibilities of involved risks.
homeopathy and acupuncture.
In answer to the question of who should seek consent, it
While debate continues about the efficacy of many thera-
is advised that it is always best for the actual person who is
pies, it has to be acknowledged that increasingly patients
in charge of treating the patient. However, it is deemed
express an interest in their use and reports have indicated
acceptable that consent may be sought on behalf of collea-
that up to one-third of patients with cancer have used com-
gues if the healthcare professional involved is capable of
plementary therapies [2]. While this debate is ongoing,
performing the procedure and can explain fully what the
and as demands for conventional reliable evidence for
procedure involves or has been trained to seek consent
efficacy increases and research continues, the aim must
for that procedure.
be an acknowledgement among health professionals that
patients will continue to search these therapies out. This
means that we must be informed and open to dialogue
SPIRITUAL NEEDS with patients and their families. This is of particular impor-
tance, as some therapies patients may engage in may be
Over the last 20 years, the emphasis on spiritual care has viewed as more alternative treatments which could possi-
become more acute, as has recognition that the spiritual bly result in a tension with orthodox treatment and,
dimension is important when patients and their carers indeed, there is growing concern among clinicians that
face a life-threatening condition. Defining spirituality is sometimes their use can interfere with conventional treat-
challenging, to a degree it is intangible, but can be said ments, such as chemotherapy or, indeed, produce harmful
to encompass those facets of an individual which give effects.
a sense of purpose and meaning to life. In essence, an It should be recognized that the reasons given by patients
awareness of the existential aspects of life and its mean- for seeking out complementary therapies are varied and
ing may be awakened. Contemporary medical literature often relate to the perception that they are natural and
supports the importance of spirituality for patients and pro- holistic, and that they will improve quality of life and help
poses that strong spiritual beliefs can aid individuals fighting relieve the symptoms of both disease and the effects of
illness. It has been suggested that spiritual well being can treatment. They offer the patient a sense of personal
have a positive effect on a patients coping skills and their involvement in their own care and often the feeling that
quality of life and can promote feelings of peace and they are taking some control of their disease. In addition,
acceptance, although there are those who identify the dan- this form of treatment tends to a feeling of psychological
gers of the spiritual challenge when patients are asking empowerment as patients feel it allows them to cope better
Why me? with their illness. So, while the reasons for seeking out
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Walter and Millers Textbook of Radiotherapy
complementary therapies are highly individual and may Emotions such as anger, resentment, frustration and grief
not be based on the same philosophical approach shared are often displayed by patients and their families, and
by many clinicians, they surely have to be regarded as per- communication skills training is particularly helpful and,
sonally valid for patients. Thus, the aims for heath profes- indeed, desirable to help improve the situation for all
sionals should first be to encourage disclosure by patients concerned. It is also important to challenge unrealistic
if they are using complementary therapies, and then to expectations of professional achievability. Often health
try to provide high quality information and opportunity professionals believe their task is to help people get better,
for discussion that empowers patients to make their own however, in cancer care, it has to be accepted that this is
decisions. not always possible. The juxtaposition between benefits
and toxicities of treatment and concerns on the impact of
quality of life for the patient and their close families can
be issues of great concern and stress for staff which can
THE IMPACT ON STAFF result in significant emotional costs to those who feel
unsupported in trying to meet these clinical demands.
In cancer care, the main focus is justifiably on the needs of Recognition and understanding of the emotional
the patient and their families and friends. However, it is issues of health professionals working in cancer care is
important to bear in mind that such care does not exist therefore important to help reduce the likelihood of
in a vacuum and can pose particular burdens for the health stress. Attention must be paid to providing appropriate
professionals involved. How we react to the pressures of training in communication and coping strategies. In
caring is dependent on a multiplicity of factors but mainly addition, multiprofessional team working should also
our interpersonal resources, skills and life experiences. aim to provide a supportive atmosphere and opportunity
Indeed, many of the influencing factors that patients bring to allow staff to share their feelings and perceived diffi-
to coping with a diagnosis of a life-threatening illness culties in dealing with particular patient cases or situa-
(see Figure 34.1) also hold true for all of us in terms of tions which may present them with complex situations.
our attitudes and beliefs and coping mechanisms as indivi- This would allow them to draw on the expertise and sup-
duals, as well as our training, skills, knowledge and experi- port of others and negate any feelings of isolation and
ence as healthcare professionals. despondency.
While this has historically been a rather neglected area, Finally, it must be acknowledged that if health profes-
the issue of supporting the needs of those working with sionals are to work effectively with patients and families
cancer patients is becoming more widely acknowledged in cancer care, the emotional costs to them must be recog-
within medicine and psycho-oncology and the levels and nized, and not simply dismissed under the umbrella term
types of stress experienced by oncologists and other health of staff stress. Appropriate support mechanisms must be
professionals is becoming a growing area of interest and established to allow individuals to continue to offer high
research. quality supportive care without this coming at the cost of
There are particular different types of strategies for cop- staff stress and burn-out. In short, if we are to be able to
ing which can be aimed at dealing with preparing staff care for our patients, we must also and perhaps first, be
for many of the intense emotions they will be faced with. able to care for ourselves.
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2003;67:21320. oncology. 3rd ed. John Wiley & the spiritual needs of people
[9] Zabora J, BrintzenhofeSzock K, Sons; 1999. dying of lung cancer or heart
Curbow B, et al. The prevalence [11] Department of Health. The NHS failure: a prospective qualitative
of psychological distress by cancer cancer plan. HMSO; 2000. interview study of patients and
site. Psychooncology [12] Department of Health. The NHS their carers. Palliat Med
2001;10:1928. plan. HMSO; 2000. 2004;18:3945.
609
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Chapter | 35 |
Medical complications of malignant disease
Robert Coleman
612
Chapter | 35 | Medical complications of malignant disease
hypoalbuminaemia or portal hypertension. Ascites is most situation worse, and tubular damage to the kidney, as com-
commonly caused by advanced carcinomas of the ovary, monly occurs in multiple myeloma, may also be important.
gastrointestinal tract, breast and pancreas. Patients present Hypercalcaemia causes many symptoms, including leth-
with abdominal distension which becomes progressively argy, nausea, thirst, constipation and drowsiness. Because
uncomfortable, limits food intake and splints the dia- the symptoms are non-specific and commonly encoun-
phragm, making breathing difficult. Diagnosis is by clinical tered in many patients with advanced cancer, the diagnosis
examination and is confirmed by ultrasound and aspira- can be easily missed. As a result, a high index of suspicion is
tion cytology. required. Often, however, the diagnosis is identified by
Treatment by tube drainage (paracentesis) and ultrasound- routine biochemical testing which usually includes mea-
guided catheter insertion, or at least marking of a safe surement of serum calcium. The level of serum calcium that
and appropriate position to insert the drain, is generally causes symptoms varies from one patient to another and
recommended to reduce the risk of bowel perforation. according to the speed of onset. Patients are better able
Drainage of the fluid should be performed relatively to tolerate slowly developing hypercalcaemia than a sud-
slowly, generally not exceeding a rate of 500 ml/hour. den rise. However, most patients will have symptoms when
Drainage to dryness of ascites is not realistic and therefore the serum calcium exceeds 3.0 mmol/L.
sclerosants are much less effective for ascites than for pleu- Appropriate treatment will rapidly improve the patients
ral effusions. Diuretics are commonly prescribed to prevent condition and relieve the unpleasant symptoms. This can
reaccumulation, but are rarely effective in relieving estab- be reliably achieved without side effects by rehydration
lished ascites. Intraperitoneal radioactive colloids or che- of the patient and inhibition of bone breakdown by one
motherapy are sometimes of benefit and agents such as of the class of drugs called bisphosphonates. Rehydration
thiotepa, mitoxantrone (mitozantrone) and carboplatin should be with normal saline and will typically require
have all been used with some success. For recurrent ascites, 36 litres over 2448 hours. Rehydration reduces the
surgical procedures should be considered if medical treat- serum calcium somewhat and relieves many of the symp-
ments have failed to control the underlying disease. A peri- toms, but is rarely sufficient treatment and the benefits
toneovenous shunt can be inserted, which drains the fluid are usually short lived over a matter of a few days. A single,
through a one-way valve into the venous system. Interest- short infusion of one of the potent bisphosphonates that
ingly, despite drainage of large numbers of malignant cells are now available will restore the serum calcium to normal
into the circulation, metastatic disease in the lungs and in around 90% of patients with a duration of action of
other sites do not appear to be more common. around 34 weeks. Zoledronic acid is the most commonly
The most effective method of controlling ascites though is used agent and has the highest probability of success, but
treatment of the underlying malignancy. Ascites can be abol- pamidronate, ibandronate and clodronate are also effective
ished often in ovarian cancer as response rates are high but in the majority of cases. Repeated infusions are usually
may be more difficult to control in gastrointestinal tumours required every 34 weeks unless successful systemic ther-
as response rates to chemotherapy are comparatively low. apy can be instituted. For this reason, patients should be
closely monitored every few weeks following a diagnosis
of hypercalcaemia. Recurrent hypercalcaemia despite regu-
lar bisphosphonates has a very poor prognosis and may be
METABOLIC AND ENDOCRINE a terminal event.
MANIFESTATIONS OF MALIGNANCY
Inappropriate secretion of
Hypercalcaemia antidiuretic hormone (ADH)
Hypercalcaemia is a complication in around 5% of patients
This syndrome results in retention of fluid by the kidney and
with advanced malignancy, and is particularly common in
is characterized by a low serum sodium. This causes weak-
patients with carcinomas of the breast, lung and multiple
ness and confusion, occurring most commonly in patients
myeloma. Three mechanisms are involved. First, metastatic
with small cell lung cancer. Treatment is by fluid restriction,
cancer cells in bone stimulate osteoclasts, the normal bone
drugs such as demeclocycline which inhibit the action of
cells which resorb (break down) bone, to destroy bone faster
ADH, and chemotherapy for the underlying malignancy.
than the osteoblasts, the normal bone cells which build
bone, can repair the damage. Secondly, the tumour may
secrete proteins, such as parathyroid hormone related pro- Other endocrine manifestations
tein (PTHrP) into the circulation, which have similar
destructive effects on bone but also promote the kidney to
of malignancy
reabsorb more calcium from the urine than is appropriate. Many cancers produce hormones and peptides with bi-
Finally, dehydration, which occurs due to the diuretic effect ological activity. These include adrenocorticotrophic
of an increased calcium load on the kidney, makes the hormone (ACTH), which may result in the features of
613
Walter and Millers Textbook of Radiotherapy
Cushings syndrome, hypoglycaemia from production of If patients are infected while neutropenic, urgent admis-
insulin-like substances and gynaecomastia from tumour sion to hospital is usually required, blood and urine cul-
production of human chorionic gonadotrophin (HCG). tures taken and, where clinically indicated, sputum, throat
or wound swabs sent for culture. Treatment with broad-
spectrum intravenous antibiotics should be commenced
Hyperuricaemia and tumour lysis immediately after taking the necessary cultures, as untreated
syndrome septicaemia can be rapidly fatal. The choice of antibiotics
An acute metabolic disturbance may result from the rapid varies according to the clinical situation and individual hos-
destruction of a tumour following chemotherapy. This is pital policy and may change from year to year as directed by
particularly likely to occur in childhood leukaemia and rap- the type of local pathogens and patterns of resistance. In
idly growing lymphomas or germ cell malignancies. As che- some patients, intravenous fluids, inotropic support and
motherapy destroys the cancer, the cells release products of high dependency care may be required. Occasionally, even
nitrogen metabolism, especially urea and urate, plus large in specialist cancer centres and despite efficient and aggres-
amounts of potassium and phosphate into the circulation. sive treatment of infection, patients still die from over-
The high urate concentration may result in urate crystal for- whelming infection following chemotherapy.
mation in the kidneys and lead to acute renal failure. A high
potassium level is the most dangerous component of
tumour lysis syndrome and may cause cardiac dysrhyth-
mias and even sudden death. An increased phosphate level PARANEOPLASTIC SYNDROMES
may complex with calcium and result in tetany. The syn-
drome can be prevented by prescribing allopurinol (or
an intravenous equivalent) to prevent the production of
Neurological
large amounts of urate and intravenous fluids to encourage Cancers, particularly of the bronchus, are associated with a
the kidneys to excrete the products of cell breakdown. Ide- number of neurological syndromes which are unrelated
ally, these interventions should be commenced a day or to direct compression or infiltration of neural tissue. The
two before chemotherapy. mechanisms that give rise to these problems are poorly
understood. They are uncommon, and usually are possible
to diagnose only by excluding the presence of malignant
disease in the central nervous system or around nerve roots.
INFECTION The syndromes include numbness and weakness due to
sensory and motor peripheral neuropathies respectively,
paralysis from spinal cord damage, unsteadiness from
Infections are a major cause of death in cancer. Not only do
cerebellar degeneration, dementia from cerebral damage
they occur frequently, but they are often more severe than
and a form of muscle weakness which resembles myasthe-
in other patients, less responsive to therapy and often
nia gravis. These neurological conditions may be the first
related to organisms which, in normal health, would not
manifestation of cancer. Sadly, treatment for the underly-
cause any problem. The susceptibility of cancer patients
ing cancer frequently fails to produce much neurological
to infection results from suppression of host defence
improvement.
mechanisms produced by the disease and its treatment.
Infections are particularly frequent when the neutrophil
count is suppressed by chemotherapy. Hypertrophic pulmonary
Advanced cancer and the treatments prescribed are asso- osteoarthropathy
ciated with impaired neutrophil and lymphocyte function,
depressed cell-mediated and humoral immunity, and dam- Lung cancer is the principal cause of this condition in which
age to skin and mucous membranes, which allows organ- the bones of the forearms and shins become inflamed and
isms to enter the bloodstream more easily. Escherischia painful. Plain radiographs show characteristic appearances
coli, pseudomonas, staphylococci and streptococci are the and usually the patient has a deformity of the nails known
most frequent bacterial pathogens. Viruses, such as herpes as clubbing. Anti-inflammatory drugs relieve many of the
simplex and herpes zoster (shingles), fungi, particularly symptoms and the condition may improve if the underly-
Candida, and protozoal infection of the lungs with pneu- ing tumour can be removed or destroyed.
mocystis are important non-bacterial causes of infection
requiring specific treatment. Most of the infecting organ-
Other paraneoplastic syndromes
isms come from within the patient, for example gut bacteria
and, providing sensible precautions are taken with regards A variety of general effects of cancer are sometimes
to personal hygiene, infections transmitted from family or described as paraneoplastic phenomena, and almost every
healthcare staff are of relatively minor importance. organ in the body can be affected by one of these
614
Chapter | 35 | Medical complications of malignant disease
syndromes. Fever, cachexia, anaemia, thrombophlebitis renal impairment are uncommon but well-recognized
and clotting disorders are all relatively common and may complications of malignant disease. Each should be treated
be the presenting symptoms of malignancy. In addition, symptomatically while the increased risk of thromboembo-
arthritis, skin rashes, itching, muscle inflammation and lism may warrant prophylactic anticoagulation.
FURTHER READING
Gushchin V, Demmy TL, Kane 3rd guided pericardiocenteses: clinical conference. Clin Infect Dis 2004;39
JM. Surgical management profile, practice patterns, and (Suppl. 1):S16.
of metastatic peritonael or outcomes spanning 21 years. Mayo Gemici C. Tumour lysis syndrome in
pleural disease. Semin Oncol Clin Proc 2002;77:42936. solid tumours. Clin Oncol
2007;34:21525. Becker G. Medical and palliative 2006;18:77380.
Luh SP, Chen CY, Tzao CY. Malignant management of malignant Storstein A, Vedeler CA. Paraneoplastic
pleural effusion treatment outcomes: ascites. Cancer Treat Res neurological syndromes and
pleurodesis via video-assisted thoracic 2007;134:45967. onconeural antibodies: clinical and
surgery (VATS) versus tube Percherstorfer M, Brenner K, Zojer N. immunological aspects. Adv Clin
thoracostomy. J Thorac Cardiovasc Current management strategies for Chem 2007;44:14385.
Surg 2006;54:3326. hypercalcemia. Treat Endocrinol Ellison DH, Berl T. Clinical practice.
Tsang TS, Enriquez-Sarano M, 2003;2:27392. The syndrome of inappropriate
Freeman WK, et al. Consecutive 1127 Picazo JJ. Management of the febrile antidiureses. N Engl J Med
therapeutic echocardiographically neutropenic patient: a consensus 2007;356:206472.
615
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Index
Note: Page numbers followed by b indicate boxes, f indicate figures and t indicate tables.
617
Index
618
Index
619
Index
620
Index
621
Index
622
Index
Cell sequestration, and capillary spinal cord tumours, 553554 medulloblastoma, 545
blockade, 103 vestibular (acoustic) schwannoma, meningioma, 545547
Central Axis (CAX), beam, 166 551552 neurosurgery principles, 535536
Central Index for Dose Information skull base irradiation, 554555 normal tissue tolerance to
(CIDI), 6465 target volume radiotherapy, 536537
Central nervous system (CNS) cerebral metastases, 555 performance status in treatment
anatomy, 532534 chordoma/chondrosarcoma of skull decision, 535
toxicity effects of treatment, in base, 552 pituitary gland, 547549
children, 587588, 595596 craniopharyngioma, 549 primary central nervous system
see also Brain ependymoma, intracranial, 542 lymphoma, 543544
Central nervous system (CNS) germinoma, 544 spinal cord, 553554
radiotherapy meningioma, 546 steroid therapy principles, 537
dose and energy palliative stereotactic radiosurgery, types, 530532
cerebral metastases, 555 555 vestibular (acoustic) schwannoma,
chordoma/chondrosarcoma of skull pituitary tumours, 548 550552
base, 552 primary central nervous system Centre of rotation (COR), SPECT
craniopharyngioma, 550 lymphoma, 543544 imaging, 101
ependymoma, intracranial, 542 spinal cord tumours, 553 Cerebellum, 534
germinoma, 545 vestibular (acoustic) schwannoma, Cerebral metastases, 532, 554555
medulloblastoma, 545 551 Cerebrospinal fluid (CSF), 533534, 544
meningioma, 546 technique Ceric dosimetry, 51
palliative stereotactic radiosurgery, cerebral metastases, 554 Cervical cancer
555 chordoma/chondrosarcoma of skull aetiology, 259, 468469
pituitary tumours, 548 base, 552 CIN1, CIN2 and CIN3, 469
primary central nervous system craniopharyngioma, 549550 clinical trials, 473
lymphoma, 544 ependymoma, intracranial, 542 in endocervical canal, 471f, 474f
spinal cord tumours, 553 germinoma, 544 extending into parametrium, 472f
vestibular (acoustic) schwannoma, meningioma, 546 FIGO staging system, 470472, 470t,
551 palliative stereotactic radiosurgery, 477478
gliomas see under High-grade gliomas 555 investigations, 470472
(HGGs); Low-grade gliomas pituitary tumours, 548 lymphatic drainage of cervix, 469f
(LGGs) primary central nervous system method of spread, 469
palliative lymphoma, 543544 pathology, 469
primary central nervous system spinal cord tumours, 553 patient preference, 296
lymphoma, 544 vestibular (acoustic) schwannoma, screening for, 259, 471f
spinal cord tumours, 553 551 symptoms, 470472
planning principles, 536537 whole brain irradiation, 554 tumour hypoxia, 285
results Central nervous system (CNS) tumours, Cervical cancer treatment, 472477
chordoma/chondrosarcoma of skull 529555 chemoradiotherapy, 476477
base, 552 additional supportive care principles, complications, 477
craniopharyngioma, 550 537 dosimetry, 195
ependymoma, intracranial, 542 brain see Brain tumours future trends, 477
germinoma, 545 cerebral metastases, 554555 intracavity brachytherapy, 474476
meningioma, 547 in children, 595600 postoperative radiotherapy, 473
palliative stereotactic radiosurgery, chordoma/chondrosarcoma of skull stage I disease, 473
555 base, 552 stage II-IVa disease, 472f, 473476,
pituitary tumours, 549 see also Chondrosarcoma; 473f, 474f, 475f, 476f, 477f
primary central nervous system Sarcomas Cervical intraepithelial neoplasia (CIN),
lymphoma, 544 craniopharyngioma, 549550 259
spinal cord tumours, 553 diagnosis, 535 Cesium-137, 191
vestibular (acoustic) schwannoma, driving following CNS tumour Cetuximab, 314, 407
552 diagnosis, 537538 CEV (retinoblastoma chemotherapy
side effects ependymoma, intracranial, 542 regime), 566
cerebral metastases, 555 see also Ependymoma Chambers
craniopharyngioma, 550 germinoma, 544545 ionizing see Ionization chambers
meningioma, 546547 gliomas see Gliomas monitor, 35, 4243
pituitary tumours, 548549 management principles, 535538 Chamber stem effect, 45
623
Index
624
Index
625
Index
Computing, in radiotherapy, 201209 Core biopsy, 391, 434 Cytarabine (Ara C), acute myeloid
benefits and hazards of Cornea, 559560 leukaemia, 527
computerization, 202 Cornwall, radon gas, 62 Cytochrome P450 family, 313
bit depth of image, 207 Coronary artery disease, 274 Cytosine arabinoside (Ara-C), 309, 527,
colour of image, 207 Coulomb (electrostatic) force 588
compression, image quality, 207 charged and uncharged particles, 15 Cytotoxic therapy
costs and benefits, 201 electromagnetic force, 45 alkylating agents, 305
curves, annotations and overlays, 208 nuclear structure, 68 antimetabolites, 305309
data burden, 208, 209t and strong force, 8f drawbacks, 301302
data security, 208209 Coulomb field drug classification, 305315
data storage, 206207 pair-production, 18f, 26, 26f, 27 drug resistance, 303304
dimensions and scale of image, 207 x-ray production, 19 enzymes, 312
history, 202 Cowdens syndrome, 386, 433 high-dose chemotherapy, 304
image quality, 207 COX-2 enzyme, 255 hormones see Hormones
lifetime of equipment, 201202 Craniopharyngioma, 549550, 599 mitotic inhibitors, 309310
Moores law, 201 Craniospinal radiotherapy (CSRT), 589, non-anthracycline antibiotics, 312
networking, 202203, 204206, 204f, 598599 platinum analogues, 311312
205f Critical examinations, radiation levels, principles, 303304
quality control, 219 7475 selection and scheduling of
radiotherapy data types, 207, 208 Cross-sectional imaging, 107, 343 chemotherapy agents, 304
reliability issues, 202 Crude incidence rate, 251 targeted therapies, 314
RT dose, 208 Crude survival rate, 251 topoisomerase inhibitors, 310311
RT image, 208 Cryosurgery, with liquid nitrogen, 323 see also Chemotherapy
RT plan, 208 Cryotherapy, 565566
RT structure sets, 208 Csda range, 1617 D
RT treatment summary, 208 CTD (myeloma chemotherapy regime),
software development, 209210 518, 527 Dacarbazine, 335, 428
tomographic imaging, 207 Cure, cancer, 251252 Hodgkins lymphoma, 526, 590
Concurrent chemotherapy and chance of, 296297 Damage, radiotherapy see Radiotherapy
radiotherapy (chemo-rt) Curettage and electrolysis, non- effects
bladder cancer, 491, 492493 melanoma skin cancer, 323, 324f Data, radiotherapy
head and neck cancer, 351352 Cushings syndrome, 418, 547 archiving, 209
rectal cancer, 411 Customer focus, quality management backing up, 208209
see also Chemoradiation/ systems, 225 burden of, 208, 209t
chemoradiotherapy Cyclophosphamide, 261, 304 data element, 205
Cone beam imaging, 86, 142 breast cancer, 442443, 455, 458, 462 data objects, 205206
Cone biopsy, cervical cancer, 473 chemotherapy/radiotherapy image quality, 207
Conformal radiotherapy (3DCRT) interactions, 588 security, 208209
cervical cancer, 477 chronic lymphocytic leukaemia, 520 storage, 206207
CNS tumours, 536 Hodgkins lymphoma, 526 types, 207, 208
craniopharyngioma, 549550 leukaemia, 590 Daunorubicin, 311, 527
head and neck cancer, 347, 349350 mesothelioma, 428 Dead time, 5455
high-grade gliomas, 539 multiple myeloma, 518, 527 Debulking surgery, ovarian cancer, 480
pancreatic cancer, 406, 407 neuroblastoma, 591 Decay
Conjunctiva, 558 non-Hodgkins lymphoma, 515516, alpha, 910
Conjunctival lymphoma, 563f 526 beta, 1011
Conjunctival melanoma, 564f resistance to, 439 and brachytherapy, 191
Consent to treatment, 606607 CYP171A, 313 decay series and radioactive
Consistency check devices, ionization Cyproterone, 313 equilibrium, 11, 12f
chambers, 11 Cystadenocarcinoma, pancreatic cancer, exponential, 9
Contamination monitoring, 74, 119 405 and radioactive equilibrium, 11
Contouring devices, non-CT, 149150 Cystadenoma, pancreatic cancer, 405 Decay constant, 9
Contours, patient, 161162 Cystectomy, bladder cancer, 491 Decision making, quality management
contour effects, electron therapy, 179 Cystoscopy, bladder cancer, 489 systems, 226
Contrast agents, 92 Cystourethrectomy, urethra, 506 Dedicated radiotherapy systems, 87
Contrast media, x-rays, 80 Cystourethroscopy, bladder cancer, 490, Dehydration, 604
Control systems, megavoltage linear 491t Delivery, radiotherapy process, 217
accelerator machines, 131, 132f Cysts, ultrasound imaging, 94 Dentition, 344
626
Index
Deoxyribonucleic acid see DNA Digital radiography, 8284 and dose rate, 42
(deoxyribonucleic acid) Dihydrocodeine, 299 film dosimetry, 4546
Deoxyuridine monophosphate (dUMP), Dihydrofolate reductase, 305 free air chamber, 38
308 Dihydrofolic acid, 305 impurity bands, 47
Department of Environment, 69, 74 Diode detectors, 4748 intercomparisons, transfer of
Department of Health, Reference Guide Direct carcinogens, 271 calibration, 36f, 43
(consent), 606 Direct readout dosimeters, 7273 international standards, 35
Depression, 299, 300 Disease-free survival, 251 MOS-FET detectors, 4849
Depth dose tables, 419 Disposal and movement logs, radiation national standards, 35, 36f
Depth of field concept, head and neck records, 74 radiochromic film, 46
cancer, 347348 DNA (deoxyribonucleic acid) secondary standard instrument, 35
Dermatofibrosarcoma protuberans, 337f gene profiling, 439 semiconductor detectors, 47
Dermis, 290 and ionizing radiation, 280281 standard calorimeter, 3638
Descriptive epidemiology, 250, 251 and platinum analogues, 311 strontium consistency check device,
Detectors repair 4344
chemical and biochemical, 51 and cell signalling, 283284 thermoluminescent dosimetry, 4951
diamond, 49 defective or failed, 269270 traceability, 3536 see also Dosimetry;
diode, 4748 and topoisomerase inhibitors, 310 Ionization chambers
MOS-FET, 4849 DNA double-strand break (DSB), 281, Dose response curve, 4546
other radiation, 5356 283284 Dose statistics, 171, 172t
semiconductor, 4951 DNA-PK, 283284 Dose surface histograms, 171
Deterministic effects, radiation, 61 Docetaxel, 310 Dose surface map, 172f
Developed countries, cancer in, 250 breast cancer, 462463 Dose volume histograms (DVH)
Dexamethasone head and neck cancer, 352 calculation requirements/methods,
CNS tumours, 537 non-small cell lung cancer, 422 170171
high-grade gliomas, 540 stomach cancer, 403 clinical use/limitations, 171
multiple myeloma, 518, 527 Documentation, software development, evaluation tools, 169171
Diabetes, pancreatic cancer, 405 210 see also Record-keeping expression of, 169
1, 2diaminocylohexane (DACH), 311312 Doping process, semiconductor uses of, 169
Diamond detectors, 49 detectors, 47 Dose-volume histograms (DVHs), 548
Diamorphine, 299 Doppler effect, ultrasound imaging, 94 Dose wall histograms, 171
Diarrhoea, management of, 604 Dose Dosimeters
Diazepam, 299 absorbed, 34, 35 direct readout, 7273
Diclofenac, 299 algorithms for calculation, 166167 film badge, 73
Dicom (Digital Imaging and biologically effective, 289 optically stimulated luminescent, 74
Communication in Medicine) checking, 184 personal radiation, 7274
standard effective, 6162 thermoluminescent, 7374
communication, 205 electron therapy, 178179 Dosimetry
conformance statement, 206 equivalent, 61 alanine-EPR, 5253
data objects, 205206 limits, 6465 biological, 53
as data transfer protocol, 204205 measurement see Dose measurement brachytherapy, 195196
history, 202 pencil beam models, 166, 167f ceric, 51
services, 205 percentage depth-dose (PDD), 27 chemical, 35
Dietary influences on cancer, 263265 radiotherapy data types, 208 and computed tomography, 162
breast cancer, 434 standards, 35, 3738 Fricke, 51
head and neck cancer, 260, 343344 stored beam data models, 166, 167f gel, 5152
stomach cancer, 257258 thresholds, for biological effects, 61t gynaecological treatments, 195196
Differentiation, cellular, 268, 295 and units of kerma, 35 implant types, 196
Diffuse large B cell lymphoma (DLBCL), x-ray imaging, 85 see also under specific for iridium wire, 195
513, 514 cancers specific conditions, breast cancer,
in children, 591 Dose area product (DAP) readings, 67 446
treatment, 516, 522, 526527 Dose measurement thermoluminescent, 35, 40, 4951
Diffusion, 103 alternative systems, 4551 total body irradiation, 590
Digitally reconstructed radiographs band theory of solids, 4647 in-vivo dosimeters, 35, 48 see also Dose
(DRR) charged-particle equilibrium, 3839 measurement; Ionization
radiation treatment planning, 146, determination based on calibrated chambers
152, 153 instruments, 3940 Doubling time, 275, 291
tomographic imaging, 87 diamond detectors, 49 Downs syndrome, 519
627
Index
Doxorubicin, 311 Elective nodal irradiation, non-small cell breast cancer, 448
breast cancer, 454, 455456, 462 lung cancer, 419 eye and orbit, affecting, 561562
chemotherapy/radiotherapy Electrical hazards, 75 mesothelioma, 426
interactions, 588 Electrocardiogram (ECG), R-wave, 100, standoff and stand in, 179
endometrial cancer, 479 108109 total skin electron irradiation, 181
Ewings sarcoma, 579580 Electromagnetic force, 45 Electrostatic (Coulomb) force
hepatocellular carcinoma, 404 Electromagnetic spectrum, 5, 5f see Coulomb (electrostatic)
Hodgkins lymphoma, 526 Electromagnetic waves, 5 force
mesothelioma, 428 Electron backscatter, keratinocyte skin Elkind repair, 283
non-Hodgkins lymphoma, 526 tumours, 327328, 328f Embolization, kidney cancer, 488
sarcomas of uterus, 479 Electron beam Emotional adjustment, 604605
soft tissue sarcomas, 575 keratinocyte skin tumours, 327, 327f Employers, liability for radiation
Drinking see Alcohol consumption megavoltage linear accelerator exposure, 6768
Driver and Vehicle Licensing Authority machines, 130131 Endemic goitre, 386
(DVLA), 537538 development, 125 Endocrine deficiencies, resulting from
Drug resistance, 303304 general layout and components, treatment in children, 588
Dry eye, 559, 560 127 Endocrine failure, irradiation of pituitary
DTIC (dimethyl triazeno imidazol Electron beam machines, intraoperative, and thyroid glands, 361
carboxamide), 335 140 Endocrine therapy, breast cancer,
Dual and Quad merge techniques, Electron capture (EC), 11 438439
simulation, 151 Electronic portal imaging device (EPID), Endometrial cancer, 477479
Ductal carcinoma-in-situ (DCIS), 434, 87, 156 brachytherapy, 479
437439 Electron interactions clinical trials, 478, 479
Dukes staging system, colon cancer, 408 beam hardening, 2021 future trends, 479
Dura, meninges, 534 collisional and radiactive pathological examination of excised
Dutch PORTEC trial, endometrial (bremsstrahlung) energy loss, tissue, 296
cancer, 478, 479 1718 pathology, 477
Dynamic treatment techniques, range and path-length, 1617 postoperative radiotherapy, 478479
megavoltage beams, 166 stopping power and linear energy progestogens for, 313314
Dysgerminomas, 482 transfer (LET), 1819 radiotherapy, 478479
Dysphagia x-ray production, 1920 results of treatment, 479
hypopharyngeal cancer, 383 see also Photon interactions routes of spread, 477478
oesophageal cancer, 398 Electron microscopy, 277 staging, 478t
oesophageal stenting for, 401 Electron paramagnetic resonance (EPR), treatment, 478479
thyroid cancer, 386 52 Endoscopic biliary stenting, pancreatic
Dysplasia, 272 Electrons cancer, 407
Dyspnoea, 299, 418 ionizing radiation, 280281 Endoscopic resection (TURBT), bladder
Dysthyroid eye disease mass, 3 cancer, 491
clinical features, 560 special techniques, 180181 Endoscopic retrograde
pathology, 558, 560 see also Electron shells; Electron cholangiopancreatography
radiotherapy, 560561 spin resonance (ESR); Electron (ERCP), pancreatic cancer, 406
therapy Endoscopic ultrasound (EUS)
Electron shells oesophageal cancer, 398399, 400
E
and binding energy, 6, 7t rectal cancer, 411
Early Breast Cancer Trialists Group, 442 electromagnetic force, 5 Endoscopic ultrasound-guided fine
EBV see Epstein-Barr virus (EBV) energy differences, 6 needle aspiration (EUS FNA),
ECG see Electrocardiogram (ECG) Electron spin resonance (ESR), 52 pancreatic cancer, 406
Echo time (TE), 89 Electron therapy, 178180 Endoscopic ultrasound probes, 95
Effective attenuation coefficient, 28 arcing electron treatment, 180181 Endoscopic mucosal resection (EMR),
Effusions, 611613 compared to kilovoltage therapy, 400
Elastography, 94 181182 Endoscopy, 256
Elderly patients energy and depth dose characteristics, Endoscopy, upper GI, oesophageal
co-morbid conditions, 296 178179 cancer, 398
multiple myeloma treatment, 518 field matching, 180 Energy absorption/energy absorption
osteosarcoma (osteogenic sarcoma), heterogeneities, 179180 coefficients, 2324
576 patient contour effects, 179 ultrasound imaging, 93
skin cancers, 319 penumbra, 179 Energy loss, collisional and radiactive
vulval cancer, 483 specific conditions (bremsstrahlung), 1718
628
Index
ENT clinic referrals, hypopharyngeal Erythroplakia, head and neck cancer, Extended focus skin distance (FSD)
cancer, 381 342, 343 plans, megavoltage beams, 164
Enucleation, 566 Escherischia coli, 614 External beam radiotherapy (EBRT), 279
Environmental tobacco smoke (ETS), Esophagogastric junctional tumours, 401 anal cancer, 414
254 Essential thrombocythemia (ET), 520 breast, 145
Enzymes, 312 Ethmoidectomy, 366367 breast cancer, 449
Ependymoma Ethmoid sinus, 365 cervical cancer, 473474
in children, 597 tumours, 366367 eye and orbit, 558
intracranial, 542, 554 Etidronate (hydroxyl ethylidine goal of radiation treatment planning,
spinal cord tumours, 554 diphosphonate), 116 160
Epidemiology of cancer, 250251 Etoposide, 261, 311 hepatocellular carcinoma, 404
anal cancer, 412 Ewings sarcoma, 579580 low dose radiation, 392393
bladder cancer, 489 germ cell tumours, 482 oesophageal cancer, 176, 399, 400
breast cancer, 432433 Hodgkins lymphoma, 526 palliative high dose, 392
causality criteria, 252 medulloblastoma/PNET, 597598 pancreatic cancer, 406407
colon cancer, 407 neuroblastoma, 591 prostate cancer, 200
lymphoma, 512 non-Hodgkins lymphoma, 527 soft tissue sarcomas, 573
oesophageal cancer, 396 retinoblastoma, 566 thyroid cancer, 389, 392393
pancreatic cancer, 405 rhabdomyosarcoma, 593 tongue and mouth tumours, 199
and prevention, 252 sex-cord tumours, 482 Eye and orbit
stomach cancer, 401 testicular cancer, 506 anatomy, 557558
terminology, 250251 Europe, cancer in, 250 aniridia (congenital absence of iris),
Epidermal Growth Factor Receptor European Association of Nuclear 591
(EGFR), 284, 314 Medicine (EANM) benign disease, 558, 560561
Epidermal growth factor receptor bone pain palliation, 116 malignant disease, 558
(EGFR), 270 iodine-131 miBG therapy, for movement of eye, 557558
colon cancer, 410 neuroendocrine disease, 116 and NHL radiotherapy treatment, 523
head and neck cancer, 352 iodine-131 use, thyroid disease, 114 pathology, 558
Epidermal growth factor receptor/ phosphorus-32, for refractory primary malignant tumours
vascular endothelial growth myeloproliferative disease, 115 arising from adjacent structures, 562
factor (EGFR/VEGF), European Ewings Tumour Working lymphoma, 562563
oesophageal cancer, 400 Initiative of National Groups melanoma, 563565, 563f, 564f
Epigenetic radiation signalling (Euro-EWING 99), 594 metastasis, 566568
mechanisms, 284285 European High-Risk NB protocol, 591 retinoblastoma, 565566
Epileptic seizure, in brain tumours, 534 European Organisation for Research and skin and adnexia, 561562
Epipodophyllotoxins, 310 Treatment of Cancer (EORTC), radiotherapy
Epirubicin, 311 442443 irradiation principles, 560
breast cancer, 454, 455456, 458, 463 European Osteosarcoma Intergroup metastasis, 567568
non-Hodgkins lymphoma, 527 (EOI), 595 ocular lymphoma, 563
rhabdomyosarcoma, 593 European Prospective Investigation into radiation and ocular morbidity,
stomach cancer, 403 Cancer and Nutrition (EPIC), 558, 559560
Eppendorf electrodes, 285 254, 407 retinoblastoma, 565566
Epstein-Barr virus (EBV) European Society for Therapeutic technique and dose, 561562
antibodies, 360 Radiotherapy and Oncology, 203 Eye shielding, 124125, 330f
head and neck cancers, 260, 265, 342 Event counters, 53
lymphoma risk, 261, 271, 512 Ewings sarcoma, 570, 579580
nasopharyngeal cancer link, 342, 360 in children, 587, 594595 F
Equilibrium soft tissue, 594
charged-particle, 2728, 3839 Examination under anaesthesia (EUA) Familial adenomatous polyposis (FAP),
and decay series, 11 cervical cancer, 470472 272
thermal, returning to, 8889 oropharyngeal cancer, 373 colon cancer, 408
Equilibrium radionuclide rhabdomyosarcoma, 594 pancreatic cancer, 405
ventriculography, 108 Excitation and ionization (collision thyroid cancer, 386
Equipment checks, radiation, 74 processes), 16, 25, 34 Family history, 270 see also Hereditary
Erbitux (cetuximab), 314 Exeter overdose, 212 factors
Erlotinib, 314 Experimental epidemiology, 250, 251 Fanconis anaemia, 519
pancreatic cancer, 407 Exponential attenuation, 2122 Farmer chamber, 45, 48f
Erythema, 289290 Exponential decay, 9 Fat, as breast cancer risk factor, 434
629
Index
630
Index
pitch and roll movement, 139, 140f Genetic structures, biological dosimetry, oesophageal cancer, 400
radioisotope source, 137f, 138 53 rectal cancer, 412
rotating gantry, 139 Geometry soft tissue sarcomas, 574
swabs, 138 broad-beam, 2324 Ground state, 6, 16
Gamma rays narrow-beam, 21 Growth disorders, 268, 524, 587
in brachytherapy, 189 transverse imaging, 207 Growth fraction, 291
see also Brachytherapy Germ cell tumours (GCT) Gullet, cancer of see Oesophageal cancer
decay process, 137 in children, 599 Gynaecological cancer, 467483
definitions, 98 intracranial, 599 anatomy of female reproductive
energy, 137 ovarian cancer, 482 organs, 467
imaging, 98 testicular cancer, 501 brachytherapy
Gamma spectroscopy, 55 Germinoma, 544545, 599 afterloading machines, 197
Gamma units, stereotactic radiotherapy/ Gestational choriocarcinoma, dosimetry, 195196
radiosurgery, 182 spontaneous regression, 276 manual loading and afterloading,
Gantry, tomographic imaging, 86 Glandular (secretory) epithelium, 277 196
Gardners syndrome, 386, 570 Gleason grading system, prostate cancer, cervical cancer see Cervical cancer
Gas amplification devices, 5355 494, 496, 499 incidence rate, 467468
Gastrectomy, palliative, 402 Glioblastomas (GBM), 297298, 531, ovarian cancer see Ovarian cancer
Gastric cancer see Stomach cancer 531f, 538, 554 see also High-grade uterus, sarcomas of, 479
Gastric epithelium, cell proliferation in, gliomas (HGGs) vaginal, 482483
258 Gliomas, 92 vulval, 295, 482483
Gastritis, 258 brainstem, 597 Gyromagnetic ratio, 87
Gastrointestinal cancer see Colon cancer; heterogeneous nature, 535
Hepatocellular carcinoma; high-grade see High-grade gliomas H
Oesophageal cancer; Pancreatic (HGGs)
cancer; Rectal cancer; Stomach low-grade see Low-grade gliomas Hadron/hadron therapy, 68
cancer (LGGs) Half-life
Gastrointestinal reflux disease (GERD), male to female ratio, 531532 and brachytherapy, 190191
397 origins of, 531 exponential decay, 9
Gastrointestinal stromal tumours performance status in treatment radiopharmaceuticals, 102, 113114
(GISTS), 401, 415 decision, 535 Half-value layer (HVL)
Gastroscopy, 258, 401402 WHO classification, 531 brachytherapy, 194
Gated imaging Globe, orbit, 557 orthovoltage machine, 124
computed tomography, 87 Glomerular filtration rate (GFR), 109 x-rays, 22
gated blood pool imaging, heart, 108 Glottic cancers, treatment, 378379 Haloperidol, 299300
MUGA (multiple gated acquisition), GLUT1 and GLUT3 (membrane Hand-foot syndrome, 489
108109 transport proteins), 110 Hands, radiation damage, 76
Gaussian distribution, 214 Gompertzian growth curve, 303 Handshake, Dicom communication,
Gefitinib, 314 Gonadotrophin-releasing hormone 205
Geiger counters, 5455, 72 (GnRH) analogues, 313 Hashimotos thyroiditis, 386, 391
Gel dosimetry, 5152 Gorlins syndrome (basal cell naevus Head and neck cancer, 341354
Gemcitabine, 309 syndrome), 319, 531532 aetiology, 260, 342
cervical cancer, 477 Goserelin, 313, 454, 460 demographics, 342
head and neck cancer, 352 Granisetron, 299300, 604 dentition, 344
hepatocellular carcinoma, 404 Granulocyte colony-stimulating factor description, 341342
non-small cell lung cancer, 422 (GCSF), 463, 505, 595 dietary factors, 343344
pancreatic cancer, 407 Granulosa cell tumours, 482 diffuse large B cell lymphoma, 514
Gender differences, cancer types, 250 Graphite use, calorimetry, 3638 see also Diffuse large B cell
effects of radiotherapy in children, Graves disease, 561f lymphoma (DLBCL)
588 Grawitzs tumour, 486 early diagnosis, 342
gliomas, 531532 Gray (Gy), dose quantity, 61 Epstein-Barr virus link, 260, 265, 342
head and neck cancers, 342 Grey matter, brain, 532 incidence rate, 341342
lung cancer, 417 Gross tumour volume (GTV), 149 indications for radiotherapy, 344
oesophageal cancer, 396 brainstem glioma, 597 investigation, 343
Gene expression arrays, 292 CNS tumours, 536, 541, 542, 546 molecular oncology, future
Gene profiling, ductal carcinoma-in-situ, Ewings sarcoma see also Clinical target developments, 354
439, 440f volume (CTV) presentation, 343
Genetic defects see Hereditary factors head and neck cancer, 345, 346, 347 prevention, 342
631
Index
Head and neck cancer (Continued) pathological fracture, 583 Histology, 275, 295
radiation-induced cell death, 286287 Hemilaryngectomy, laryngeal cancer, breast cancer, 434435, 436
soft tissue sarcomas, 575 378 HIV/AIDS
treatment see Head and neck cancer Hemopoietic stem cell transplantation cervical cancer, 468469
treatment (HSCT), 512, 521 immune surveillance, 272
tumour types, 343 see also Brain treatment, 516, 518, 520 Kaposis sarcoma, 337, 338f
tumours; Floor of mouth cancer; Hepatectomy, 404 lymphoma treatment, 517
Hypopharyngeal cancer; Hepatitis B, 263 non-Hodgkins lymphoma risk, 261
Laryngeal cancer; Lip cancer; Hepatocellular carcinoma, 404 Hoarseness
Nasopharyngeal cancer; Neck HER2 see Human Epidermal Growth laryngeal cancer, 376378
tumours; Nose and nasal cavity Factor Receptor 2 (HER2) oesophageal cancer, 399
cancer; Oral cavity cancer; Herceptin see Trastuzumab (Herceptin) Hodgkins lymphoma (HL)
Oropharyngeal cancer; Paranasal Hereditary factors aetiology, 260
sinus tumours; Thyroid cancer bladder cancer, 489 paediatric oncology, 590
Head and neck cancer treatment, breast cancer, 433 pathological characteristics, 512513
341342 carcinogenesis, 269270 prognosis, 515
chemotherapy, 298, 351352 colon cancer, 408 and viruses, 271 see also Lymphoma;
CT simulation procedure, 154 gastrointestinal stromal tumours, 415 Non-Hodgkins lymphoma
image guided radiotherapy, 347, 350 gliomas, 531532 (NHL)
and non-Hodgkins lymphoma, 523 medullary thyroid cancer, 391 Hodgkins lymphoma treatment
patient immobilization, 145 pancreatic cancer, 405 ABVD regime, 526
radiotherapy stomach cancer, 401 BEACOPP regime, 526
conformal, 347, 349350 Hereditary non-polyposis colorectal chemotherapy, 515, 526
definitive, 344, 345, 347f, 350352 cancer (HNPCC), 270, 401, 408 ChlVPP regime, 526, 590
dose, 350351 Herpes, 614 etoposide, 311
fractionation, 350351 HGGs see High-grade gliomas (HGGs) generally, 515
image guided, 347, 350 High Activity Sealed Radioactive Sources mantle radiotherapy, 434, 590
indications for nodal irradiation by and Orphan Sources Regulations radiotherapy, 434, 521
tumour site, 346t 2005, 69 Stanford V, 526 see also Non-
palliative, 344 High Activity Sealed Sources (HASS), Hodgkins lymphoma treatment
pitfalls (IMRT), 350 69 Homologous recombination repair
planning, 345 High dose rate (HDR), 217 (HRR), 283
postoperative, 344, 345347, 351, brachytherapy, 197, 200, 449 Hooded anode, orthovoltage machine,
352 High-grade gliomas (HGGs), 538540 123124, 124f
radical, 343344 in children, 597 Hormonal sensitivity, bladder cancer,
scope of (IMRT), 349350 clinical features, 538 494
target volume, 345347, 347f deterioration during radiotherapy, Hormone receptor status, bone
technique, 347350 540 metastases, breast cancer,
toxicity, 352354 neurosurgery principles, 535536 460461
surgery, cosmetic and functional pathology, 538 Hormone replacement therapy (HRT),
considerations, 295 radical treatment, 539540 256
Head shells, patient immobilization, radiotherapy, 540 and breast cancer, 433
146147, 586587 deterioration during, 540 and endometrial cancer, 477
Health and Safety Executive (HSE) dose and energy, 539, 540 Hormones
clinical incidents, 239 palliative, 540 carcinogenesis, 271
contamination checks, 74 results, 540 female, 313314
dose limits, 6465 side effects, 539540 thyroid stimulating, 387, 388, 389,
local rules, radiation protection target volume, 539, 540 393394
advisors and supervisors, 6667 technique, 539, 540 see also Gliomas Hormone therapy, 302
personal radiation dosimeters, 72 High intensity focused ultrasound antiandrogens, 313
Healthcare Commission, clinical (HIFU), 92 antioestrogens, 312
incidents, 239 Highly active antiretroviral treatment aromatase inhibitors, 312313
Heart, radionuclide imaging, 100, (HAART), 337, 517 breast cancer, locally advanced, 458
108109 High tension (HT) polarizing voltage, 38 endometrial cancer, 479
Helicobacter pylori, 258, 261, 512 High voltage circuits, orthovoltage gonadotrophin-releasing hormone
Hematuria, kidney cancer, 487 machines, 122123 analogues, 313
Hemibody radiotherapy Hiroshima, atomic attack on, 61, 64, prostate cancer, 499
multiple myeloma treatment, 525 265, 434 Horners syndrome, 418
632
Index
633
Index
634
Index
635
Index
L Left ventricular ejection fraction (LVEF), head and neck cancer, 342, 343
108109 oral cavity cancer, 371
Lacrimal glands, 537, 558, 559560, 562 Legislative requirements (radiation), Leukoscan, technetium-99m labelled,
Lactate dehydrogenase (LDH) 6369 109
Ewings sarcoma, 579 Administration of Radioactive Lexidronam (ethylene diamine
testicular cancer tumour marker, Substances Advisory Committee, tetramethylene phosphonate),
501502 69 116
Lactation, and breast cancer, 433 High Activity Sealed Radioactive LGGs (low-grade gliomas), 540542
Laparoscopy, 401402, 406 Sources and Orphan Sources Lhermittes sign, 421, 587
Laparotomy, 480 Regulations 2005, 69 Lhermittes syndrome, 290, 353354
Lapatinib, 314 Ionising Radiation (Medical Lichen planus, 342
Larmor frequency, 8788, 90 Exposure) (Amendment) Life expectancy, 297
Laryngeal cancer, 260, 290, 296297, Regulations 2006 [10], 67 Lifestyle, breast cancer, 434
350351 Ionising Radiation (Medical Life table, 251
aetiology, 376 Exposure) Regulations 2000, 66, Li-Fraumeni syndrome, 401, 433,
diagnosis and staging, 378 6769, 85 531532, 570
incidence rate, 376 Ionising Radiations Regulations 1993 Light ion beams, 121
lymphatic spread, 376 [3], 6465, 6667, 72 Limbs
pathology, 376 Radioactive Material Road Transport beam arrangements, sarcomas, 175
signs and symptoms, 376378 Regulations 2002, 74 limb-conserving surgery
staging of cancer, 377t Radioactive Substance Act 1993 [12], chondrosarcoma, 581
supraglottic carcinoma of larynx, 379 69, 74, 119 osteosarcoma (osteogenic
Laryngeal cancer treatment, 378380 unsealed radionuclides, 117119 sarcoma), 577578
advanced cancer (T3 and T4), 379, 380 Leiomyosarcoma, 479 soft tissue sarcomas, 571, 573
chemotherapy, 380 Leksell Stereotactic System Frame, soft tissue sarcomas, 571, 575
complications, 379380 147 Linacs, stereotactic radiotherapy/
early tumours (stages 1 and 2), 378, Lenalidomide (myeloma chemotherapy radiosurgery, 182
379380 regime), 527 Linear accelerator machines
glottic cancers, 378379 Lens of eye, 558 beam monitor chambers, 42, 43
postoperative radiotherapy, 379380 Lentigo maligna melanoma, 331 isocentric, 218
radical radiotherapy, 378 LET see Linear energy transfer (LET) lifetime, 201202
results, 380 Letrozole, breast cancer, 453, 460 megavoltage
Laryngectomy, 379 Leucovorin, 305 accelerator controls, 131
Larynx, anatomy, 375376, 376f Leukaemia control systems, 131, 132f
Laser ablation, non-melanoma skin acute see Acute lymphoblastic development, 125
cancer, 323324 leukaemia (ALL); Acute myeloid dual scattering system, 130131
Lateral walls leukaemia (AML) electron beam, 130131
nasopharynx, 358, 359f aetiology, 261 gantry assembly, 126, 127
nose and nasal cavity, 363 atomic bomb survivors, 271, 519 general layout and components,
oropharynx, 372 chemotherapy-related, 586 126127
Late reactions to treatment in children, 589590 gun filament assembly, 126
bladder cancer, 493 chronic see Chronic lymphocytic isocenter, 132, 133f, 134f
Ewings sarcoma, 580 leukaemia (CLL); Chronic LA radiation head, 128f
head and neck cancer, 353354 myeloid leukaemia (CML) laser backpointer, 132134, 135f
high-grade gliomas, 540 human T-cell leukaemia virus type 1 patient-beam alignment, 131134,
non-Hodgkins lymphoma treatment, (HTLV-1), 512, 519 133f, 134f
524 as proportion of all cancers/cancer quality control checks, 220
non-small cell lung cancer, 421 deaths, 519 radiation beam axis, indicators, 132,
penile cancer, 508 Leukaemia treatment 133f
prostate cancer, 498 acute myeloid leukaemia, 519 record and verify systems, 134135,
soft tissue sarcomas, 575 asparaginase, 312 136f
testicular cancer, 504 see also Acute chronic lymphocytic leukaemia, 520 solid wedge photograph/wedge
reactions to treatment chronic myelogenous (myeloid) beam profile, 130f
Lead, 70 leukaemia, 520 special techniques, 135137, 136f,
Leadership, quality management splenic radiotherapy, 525 137f
systems, 225 total body irradiation, 182, 524 stability controls, 131
Leak tests, radiation records, 74 vincristine, 309310 uniformity, 128, 129f
Left ventricle (LV), 108 Leukoplakia, 272 x-ray beams, 127130
636
Index
637
Index
Lymphoma treatment (Continued) brain tumours, 535 Manchester A point, dosimetry, 195
initial management, 515 breast cancer, 434, 435436 Manchester technique, brachytherapy,
post-transplant, 517 cervical cancer, 470472 474475
in pregnancy, 517 CNS tumours, 536, 546 Mantle radiotherapy
vincristine, 309310 see also Hodgkins Ewings sarcoma, 579 Hodgkins disease (HD), 434
lymphoma treatment; Multiple eye and orbit, affecting, 564 Hodgkins lymphoma, 590
myeloma treatment; Non- head and neck cancer, 343 Marginal surgery, Ewings sarcoma/
Hodgkins lymphoma treatment laryngeal cancer, 378 PPNET), 595
lung cancer, 418 Marie Curie nurses, 298
M mesothelioma, 425 Marjolins ulcer, 320f
nasopharyngeal cancer, 360 Mass, 3, 4
Macmillan Cancer Support, 298, 604 oral cavity cancer, 369 Mass attenuation coefficient, 2122, 24f
Macroaggregated albumin (MAA), osteosarcoma (osteogenic Mass-defect, 9
technetium-99m, 102 sarcoma), 577 Mass energy absorption coefficient, 2324
Magic number, 910 pancreatic cancer, 406 Mastectomy, 257
Magnetic resonance imaging (MRI) pituitary tumours, 548 ductal carcinoma-in-situ, 438
acquisition process, 217 rectal cancer, 411 follow up, 464
alteration of contrast in image, 89 soft tissue sarcomas, 571 local recurrence following, 437, 450
body tumours, 92 thyroid cancer, 387, 390 morbidity following, 450451
brachytherapy, 196 spectroscopy, 91 radiotherapy following, 442448
brain, 532533 transverse magnetization, 89 reconstruction following, 440
brain tumours, 92 used with CT images, 207 see also Breast cancer treatment
clinical applications in oncology, Magnetic resonance (MR) Matter, radiation interactions with,
92 gel dosimetry, 52 1531
de-phasing of transverse patient data, 162 Maxillary sinuses, 364365
magnetization over time, 89 Magnetic resonance spectroscopy (MRS), tumours, 366367
encoding of positional information in single voxel, 91 Maxillectomy, 366367
signal, 8991 Magnetron, 127 Measurement equipment, quality
Fourier transformation, 90, 91 Males, breast cancer in, 465 control, 219
frequency encoding gradient, 90 Malignant disease see Cancer Measurement of dose see Dose
Hodgkins lymphoma, 517 Malignant fibrous histiocytoma (MFH), measurement
imaging sequences, 8991 581 Mechanical hazards, 75
Larmor frequency, 8788, 90 Malignant melanoma see Melanoma Medial survival time, 252
management principles, 294 Malignant teratoma intermediate (MTI), Medical and Dental Guidance Notes
multimodality images, radiation testicular cancer, 501 (MDGN)
treatment planning, 155 Malignant teratoma trophoblastic radiation protection, 118
net magnetization vector, 88f (MTT), testicular cancer, 501 thyroid tumours, 115
overview of imaging process, 8789 Malignant teratoma undifferentiated Medical physics expert (MPE), 6869, 75
paranasal sinus tumours, 366 (MTU), testicular cancer, 501 Medical Research Council (MRC), 590
phase encoding gradient, 9091 Mammography, 7879, 257, 434, ASTEC trial, endometrial cancer, 478
protons processing parallel or anti- 435436 Medicine and Healthcare Products
parallel to applied magnetic field, Management of Health and Safety at Regulatory Agency (MHRA),
88f Work (MHSW) Regulations 1999 clinical incidents, 239
quality control, 217 [6], 64 Medicines (Administration of
radiation treatment planning, 146 Management principles, cancer patients, Radioactive Substances)
radiofrequency (RF) pulses, 87, 88, 89, 293299 Regulations 1978 [13] (MARS
9091 bad news, breaking, 294t Regulations 1978), 69
radionuclide imaging compared, breast cancer Medicines and Healthcare Products
9798 locally advanced, 457 Regulatory Agency (MHRA), 104
returning to thermal equilibrium, metastatic, 460 Medium dose rate (MDR),
8889 cerebral metastases, 554555 brachytherapy, 191, 197
scanners, 91 CNS tumours, 535538 Medulla, 532
signal production, 8788 primary central nervous system Medullary thyroid cancer (MTC), 390391
soft tissues, 78 lymphoma, 543 Medulloblastoma, 545
specific conditions treatment options, giving information in children, 597599
anal cancer, 413414 on, 293294 Megavoltage linear accelerator machines
astrocytoma, 596 Management responsibility, ISO 9000, see under Linear accelerator
bladder cancer, 490 228 machines
638
Index
Megavoltage photon therapy beams osteosarcoma (osteogenic Mohs micrographic surgery (MMS),
see Treatment beams sarcoma), 576 322323, 324, 325f
(megavoltage photon therapy) bone metastases see Bone metastases Molecular studies, 292, 354
Megestrol acetate, endometrial cancer, cerebral, 532, 555 Molecules, biological, 53
479 distant, 295, 488 Molybdenum, 11
Melanoma kidney cancer, 487 Monitor chambers, 35, 4243
acral lentiginous, 332 eyelid, 567 Monitoring
adjuvant treatment, 334 head and neck cancer, 343 contamination, 74, 119
aetiology, 260, 331 implantation, 274 immediate, short-term and long-term,
arising from melanocytes, 295 lung, resection of, 578 216
diagnosis, 332 by lymphatic vessels, 273 radiation levels, 7275
familial, 405 melanoma, 334335 response to treatment, teratoma, 505
and immunity, 272 osteoblastic, 116 Monoclonal antibodies, 521
lentigo maligna, 331 prostatic, 567, 567f Monoclonal gammopathy of uncertain
management, 334 specific conditions significance (MGUS), 517
nodular, 331 colon cancer, 408 Monoenergetic photons (MeV), 2122
nose and nasal cavity cancer, 363 eye and orbit, 566568 Monte Carlo algorithms, 166167, 178
ocular, 563565 kidney cancer, 486, 488 Moores law, 201
paranasal sinus tumours, 365 non-small cell lung cancer, 421, Morphine, 299
recurrent and metastatic, 422t Mortality rate, 251
management, 334335 osteosarcoma, 578 Mortality statistics, 274
spontaneous regression, 276 prostate cancer, 499500 MOS-FET (metal oxide field effect
stage and prognosis, 333 small cell lung cancer, 422t transistors) detectors, 47, 4849
sub-types, 331332 thyroid cancer, 115, 390 Motion control, simulation, 151
superficial spreading, 331 in-transit, 334 see also Spread of Motor cortex, 532
TNM staging, 332333 cancer Moulds, keratinocyte skin tumours, 330
Melphalan, 261 Metastron (strontium chloride), 116 Movement, patient, x-ray images, 8485
Meninges, 534 Methotrexate, 304, 305 Moving strip radiotherapy technique,
Meningioma, 545547 bladder cancer, 493 481
Menopausal status, bone metastases, breast cancer, 442443 MST (morphine sulfate continuous
breast cancer, 460461 chemotherapy/radiotherapy tablets), 299
Menopause, 256 interactions, 588 Mucosa-associated lymphoid tissue
Menstruation, and breast cancer, 433 enzymatic pathway for, 310f (MALT), 512, 516
Mercapto acetyl triglycine (MAG3), head and neck cancer, 351 Mucositis, head and neck cancer,
technetium-99m labelled, 103, non-Hodgkins lymphoma, 527 352353
109 resistance to, 439 MUGA (multiple gated acquisition),
6-Mercaptopurine, 308 Methoxy isobutyl isonitrile (MIBI), 103, 108109
Merkel cell tumours, 318, 335336 107, 109 Multidisciplinary team meeting (MDT),
Mesothelioma, 254 Methylene diphosphonate (MDP), 107 294, 341342
Butchart staging system, 426t Metoclopramide, 604 soft tissue sarcomas, 571, 573
chemotherapy, 427, 428 MIBG (meta-iodobenzyl guanidine) Multileaf collimation (MLC)
computed tomography, 426f in children, 591 forward and inverse planning, 171172
natural history, 425426 iodine-131 labelled, in intensity modulated radiotherapy, 165
neuroendocrine tumours, 428 neuroendocrine disease, 116117 linear accelerator machines, 129130
radiotherapy, 426 tumour imaging, 107108 megavoltage beams, 165
staging system, 427t MIBI (methoxy isobutyl isonitrile) specific conditions
thymoma, 428, 429t cardiac imaging, 109 head and neck cancer, 347
Metabolic factors, breast cancer, 434 metabolic trapping, 103 hypopharyngeal cancer, 382
Metabolic pathway, 103 tumour imaging, 107 testicular cancer, 504
Metabolic trapping, 103 Microtubule spindle, 309310 stereotactic treatment planning, 183
Meta-iodobenzyl guanidine (MIBG) Milan-Bentley algorithm, 166, 167f verification process, 151
see MIBG (meta-iodobenzyl Misonidazole, 286287 wedges, 164
guanidine) Mitomycin, tumours of vagina and Multimodality images, radiation
Metaplasia, 268 vulva, 483 treatment planning, 155
Metastasis, 273274, 273f Mitotic cell death, 288 Multiple drug resistance gene (MDR1),
across cavities, 274 Mitotic count, 291 303
blood-borne, 274 Mitotic inhibitors, 309310 Multiple endocrine neoplastia
in melanoma, 334335 Mitoxantrone, 613 syndromes (MEN), 386, 391
639
Index
Multiple field plans, beam arrangements, Nasopharyngeal cancer, 260, 265 osteosarcoma (osteogenic sarcoma),
175 aetiology, 360 577
Multiple myeloma diagnosis and staging, 360361 paranasal sinus tumours, 367
clinical features, 517518 distal failure, 360 stomach cancer, 403
diagnosis, 518 Epstein-Barr virus link, 342, 360 Neoplasia, 268269
investigations, 518 incidence of tumours, 358359 benign and malignant neoplasms,
pathology, 517 lymphatic spread, 360 268269
prognostic factors, 518 pathology, 360 characteristics, 268t
as proportion of all cancers/cancer Rouvieres node, 360 classification, 276277
deaths, 517 signs and symptoms, 360 clonal nature of neoplasms, 269
radiotherapy, 518519 staging, 359361 defined, 268
smoldering, 517 and viruses, 271 Nephrectomy, 487
Multiple myeloma treatment, 518519, WHO classification, 360 spontaneous regression following,
525 Nasopharyngeal radiotherapy treatment 486
chemotherapy, 518, 527 complications, 361362 Nephroblastoma see Wilms tumour, in
hemibody radiotherapy for results, 362 children
widespread deposits, 525 technique, 361 Net magnetization vector, 88f
palliative, 525 Nasopharynx, anatomy, 358, 359f Networking
pathological fracture, 525 National Adjuvant Breast and Bowel application layer: the program, 204
rib deposits, 525 Project (NSABP), 456457 Dicom, 204206
severe pain, 525 National Cancer Peer Review (NCPR), gateways, 204
soft tissue mass, 525 232233, 233b IP address, 203
spinal cord compression, 518519, National Electrical Manufacturers ipconfig, sample output, 204f
525 Association, USA, 202, 204 link layer: physical infrastructure,
spinal deposits, 525 National Health Service (NHS) 202203, 204f
Multiply damaged sites, concept, 281f, Cancer Plan, 240241, 605, 606 network layer: addressing, 203, 204f
281282 quality in, 232238, 234t network loop vs. network switch, 203f
Multitarget equation/multitarget with National Institute of Clinical Excellence network security, 204, 205f
single hit equation, 288 (NICE), 378 ping, sample output from, 204f
Multityrosine kinase inhibitor, National Patient Safety Agency (NPSA), potential impact of hazards, and
hepatocellular carcinoma, 404 clinical incidents, 239 mitigation measures, 205f
Mutation, carcinogenesis, 269, 270 National Physical Laboratory private networks, 203
Mutator phenotype, 269270 dose measurement, 35, 3738 quality control, 219
Mutual information, 155 equipment checks and calibration, 74 subsets separated by gateway, 204f
Mutually beneficial supplier National Radiation Protection Board, 67 TCP/IP model, four network layers,
relationships, quality National Radiological Protection Board, 202, 203t
management systems, 226 65 transport layer: send and receive, 204
MV photon beams, 24, 28f National Standards Laboratory, dose Neuroblastoma (NB), 116
Myc-n oncogene, 591 measurement, 35 in children, 591
Mycosis fungoides, 335f, 516517, National Surgical Adjuvant Breast Project spontaneous regression, 276
525526 B-17 trial, 438 Neuroendocrine disease
Myelitis, 353354 National Wilms Tumour Study Group iodine-131 therapy, 116117
Myelodysplastic syndrome (MDS), 519 (NWTS), US, 586, 591 mesothelioma, 428
Myeloma see Multiple myeloma; Nausea and vomiting pancreatic cancer, 405
Multiple myeloma treatment clinical decisions, 299300 Neurofibromatosis, 531532, 596
Myeloproliferative disorders, 520521 morphine-induced, 299 Neurological effects, non-Hodgkins
patient care, 604 lymphoma treatment, 524
radiation-induced, 289 Neurological syndromes, malignant
N
Neck tumours disease, 614
Nadir, 304 aetiology, 260 Neuropathic pain, 297298, 299
Nagasaki, atomic attack on, 61, 64, 265, lymph node levels, 345, 347f Neurophysiological effects of
434 magnetic resonance imaging, 78 radiotherapy, in children,
Nanocoulombs, dose measurement, 42 Necrosis, 288, 295 587588
Naphthylamine, 263 Necrotizing leukoencephalopathy, 587 Neurosurgery principles, 535536
Narrow-beam geometry, 21 Neoadjuvant chemotherapy, 302 Neutrinos, 34, 10
Nasal sinuses, and NHL radiotherapy bladder cancer, 491492 Neutron beams, 121
treatment, 523 nasopharyngeal cancer, 361 Neutron emitters, brachytherapy, 190,
Nasolacrimal duct carcinomas, 562 oesophageal cancer, 400 194
640
Index
Neutron interactions, 3031 and breast, 523 surgery, 418419 see also Lung cancer;
Neutrons and cardiac disease, 524 Small cell lung cancer (SCLC)
fast, 3031 dose distribution, 522 Nordic Society of Gynaecological
heavy particle radiotherapy, 291 extranodal involved fields, 523 Oncology (NSGO), 479
mass, 3 and fertility, 524 Normal tissue
treatment room design, 143 field borders, 522 acute responses, 289290
Nevada desert, atomic bombs dropped and GI lymphoma, 523 subacute reactions, 290
in, 64 and growth disorders, 524 tolerance, 290, 536537
New technologies, 291292 and head and neck, 523 Normal tissue complication probability
Nexavar (sorafenib), 315 inverted Y, 522 (NTCP), 161, 443
NHL see Non-Hodgkins lymphoma involved fields, 522523 Nose and nasal cavity, anatomy,
(NHL) involved sites, 523 362363
Nimorazole, 286287 and lung, 524 Nose and nasal cavity cancer
4-nitrodiphenyl, 263 and nasal sinuses, 523 aetiology, 363
Nitrogen mustard, 335 neurological effects, 524 diagnosis and staging, 363
Nodular basal cell carcinoma, 320, 321f and orbit, 523 incidence rate, 363
Nodular melanoma, 331 shielding, 522 lymphatic spread, 363
Non-anthracycline antibiotics, 312 and spleen, 523 pathology, 363
Non-coplanar planning, beam and thyroid gland, 523, 524 radiotherapy, 364
arrangements, 176 toxicity, 524 signs and symptoms, 363
Non-Hodgkins lymphoma (NHL) Waldeyers ring, 523 staging system, 363
aetiology, 260261 R-COP, 526 treatment, 364
aggressive, 513, 515516 relapsed disease, 527 NPC (cancer of nasopharynx)
chemotherapy, 526527 T-cell rich, 526527, 591 see Nasopharyngeal cancer
in children, 512, 591 see also Hodgkins lymphoma NSCLC Staging system, non-small cell
diffuse large B cell lymphoma treatment; Primary central nervous lung cancer, 418
see Diffuse large B cell lymphoma system lymphoma (PCNSL) N-type material, semiconductor
(DLBCL) Non-homologous end-joining (NHEJ), detectors, 47
extranodal, 514 283284 Nuclear interactions, 27
follicular and marginal zone, 516, Non-lymphoblastic leukaemia (ANLL), Nuclear medicine, defined, 98
522, 526, 591 in children, 589 Nuclear structure, 69
incidence rate, 512 Non-melanomatous skin cancer Null hypothesis, quality control,
indolent, 513, 516517, 522 (NMSC) 214215
Kaposis sarcoma, 337 deaths from, 318 Nutritional support, 298, 603604
mantle cell lymphoma, 513 treatment, 322325, 324f
pathological characteristics, 513514 see also Basal cell carcinoma O
prognosis, 515 (BCC); Keratinocyte skin
radiolabelled monoclonal antibodies tumours; Squamous cell OAR see Organs at risk (OAR)
in, 114, 117 carcinoma (SCC) Obesity, as cancer risk factor, 265, 397
T-cell rich, 512, 513 Non-small cell lung cancer (NSCLC), Observers eye view (OEV), 169
testicular involvement, 506 418421 Obstetrics, ultrasound imaging, 94
treatment see Non-Hodgkins bone metastases, 421 Occipital cortex, 532
lymphoma treatment; see also brain metastases, 421 Occipital lobe, 534
Hodgkins lymphoma (HL); chemotherapy, 422 Occupational exposure to carcinogens,
Lymphoma chest retreatment, 421 250, 263, 264t
Non-Hodgkins lymphoma treatment contradictions for surgery, 420t Octreoscan kit, tumour imaging, 108
chemotherapy, 311, 526527 incidence rate, 417418 Octreotide
CNS prophylaxis, 527 radiotherapy receptor binding, 103
drug choice, methotrexate, 305 doses, 420, 420t tumour imaging, 108
follicular grade 3, 526527 indications for, 420t Octreotide, radiolabeled, 428
mantle cell lymphoma new trends, 422 Oeophagitis, 421
chemotherapy, 526527 palliative, 421 Oesophageal cancer
optimal treatment for, 516 radical, 419421 adenocarcinoma risk factors, 397
radiotherapy, 522523, 524 reactions, 421 aetiology, 259, 396
myeloablative regimen, 527 target volume, 419 chemoprevention, 266
radiotherapy, 522524 technique, 419 clinical manifestations, 398
and bone, 523, 524 tolerances, 419420 diagnostic evaluation, 398399
and brain, 523 staging, 418 dietary influences, 265
641
Index
Oesophageal cancer (Continued) signs and symptoms, 368369 Ostreoscan, tumour imaging, 108
epidemiology, 396 spread, 368 Ostreotide, somatostatin receptor
esophagogastric junctional tumours, staging system, 367368 imaging, 108
401 treatment, 199, 370372 see also Floor Ovarian cancer
pathology, 396 of mouth cancer; Lip cancer aetiology, 479480
squamous cell carcinoma, risk factors, Oral contraceptive pill, 256, 433 ascites, 480, 612613
396397 Oral contrast, 400 chemotherapy, 480
staging, 398t Oral mucosa, cancer of, 260 clinical features, 480
Oesophageal cancer treatment, 399 Organs at risk (OAR), 146 epithelial tumours, treatment results,
adjuvant radiation/chemoradiation, head and neck cancer, 349 481482
400 radiation treatment planning, 160 genetic factors, 433
brachytherapy, 198 stereotactic treatment planning, 183 intraperitoneal chemotherapy, 304
chemotherapy, 400 thyroid cancer, 393 investigations, 480, 481t
definitive chemoradiation, 399400 volume definitions, 149 method of spread, 480
endoluminal techniques, 400401 Oropharyngeal cancer, 260, 342 pathology, 480
radiotherapy, 399 aetiology, 373 radiotherapy, 481482
adjuvant radiation/chemoradiation, diagnosis and staging, 373374 rare tumours, 482
400 incidence rate, 372373 sex-cord tumours, 482
brachytherapy, 400 lymphatic spread, 373 as silent killer,, 480
external beam, 176, 399, 400 pathology, 373 staging, 480, 481t
palliative, 400 signs and symptoms, 373 subdivision of tumours, 480
surgery, 399 staging system, 373 surgery, 480
Oesophagus, anatomy, 397398 Oropharyngeal cancer treatment, taxanes for, 310
Oestrogen excess hypothesis, breast 374375 topotecan for, 311
cancer risk, 256 complications, 375 treatment, 480, 481482
Oestrogenprogestogen hypothesis, radiation technique, 374375 Ovarian suppression, 454
257 results, 375 Overall survival rate, 251
Oestrogen receptors (ER), 312, 438439, Oropharynx, anatomy, 372373 Oxaliplatin, 311312
452, 460 Orthopantomogram (OPT) Oxycodone, 299
Oestrogens, 313314 head and neck cancer, 344f Oxygen effect, 3031, 285287
Off-axis ratios (OARs), 166 paranasal sinus tumours, 366 Oxygen enhancement ratio (OER), 195,
Ohngrens line, 366f Orthovoltage machines 285
Oils, 271 beam energy, 124
Oligodendrocytes, 531 calibration of dose output, 125
Oligodendroglioma, 532, 540, 541 collimation, 123124 P
Oligonucleotide arrays, 292 control of output, 124
Omic technologies, 292 deep x-ray (DXR) units, 122, 124 P13K-AKT, signalling through, 314
Oncogenes, 269270 example, 122f p53 mutations, 285286, 303
Oncologist, meeting for first time, extra high tension (EHT) voltage, 123 bladder cancer, 489
293294 high voltage circuits, 122123 breast cancer, 433
Oncoscint, radionuclide imaging, 108 lead cut-out and mask, skin and eye stomach cancer, 401
Oncovin, non-Hodgkins lymphoma, shielding, 124, 125f thyroid cancer, 386
515516 quality control, 218 Pacemakers, patient data, 162
Ondansetron, 299300 schematic of HT generator, 123f Paclitaxel, 310
Oophorectomy, prophylactic, 479480 skin and eye shielding, 124125 breast cancer, 461462
Operability of tumour, 295 superficial (SXR) units, 122, 124 non-small cell lung cancer, 422
Ophthalmoscopy, 564 on tube stand, 122 see also X-rays oesophageal cancer, 399400
Optical density, 82, 83f Oscillating transverse electric/magnetic ovarian cancer, 480
Optically stimulated luminescent (OSL) fields, 5 sarcomas of uterus, 479
dosimeters, 74 Osteoblastic metastases, 116 Paediatric oncology, 585599
Optic nerve, anatomy, 365, 557 Osteoblastic tumours, 578579 bone growth, effects of treatment on,
Oral cavity, anatomy, 367 Osteoradionecrosis (ORN) 587
Oral cavity cancer head and neck cancer, 344f, 353 chemotherapy, 298
brachytherapy, 199 nasopharyngeal cancer, 361 chemotherapy/radiotherapy
diagnosis and staging, 369, 370f oral cavity cancer, 359f, 372 interactions, 588
incidence of carcinoma, 367 Osteosarcoma (osteogenic sarcoma), CNS tumours, 596
radiotherapy technique, 371372 576579 CNS tumours, 595600
results of treatment, 372 in children, 576, 595 craniopharyngioma, 599
642
Index
643
Index
644
Index
fluoroscopic imaging with image Positron emission tomography (PET), following mastectomy, 442448
intensifier/TV chain, 83 34 general care, 450
forms, 100 acquisition process, 217 immobilization, 444445
intensifier screen principles, 82f beta decay, 1011 indications for postmastectomy
optical density, 82, 83f Hodgkins lymphoma, 590 radiotherapy, 443
photostimulable phosphors, digital metabolic trapping, 103 internal mammary node irradiation,
(computed) radiography using, multimodality images, treatment 446
8283 planning, 155156 intraoperative, 450
radionuclides, 100 non-Hodgkins lymphoma, 514515 limitation of lung volume
radiotherapy beam production, pair-production, 2627 irradiated, 446
141142 patient data, 162 locoregional irradiation techniques,
radiotherapy data types, 208 PET-CT, 78, 9798 443
solid state detectors, digital clinical applications, 110111 primary tumour, boost to, 448
fluoroscopy and radiography nasopharyngeal cancer, 360361 respiratory gated radiotherapy, 443,
using, 8384 scanners, 155 444f
TV camera viewing of intensifier, 83f thyroid cancer, 390 shoulder field, 445
see also X-rays quality control, 217 skin bolus, 446
Plancks constant, 5 radiation treatment planning, 146 spot recurrences, 450
Planning target volume (PTV), 146 and radionuclide imaging, 9798 supraclavicular field, 445
beam arrangements, 172, 173, radiotherapy data types, 207 supraclavicular fossa, irradiation of,
174175, 176 scanners, 101 450
compensators, 164 specific conditions target volume, 443 see also Breast
extended focus skin distance (FSD) head and neck cancer, 343 cancer treatment
plans, 164 lung cancer, 418 cervical cancer, 473
radiation treatment planning, 160 thyroid cancer, 390 and concurrent chemotherapy, 352
specific conditions see also Computed tomography endometrial cancer, 478479
bladder cancer, 492 (CT); Tomographic imaging head and neck cancer, 344, 345347,
CNS tumours, 536 Positrons 351, 352
Ewings sarcoma, 595 annihilation, 34 high dose brachytherapy, 449
head and neck cancer, 345, 347 beta decay, 1011 laryngeal cancer, 379380
pancreatic cancer, 406407 beta plus particles as, 98 low dose brachytherapy, 449
thyroid cancer, 392 Post-cricoid tumours, radiotherapy mesothelioma, 426
volume definitions, 149 technique, 382383 oral cavity cancer, 370
wedges, 164 see also Clinical target Posterior pharyngeal wall tumours, paranasal sinus tumours, 366367
volume (CTV); Target volume radiotherapy technique, 382 partial breast irradiation, 449
Plasmacytoma Posterior wall pathological examination of excised
multiple myeloma, 518 nasopharynx, 358 tissue, 296
nose and nasal cavity cancer, 363 nose and nasal cavity, 363 soft tissue sarcomas, 573
Platelet derived growth factor receptor oropharynx, 372 Wilms tumour, in children, 592
(PDGFR), kidney cancer, Post-menopausal women, breast cancer Post-subcapsular cataract, 559f
489 risk, 256 Potentially lethal damage recovery
Platinum analogues, 311312 Post-mortem examination, 274 (PLDR), 283
Pleomorphism, 269 Postoperative radiotherapy Practical ionization chambers
Pleural effusions, 611612 brachytherapy, 449 Bragg-Gray cavity theory, 39
Plummer-Vinson syndrome, 381, breast cancer, 440451 calibrated instruments, dose
396397 accelerated radiotherapy, local determination based on, 3940
Pneumocystis, 614 control rates, 447t requirements for, 40
Pneumonitis, 421, 587 chest wall and breast, 445446 Precancerous lesions, 272
Polarity effect, 45 CT stimulation, 443 cervical cancer, 470
Polarizing voltage, 38, 41 dose, energy and fractionation, head and neck cancer link, 342
Pollution, 265266 446448 keratinocyte skin tumours, 318
Polychemotherapy see Combination dosimetry, 446 lip cancer, 322
chemotherapy electron boost dose, 448 Prednisolone, 300
Polycythaemia rubra vera (PRV), 115 electrons, 448 Hodgkins lymphoma, 526, 590
Polycythaemia vera (PV), 520 external beam radiotherapy, 449 non-Hodgkins lymphoma, 515516,
Polymer gels, 52 field matching, 446, 447f 526
Polyps, 272 following breast-conserving surgery, Pregnancy
Pons, 532 441, 448 age at first full-term, 433
645
Index
646
Index
Quality management (QM), mechanical, electrical and fire hazards, Radiation treatment planning (RTP)
terminology, 224 75 system, 145
Quality management systems (QMS) monitoring of radiation levels, 7275 Radiation treatment planning System
continual improvement (QMP 6), 226 personal protective equipment, 75 (TPS), 146
customer focus (QMP 1), 225 quality control, 7475 patient data, 162, 163
factual approach to decision making radiotherapy beam production, 142 Radiative loss see Bremsstrahlung
(QMP 7), 226 shielding, 124125, 143 (radiative loss)
ISO 9000, 227228 time, 6970 Radical radiotherapy, 297
leadership (QMP 2), 225 transport of radioactive materials, 74 Radical treatment, side-effects, 294
mutually beneficial supplier treatment room design, 143 Radioactive iodine scans, 387
relationships (QMP 8), 226 unsealed radionuclides, 117119 Radioactive Material Road Transport
people involvement (QMP 3), 225 Radiation Protection Adviser (RPA), 66, Regulations 2002, 74
process approach (QMP 4), 226 67 Radioactive materials, transport, 74
system approach to management Radiation protection advisers, 6667 Radioactive Substance Act 1993 [12], 69,
(QMP 5), 226 Radiation Protection Supervisors (RPS), 74, 119
terminology, 224 6667 Radioactivity
Quality system (QS), terminology, 224 Radiation safety committee, 67 alpha decay, 910
Quanta (x-ray photons), 85 Radiation synovectomy, 115 beta decay, 1011
Quarks, 34 Radiation Therapy Oncology Group decay series and radioactive
QUASAR trial, colon cancer, 408 (RTOG), 498, 602 equilibrium, 11, 12f
Radiation treatment planning, 145156 exponential decay, 9
R algorithms for dose calculation, gamma emitters, 190
166167 internal conversion and electron
Radiation checking, 183184 capture, 11 see also Radionuclides
background, 6263, 63f CNS tumours, 536537 Radiobiology, of brachytherapy,
biological effects, 6061, 61t CT simulation, 151152, 154 194195
characteristic, 6 evaluation tools, 168171 Radiochromic film, 46
detection and measurement, 3356 forward, 171173 Radiofrequency (RF) pulses, 87, 88, 89,
interactions with matter, 1531 head and neck cancer, 348f 9091
monitoring of levels, 7275 high-grade gliomas, 539 Radiogenic damage, subcellular,
natural, 62 head and neck cancer, 348349, 280282
personal radiation dosimeters, 7274 348f Radioimmunotherapy (RIT), non-
protection see Radiation protection image guided radiotherapy, 87, Hodgkins lymphoma, 117
records, 74 145146, 156157 Radio iodine diagnostic (RAIS) scans,
treatment planning see Radiation inverse, 171173 389
treatment planning head and neck cancer, 349 Radioisotope source, gamma ray beam
weighting factors, radiation type, 62t localization process, 146, 151, 152, machines, 137f, 138
Radiation areas, controlled and 154 Radiology, bladder cancer, 490
supervised, 66 multimodality images, 155 Radionecrosis, 587
Radiation atrophy, 559, 559f non-CT contouring devices, 149150 Radionuclide imaging, 78, 97110
Radiation cell survival, models, 288289 patient data, 161163 clinical applications
Radiation cystitis, 389 patient immobilization, 145, 146149 bone imaging, 100, 104107
Radiation effects, in normal and physical simulation, 150151 cardiac imaging, 100, 108109
malignant tissue, 289291 portal imaging, 156 infections, 109
Radiation exposure, head and neck prescription and planning request, kidney imaging, 100, 109
cancer, 342 160 octreotide-somatostatin receptor
Radiation-induced cell death, 285289 principles and practice, 159186 imaging, 108
Radiation pneumonitis, 587 special techniques, 182183, 288 oncoscint, 108
Radiation protection, 5975, 142 electron therapy, 180181 PET-CT imaging, 110111
barriers, 70 stereotactic radiotherapy/ sentinel node mapping, 109110
building materials, 7072 radiosurgery, 182183 thyroid cancer, 108
commissioning, 7475, 142143 total body irradiation, 135, 136f, tumour imaging, 107108
contamination, 70 148, 182 definition of image, 97
critical examinations, 7475 specific conditions, bladder cancer, gamma cameras, 98100
distance, 70 492 performance characteristics,
equipment checks, 74 verification process, 87, 151, 152f 100101
legislative requirements, 6369, virtual simulation, 87, 146, 152154 ideal radionuclide for imaging, 102
117119 volume definitions, 149 overview of imaging process, 98
647
Index
648
Index
in normal and malignant tissue, R-COP (NHL chemotherapy regime), Regulations (RIDDOR), clinical
289291 516, 526 incidents, 239
oxygen effect, 285287 Reactions to treatment Reproductive system, effects of
radiation cell survival models, acute see Acute reactions to treatment radiotherapy in children, 588
288289 late see Late reaction to radiotherapy Resources, ISO 9000, 228229
radiation-induced cell death, skin, 289290 Respiratory depression, 299
285287, 288289 specific conditions Respiratory gating/respiratory gated
recovery, 283 bladder cancer, 493 acquisition, 149, 154
reoxygenation, 286287 non-small cell lung cancer breast cancer, 443, 444f
spinal cord damage, 297 (NSCLC), 421 Rest energy, 4
subcellular radiogenic damage, prostate cancer, 498 Rest mass, 4, 26
280282 subacute, 290 see also Complications Results of treatment
tumour hypoxia, 285287 of treatment; Side effects; Toxicity bladder cancer, 493
Radiotherapy portal imaging, 78 concerns chondrosarcoma, 581
Radiotherapy process, 216217 Reactive lymphoid hyperplasia chordoma/chondrosarcoma of skull
acquisition, 217 clinical features, 560 base, 552
analysis, 217 pathology, 558, 560 craniopharyngioma, 550
delivery, 217 radiotherapy, 560561 endometrial cancer, 479
flowchart, 231f Receptor binding, 103 ependymoma, intracranial, 542
interaction of processes in a RECIST (Response Criteria in Solid Ewings sarcoma, 580
radiotherapy department, 232f Tumours), 302 germinoma, 545
overview, 217 Recombination losses, ion, 44 high-grade gliomas, 540
quality management, 229232 Reconstruction, breast, 440 hypopharyngeal cancer, 383
Radiotherapy technology Record and verify systems, 134135, 202 kidney cancer, 489
afterloading brachytherapy machines, Record-keeping laryngeal cancer, 380
197, 218219 clinical incident records/reporting, lip cancer, 372
C-arm radiographic imaging system, 239 low-grade gliomas, 542
218 radiation records, 74 meningioma, 547
computer systems and networking, unsealed radionuclide therapy, 119 nasopharyngeal cancer, 362
219 see also Record and verify systems nose and nasal cavity cancer, 364
CT scanner, 217 Recovery, 283 oral cavity cancer, 372
isocentric linear accelerators and Rectal cancer oropharyngeal cancer, 375
cobalt machines, 218 magnetic resonance imaging, 92 palliative stereotactic radiosurgery,
measurement equipment, 219 neuropathic pain, 297298 556
MRI, PET and image registration with Rectal cancer treatment, 410412 paranasal sinus tumours, 367
CT, 217 chemotherapy, 412 penile cancer, 509
new, implementation of, 241242 CT planning, 411412 pituitary tumours, 549
orthovoltage teletherapy machines, dose and energy, 412 primary central nervous system
218 follow-up, 412 lymphoma, 544
patient positioning, 219 radiotherapy, 411, 412 prostate cancer, 498
simulator, 217218 target volume, 411 soft tissue sarcomas, 575
treatment verification, 219 toxicity concerns, 412 spinal cord tumours, 554
virtual simulator, 218 Recurrence-free survival, 251 spindle cell sarcoma, 581
Radium, 10, 190 Reese-Ellsworth classification, testicular cancer, 504, 506
Radon gas retinoblastoma, 565 vestibular (acoustic) schwannoma,
Cornwall, 62 Refractory myeloproliferative disease, 552
lung cancer, 254255, 270271 phosphorus-32 for, 115 Reticuloendothelial cells, 103
reducing risks from, 265 Regression of cancer, spontaneous, 276 Retina, 557, 559
Raised intracranial pressure (ICP), kidney cancer, 486 Retinoblastoma, 270, 558,
534 Relative biological effectiveness (RBE), 565566
Randomized controlled trials (RCTs), 19f, 29 loss of gene, 570
prostate cancer, 494495, 500 Renal cell adenocarcinoma, 486 Retreatment, 290291
Range-straggling, 1617 see also Kidney cancer Retroperitoneum, soft tissue sarcomas,
RAS-RAF-ERK (MAPK), sigalling Renal function tests, 505 571572, 573, 575
through, 314 Reoxygenation, 286 Retropharyngeal nodes, 347
Rayleigh scattering, 93 Repetition time (TR), 89 Reverse smoking, 260
R-CHOP (NHL chemotherapy regime), Reporting of Injuries, Diseases and Rhabdomyosarcoma, 298, 558, 570,
516, 526 Dangerous Occurrences 592594
649
Index
650
Index
Single photon emission computerized cessation, 253, 342 Sorafenib, 315, 390, 391
tomography (SPECT) head and neck cancers, 260, 342 hepatocellular carcinoma, 404
gamma camera performance and heart disease, 274 Source-to-surface distance (SSD)
characteristics, 101 laryngeal cancer, 378 electron therapy, 179, 180, 181
multimodality images, treatment lung cancer, 253254, 417 isocentric plans, 163
planning, 155 oesophageal cancer, 396, 397 kilovoltage vs. electron therapy, 181
overview of radionuclide imaging oral cavity cancer, 368 neutron interactions, 31f
process, 98 pancreatic cancer, 405 photon depth-dose and build-up
positron emission tomography prevalence, 342f effect, 28
scanners, 101 reducing, 263 total body electron therapy, 525
Single photon emission tomography reverse, 260 total body irradiation, 182
(SPET), overview of radionuclide in women, 342 Specific activity, 9
imaging process, 98 Society of Nuclear Medicine (SNM) SPECT imaging see Single photon
Site of tumour, 295 bone pain palliation, 116 emission computerized
Size of tumour, 295 iodine-131 use, thyroid disease, 114 tomography (SPECT)
Skin, shielding, with orthovoltage Sodium iodide, thallium-doped, 55 S-phase count, 291
machines, 124125 Sodium valproate, 299 Sphenoidectomy, 366367
Skin appendage tumours, 337339, 338f Soft tissues Sphenoid sinus, 365
Skin cancer, 317338 magnetic resonance imaging, 78 Spin, 8788
cutaneous lymphomas, 335, 336f soft-tissue tumours, Compton effect, Spinal cord
lymphoma, 327 25 compression, multiple myeloma
melanoma see Melanoma ultrasound imaging, 93 treatment, 518519, 525
Merkel cell tumours, 335336 Soft tissue sarcomas damage, non-Hodgkins lymphoma
non-melanomatous see Non- adjuvant treatment, 573 treatment, 524
melanomatous skin cancer amputation, indications for, 572573 tolerance, 537
(NMSC) chemotherapy, 575 tumours, 553554
sarcomas, 336337 clinical features, 571 Spindle cell sarcoma, 581
skin appendage tumours, 337339, clinical trials, 573, 574 Spin warp imaging method, two-
338f see also Ultraviolet light definitions, 570 dimensional, 89, 90
Skin care products, 603t diagnosis and staging, 571, 572t Spiritual needs of patients, 607
Skin pigmentation, 353 gross residual disease, 575 Spleen, and NHL radiotherapy
Skin shielding, orthovoltage machines, head and neck, 575 treatment, 523
124125 limbs, 571, 575 Splenic radiotherapy, leukaemia
Skull limb-conserving surgery, 571, 573 treatment, 525
anatomy, 534 management, 571573 Spot views, planar imaging, 100
chordoma/chondrosarcoma of skull pathology, 570571 Spread of cancer
base, 552 see also Brain; peripheral nerve tumours, 570 cervical cancer, 469
Brain tumours; Head and neck as proportion of all cancers/cancer endometrial cancer, 477478
cancer deaths, 570 functional effects, 273
Skull base irradiation, 555 radiotherapy hypopharyngeal cancer, 381
Slipped femoral epiphysis, 587 contraindications to radical, laryngeal cancer, 376
Small cell lung cancer (SCLC) 573574 lip and oral cavity carcinoma, 368
chemotherapy, 423 palliative, 575 local invasion, 273
concurrent chemoradiation, 424 primary radical, 573575 nasopharyngeal cancer, 360
incidence rate, 417418 results, 575 nose and nasal cavity cancer, 363
metastatic sites, 422t timing, 573 oropharyngeal cancer, 373
natural history, 422 reactions to treatment, 575 ovarian cancer, 480
prognostic factors, 423t retroperitoneum, 571572, 573, 575 pancreatic cancer, 405
prophylactic cranial irradiation, VORTEX trial, 574 paranasal sinus tumours, 365366
424425 WHO classification, 570t soft tissue sarcomas, 570571
radiotherapy, 423424 Software development, 209210 see also Metastasis
staging and diagnosis, 422423 Solar keratosis, 272 Spread-out Bragg peak (SOBP), 30f
surgery, 425 Solid state detectors, digital fluoroscopy Spurs, DNA double-strand break,
Smoking and radiography using, 8384 281282
bladder cancer, 489 Somatostatin receptor imaging, 108 Squamous cell carcinoma (SCC)
breast cancer, 434 Somnolence syndrome, 587 and actinic keratoses, 318
and carcinogenesis, 271 SONAR (sound navigation and ranging) aggressive, 320, 322f
cervical cancer, 468469 principle, ultrasound imaging, 94 bladder cancer, 489, 491
651
Index
Squamous cell carcinoma (SCC) thyroid cancer, 387 Stored beam data models, dose
(Continued) vaginal and vulval tumours, calculation algorithms, 166, 167f
eye and orbit, 558, 561562 276277 see also TNM Streptococci, 614
head and neck cancer, 343 classification Streptozotocin, mesothelioma, 428
immunosuppression, 319 Standardization, dose, 35 Stridor, 376378, 386
incidence rate, 318 orthovoltage machines, 125 Stroma, tumour, 275
ingested carcinogens, 318 reference standard instruments, 3738 Strontium-89, 500
vs. keratoacanthoma, 322 Standardized incidence ratio (SIR), 251 Strontium-90, 194
lip cancer, 368 Standardized mortality ratio (SMR), 251, Strontium chloride (SrCI2), 116
Mohs micrographic surgery, 322323, 254 Strontium consistency check device,
325f Stanford V (chemotherapy drug), 526 4344
nasopharyngeal cancer, 360 Staphylococci, 614 Subatomic particles, of interest to
and oesophageal cancer, 396397 Star effect, pions, 30 radiotherapy, 34, 4t
oesophagus, 259 STEAM technique, spectroscopy, 91 Subcellular radiogenic damage, 280282
paranasal sinus tumours, 365 Stem cells, hemopoietic stem cell Sublethal damage recovery (SLDR), 283
risk factors, 396397 transplantation, 521 Sublethal damage (SLD), 588
skin cancer, 320322, 322f Stem effect, 45 Sulesomab, 109
superficial x-ray treatment, 328 Stenosis, 559 Sunitinib, 407, 415
tumour site, 295 Stereotactic frames, patient Superficial spreading melanoma (SSM),
vulval cancer, 483 immobilization, 147, 148f 331
xeroderma pigmentosa, 319 Stereotactic radiotherapy (SRT), 182183 Superficial x-ray treatment
Squamous epithelium, 277 CNS tumours, 536 eye and orbit, 561562
Stability line, 89 fractionated, 550551 orthovoltage machines, 122, 124
Stable disease (SD), 302 frames, 147, 148f Superior wall
Staff, needs of, 608 gamma units, 182 nasopharynx, 358
Staging of cancer, 274275 linacs, 182 nose and nasal cavity, 363
clinical decisions, 295 non-small cell lung cancer, 422 oropharynx, 372
growth rates, 275276 radiation treatment planning, 183 Supervisors, radiation, 6667
histological grading, 275 teletherapy machines, 141 Support services, 298
limitations of grading, 275 Stereotactic teletherapy machines, 141 Supraclavicular field, breast cancer
nose and nasal cavity cancer, 363 Steroid treatment, 300, 537 radiotherapy, 445
specific conditions Stochastic hereditary effects, from Surgery
anal cancer, 413414 radiation, 60 amputation, indications for, 572573
bladder cancer, 490, 491t Stochastic somatic effects, from anal cancer, 414
breast cancer, 436437 radiation, 6061 breast cancer
colon cancer, 408, 409t Stoma care nurses, 298 breast conservation, 440441,
endometrial cancer, 478t Stomach 463464
hypopharyngeal cancer, 381, 382f anatomy, 401 breast reconstruction following
kidney cancer, 487, 488t non-Hodgkins lymphoma treatment, mastectomy, 440
laryngeal cancer, 377t, 378 523 see also Mastectomy
melanoma, 332333 Stomach cancer locally advanced, 457
mesothelioma, 426t, 427t adenocarcinoma, 401 primary chemotherapy followed by
nasopharyngeal cancer, 359361 aetiology, 257258, 401 surgery, 457
non-Hodgkins lymphoma, 514 chemoprevention, 266 clinical decisions, 297
nose and nasal cavity cancer, 363 clinical features, 401 colon cancer, 408
oral cavity and lip carcinoma, epidemiology, 401 Ewings sarcoma, 580
367368 Herceptin for, 314 Ewings sarcoma/PPNET), 595
oropharyngeal cancer, 373374 pathology, 401 kidney cancer, 486, 487
osteosarcoma, 576577 screening for, 258 laryngeal cancer, 379
ovarian cancer, 480, 481t staging, 401402 limb-conserving
pancreatic cancer, 405406 Stomach cancer treatment, 402403 chondrosarcoma, 581
paranasal sinus tumours, 365, 366, adjuvant chemoradiation, 403 osteosarcoma (osteogenic
366f palliative, 403 sarcoma), 577578
penile cancer, 507 perioperative chemotherapy, 403 soft tissue sarcomas, 571, 573
prostate cancer, 495 radiation techniques, 403 low-grade gliomas, 541
retinoblastoma, 565 surgery, 402 neurosurgery principles, 535536
stomach cancer, 401402 Stopping power, 18 non-melanoma skin cancer, 323
testicular cancer, 502, 503t Storage of contaminated belongings, 119 non-small cell lung cancer, 418419
652
Index
653
Index
Thyroid cancer (Continued) prostate cancer, 495t linear accelerator machines, 135, 136f
follicular, 388 skin cancer, 327t morbidity, 590
follow-up policy for patients, 393394 stomach cancer, 401402 side effects, 524
high-risk and low-risk patients, 387 see also Staging of cancer technique, 524
Hurthle cell carcinoma, 391392 Tobacco smoking see Smoking Total mesorectal excision (TME), rectal
hypocalcemia management, 390 Tolerances cancer, 411
iodine-131 for, 115, 116 brain, 537 Total nodal irradiation (TNI), Hodgkins
locoregional recurrence, management, in children, 588 lymphoma, 515
390 combined, 215216 Total quality management (TQM), 224
lymphoma, 391, 393 doses for organs, 160, 161t Total skin electron irradiation (TSEI),
management, 388 non-small cell lung cancer, 419420 181
medullary, 390391 normal tissue, 290, 536537 Total skin electron therapy (TSET), 181
metastatic disease, 390 quality control, 213214, 215216 Total skin electron (TSE), 135, 137f
Orphan-Annie appearance, 387388 setting, 215 Toxicity concerns
patient pathway, 386387 Tomographic imaging anal cancer treatment, 415
presentation, 386387 aims, 85 bone marrow, 304
radio-iodine ablation, 389390 cone beam CT, 86 children, radiotherapy in, 587588
radionuclide imaging, 108 contrast improvement/localization in head and neck cancer treatment,
sarcoma, 391 3D, 85 352354
surgery, 388389 conventional tomography, 85 liver, 308
thyroglubulin, 390 CT virtual simulator, 87 non-Hodgkins lymphoma treatment,
Thyroidectomy, 115, 388 dedicated radiotherapy systems, 87 524
prophylactic, 391 dynamic, 8687 non-small cell lung cancer, 425
transient hypocalcemia following, 390 filtered back projection, 85, 86f rectal cancer treatment, 412
Thyroid function tests, 387 Fourier analysis, 85 small cell lung cancer treatment, 425
Thyroid gland gantry, 86 tamoxifen, 454
ablation, 115, 389390 gated, 87 teratoma treatment, 505506
anatomy, 385386 general construction of CT scanners, Traceability, dose measurement, 3536
cold nodules vs. hot nodules, 387 86f Tracheostomy, laryngeal cancer, 380
endocrine failure due to irradiation of, multislice CT, 86 Transcelomic spread, 274
361 practical configurations, 86 see also Metastasis
function, 108 radionuclides, 100 Transitional cell carcinoma (TCC)
malignancy see Thyroid cancer radiotherapy data types, 207 neoadjuvant chemotherapy, 491492
and NHL radiotherapy treatment, 523, reconstruction from projections, 85 renal pelvis, 486
524 third generation CT scanners, 86f Transitional cell epithelium, 277, 489
Thyroid lymphoma, 391 treatment verification systems, 87 Transplantation
radiotherapy for, 393 see also Computed tomography bone marrow, 589, 590
Thyroid stimulating hormone (TSH), (CT); X-rays hepatocellular carcinoma, 404
387, 389 Tomotherapy, head and neck cancer, 348 lymphoma treatment, 517
suppression, 388, 393394 Tomotherapy machines Transport of radioactive materials, 74
Thyrotoxicosis, 114115, 560 dedicated intensity modulated, 141 Trans-rectal/trans-vaginal ultrasound, 95
Thyroxine, 388, 389 general layout and components, 126 Transurethral resection (TUR), bladder
Tiatide, technetium-99m, 109 radiation treatment planning, cancer, 491
Tirapazamine, 286287 160161 Transverse imaging geometry, 207
Tissue Maximum Ratio (TMR), 183 Tongue cancer, brachytherapy, 199, Transverse magnetization, 89
TNM classification, 274275, 295 370371 Trastuzumab (Herceptin), 270, 303, 314
anal cancer, 413 Tonsillar tumours, radiation technique, breast cancer, 461462
bladder cancer, 491t 375 pancreatic cancer, 407
breast cancer, 436437, 437t Tonsillectomy, 374 stomach cancer, 403
colon cancer, 408 Topetecan, 311 Trauma, keratinocyte skin tumours, 319,
kidney cancer, 487, 488t Topoisomerase inhibitors, 310311 320f
melanoma, 332333 Tositumomab (Bexxar), 117 Treatment beams (megavoltage photon
mesothelioma, 426 Total body electron therapy (TBE), therapy)
nasopharyngeal cancer, 359360 mycosis fungoides, 525526 arc therapy, 166
non-small cell lung cancer, 422 Total body irradiation (TBI), 182 asymmetric fields, 163
pancreatic cancer, 405406 body immobilization, 148 beam energy, 163
paranasal sinus tumours, 365 in children, 590 beam shaping devices, 165
penile cancer, 507t leukaemia, 524 blocks, 165
654
Index
compensators, 164 germ cell see Germ cell tumours pleural effusions, 611
dynamic treatment techniques, 166 histological type, 275, 295 radionuclide imaging compared,
extended focus skin distance plans, imaging 9798
164 gallium, 107 scanners, 9394
intensity modulated radiotherapy, MIBG, 107108 specific conditions
165166 MIBI, 107 breast cancer, 436
isocentric plans, 163164 oncoscint, 108 eye and orbit, affecting, 564
multileaf collimators, 165 somatostatin receptor, 108 kidney cancer, 487
segmented fields, 165 thallium, 107 thyroid cancer, 108, 387
wedges, 164 tumour kinetic information, Ultraviolet light
Treatment modality, 297298 imaging modalities, 155 carcinogenesis, 271
Treatment planning, radiation irregularly shaped, brachytherapy for, keratinocyte skin tumours, 318
see Radiation treatment planning 190 melanoma risk, 260
Treatment Planning System (TPS), keratinocyte skin see Keratinocyte skin oral cavity cancer, 368
beams eye view, 153f tumours reducing exposure to, 263
Treatment reference point, 153154 locoregional spread, 295 Undescended testis, 272
Treatment verification systems, 87, 151, magnetic resonance imaging, 92 Unique identifier (UID), 206, 208
152f malignant see Cancer; Melanoma United Nations Scientific Committee on
Treatment volume, 149 markers see Tumour markers the Effects of Atomic Radiation
prostate cancer, 500 neck, 78 see also Head and neck cancer (UNSCEAR), 6061
Treosulphan, 261 neuroendocrine see Neuroendocrine United States (USA), cancer in, 250
Tricyclic drugs, 299 disease Unsealed radionuclide therapy, 113119
Triiodothyronine, 388, 389 neutron interactions, 3031 bone pain palliation, 116
Trimodality therapy, oesophageal operability, 295 intra-articular/intracavitary
cancer, 400 organ of origin, 295 treatments, 115116
Tuberous sclerosis, 570 pathological examination of excised iodine-131 for thyroid disease,
Tube stand, orthovoltage machine on, tissue, 296 114115
122 peripheral nerve, 570 iodine-131 MIBG therapy for
Tubulin polymerizing agents, 310 response to radiation, 291 neuroendocrine disease, 116117
Tumour control probability (TCP), 161 sex-cord, 482 phosphorus-32, for refractory
Tumour hypoxia, tumour hypoxia, site, 295 myeloproliferative disease, 115
285287 size, 190, 295, 375 radiation protection, waste and
Tumour lysis syndrome, 614 skin appendage, 337339, 338f regulations, 117119
Tumour markers soft-tissue see Soft-tissue tumours radiolabelled monoclonal antibodies,
breast cancer, 439 staging see Staging of cancer in non-Hodgkins lymphoma,
ovarian cancer, 480 stroma, 275 114, 117
pancreatic cancer, 406 undifferentiated, 277 Urethra, 506
testicular cancer, 501502 vaginal, 482483 Urine testing, bladder cancer, 490
Tumours vulval, 482483 Urothelium, 277
adnexal, 337339 Tumour suppressor genes, 269270 Uterus
benign, 268269, 273 Tungsten target, 6, 8f diagram, 471f
bladder cancer x-ray beam, 127128 sarcomas of, 479
invasive (T2, T3 and T4 tumours), Tykerb (lapatinib), 314 UVA (ultraviolet A) exposure, 318, 319
491 Tylosis, 396397 UVB light, 271
superficial Ta and T1 tumours, 491 Tyrosine kinase, 390
bone imaging, 100, 104107 Tyrosine kinase inhibitors (TKIs), 314
V
brain see Brain tumours gastrointestinal stromal tumours,
central nervous system see Central 415 Vagina, diagram, 471f
nervous system (CNS) tumours kidney cancer, 487, 489 Vaginal tumours, 482483
chemotherapy, assessing response to, Valence, 6
302 Van de Graff generator designs, 125
U
clinical decisions, factors governing, Vandetanib, 391
295, 296 U-frame, thermoplastic shells, 147 Van Nuys Prognostic Index, ductal
deep-seated, 28 Ulcer, non-healing, 343 carcinoma-in-situ, 437438
degree of differentiation, 295 Ultrasound imaging, 9295 Variances, combining with tolerances,
distant metastases, 295 advantages, 78 215
fast-growing or slow-growing, 257 clinical applications, 9495 Varian RPM system, respiratory gated
functioning, 274 definitions, 92 radiotherapy, 444f
655
Index
656