IAEA Training Material on Radiation Protection in Radiotherapy

Radiation Protection in
Radiotherapy

Part 3

Biological Effects
Lecture 2: High Doses in Radiation Therapy
Overview
 Radiobiology is of great importance for
radiotherapy. It allows the optimization of
a radiotherapy schedule for individual
patients in regards to:
 Total dose and number of fractions
 Overall time of the radiotherapy course
 Tumour control probability (TCP) and normal
tissue complication probability (NTCP)

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 2

Objectives
 To understand the radiobiological background
of radiotherapy
 To be familiar with the concepts of tumour
control probability and normal tissue
complication probability
 To be aware of basic radiobiological models
which can be used to describe the effects of
radiation dose and fractionation

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 3

Contents
1. Basic Radiobiology
2. The linear quadratic model
3. The four ‘R’ s of radiotherapy
4. Time and fractionation

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 4

1. Basic Radiobiology
 The aim of radiotherapy is to kill tumor cells
and spare normal tissues
Brachytherapy sources
Beam 2
Beam 1 Beam 3

patient
tumor

 In external beam and brachytherapy one

inevitably delivers some dose to normal
tissue
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 5
Basic Radiobiology: target
 The aim of radiotherapy is to kill tumour cells - they
may be in a bulk tumor, in draining lymph nodes
and/or in small microscopic spread.
 Tumour radiobiology is complex - the response
depends not only on dose but also on individual
radiosensitivity, timing, fraction size, other agents
given concurrently (e.g. chemotherapy), …
 Several pathways to tumour sterilization exist (e.g.
mitotic cell death, apoptosis (= programmed cell
death), …)

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 6

Survival curves

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 7

Radiobiology: tumor
 Irradiation kills cells
 Different mechanisms of cell kill
 Different radio-sensitivity of different
tumours
 Reduction in size makes tumour
 better oxygenated
 grow faster

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Radiobiology: micrometastasis
 Tumours may spread first through
adjacent tissues and lymph nodes
nearby
 Need to irradiate small deposits of
clonogenic cells early
 Less dose required as each fraction of
radiation reduces the number of cells by
a certain factor

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The target in radiotherapy
 The bulk tumour
 may be able to distinguish
different parts of the tumour
in terms of radiosensitivity
and clonogenic activity
 Confirmed tumour spread
 Potential tumour spread

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Reminder
 Palpable tumour (1cm3) = 109cells !!!
 Large mass (1kg) = 1012 cells - need
three orders of magnitude more cell kill
 Microscopic tumour, micrometastasis =
around 106 cell -
need less dose

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Radiobiology: normal tissues
 Sparing of normal tissues is essential for
good therapeutic outcome
 The radiobiology of normal tissues may be
even more complex as the one of tumours:
 different organs respond differently
 there is a response of a cell organization
not just of a single cell
 repair of damage is in general more
important

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Different tissue types
 Serial organs (e.g.  Parallel organs (e.g.
spine) lung)

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Different tissue types
 Serial organs (e.g.  Parallel organs (e.g.
spine) lung)

Effect of radiation on the organ is different

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Volume effects
 The more normal tissue is irradiated in
parallel organs
 the greater the pain for the patient
 the more chance that a whole organ fails

 Rule of thumb - the greater the volume

the smaller the dose should be
 In serial organs even a small volume
irradiated beyond a threshold can lead
to whole organ failure (e.g. spinal cord)
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 15
Classification of radiation
effects in normal tissues
 Early or acute  Late reactions
reactions  Telangectesia
 Skin reddening,  Spinal cord injury,
erythema paralysis
 Nausea  Fibrosis
 Vomiting  Fistulas
 Tiredness  Occurs later than 6
 Occurs typically months after
during course of RT irradiation
or within 3 months
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Classification of radiation
effects in normal tissues
 Early or acute  Late reactions
reactions

Late effects can be a result

of severe early reactions:
consequential radiation injury

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Late effects
 Often termed complications (compare ICRP report 86)
 Can occur many years after treatment
 Can be graded - lower grades more frequent

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 18

A comment on vascularisation
 Blood vessels play a very important role
in determining radiation effects both for
tumours and for normal tissues.
 Vascularisation determines oxygenation
and therefore radiosensitivity
 Late effects may be related to vascular
damage

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Summary of radiation effects
 Target in radiotherapy is bulk tumour and confirmed
and/or suspected spread
 Need to know both effects on tumour and normal
tissues
 Normal tissues need to be considered as a whole
organ
 Radiation effects are complex - detailed discussion of
radiation effects is beyond the scope of the course
 Models are used to reduce complexity and allow
prediction of effects...

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There is considerable clinical experience with
radiotherapy, however, new techniques are
developed and radiotherapy is not always
delivered in the same fashion

Radiobiological models can help to

predict clinical outcomes when treatment
parameters are altered (even if they may
be too crude to describe reality exactly)
Radiobiological models
 Many models exist
 Based on clinical experience, cell
experiments or just the beauty or simplicity of
the mathematics
 One of the simplest and most used is the so
called “linear quadratic” or “alpha/beta” model
developed and modified by Thames, Withers,
Dale, Fowler and many others.

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2. The Linear
Quadratic Model
 Cell survival:
single fraction: S = exp(-(αD + βD2))
(n fractions of size d: S = exp(- n (αd + βd2))
 Biological effect:
E = - ln S = αD + βD2
E = n (αd + βd2) = nd (α + βd) = D (α + βd)

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 Biological effectiveness
E/α = BED = (1 + d / (α/β)) * D = RE * D

 BED = biologically effective dose, the dose

which would be required for a certain effect
at infinitesimally small dose rate (no beta
kill)
 RE = relative effectiveness

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 Quick question???

What is the physical unit for the a/b ratio?

BED useful to compare the effect of
different fractionation schedules
 Need to know a/b ratio of the tissues
concerned.
 a/b typically lower for normal tissues
than for tumour

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The linear quadratic model
1
0 2 4 6 8 10
Probability of cell survival

0.1

0.01

cell kill (low a/b)

cell kill (high a/b)

0.001
Dose (Gy)

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The linear quadratic model
1
0 2 4 6 8 10
Alpha determines
initial slope
Probability of cell survival

0.1

Beta determines
0.01
curvature
cell kill (low a/b)
cell kill (high a/b)

0.001
Dose (Gy)

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Rule of thumb for a/b ratios
 Large a/b ratios  Small a/b ratio
 a/b = 10 to 20  a/b = 2
 Early or acute  Late reacting
reacting tissues tissues, e.g. spinal
 Most tumours cord
 potentially prostate
cancer

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 29

The effect of fractionation
1
0 2 4 6 8 10
Probability of cell survival

0.1

0.01 cell kill (low a/b)

cell kill (high a/b)
fractionated (low a/b)
fractionated (low a/b)

0.001
Dose (Gy)

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 30

Fractionation
 Tends to spare late reacting normal
tissues - the smaller the size of the
fraction the more sparing for tissues
with low a/b
 Prolongs treatment

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A note of caution
 This is only a model
 Need to know the radiobiological data
for patients
 Important assumptions:
 There is full repair between two fractions
 There is no proliferation of tumour cells -
the overall treatment time does not play a
role.
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 32
3. The 4 Rs of radiotherapy
 R Withers (1975)

 Reoxygenation
 Redistribution
 Repair
 Repopulation (or Regeneration)

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Reoxygenation
 Oxygen is an important enhancement for
radiation effects (“Oxygen Enhancement
Ratio”)
 The tumour may be hypoxic (in particular in
the center which may not be well supplied
with blood)
 One must allow the tumour to re-oxygenate,
which typically happens a couple of days
after the first irradiation

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 34

Redistribution
 Cells have different radiation sensitivities in
different parts of the cell cycle
 Highest radiation sensitivity is in early S and
late G2/M phase of the cell cycle
G2 M (mitosis)

G1

S (synthesis)

G1
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 35
Redistribution
 The distribution of cells in different
phases of the cycle is normally not
something which can be influenced -
however, radiation itself introduces a
block of cells in G2 phase which leads
to a synchronization
 One must consider this when irradiating
cells with breaks of few hours.

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 36

Repair
 All cells repair radiation damage
 This is part of normal damage repair in the
DNA
 Repair is very effective because DNA is
damaged significantly more due to ‘normal’
other influences (e.g. temperature,
chemicals) than due to radiation (factor
1000!)
 The half time for repair, tr, is of the order of
minutes to hours
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 37
Repair
 It is essential to allow normal tissues to repair
all repairable radiation damage prior to giving
another fraction of radiation.
 This leads to a minimum interval between
fractions of 6 hours
 Spinal cord seems to have a particularly slow
repair - therefore, breaks between fractions
should be at least 8 hours if spinal cord is
irradiated.

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 38

Repopulation
 Cell population also grows during
radiotherapy
 For tumour cells this repopulation partially
counteracts the cell killing effect of
radiotherapy
 The potential doubling time of tumours, Tp
(e.g. in head and neck tumours or cervix
cancer) can be as short as 2 days - therefore
one loses up to 1 Gy worth of cell killing when
prolonging the course of radiotherapy

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 39

Repopulation
 The repopulation time of tumour cells
appears to vary during radiotherapy - at the
commencement it may be slow (e.g. due to
hypoxia), however a certain time after the first
fraction of radiotherapy (often termed the
“kick-off time”, Tk) repopulation accelerates.
 Repopulation must be taken into account
when protracting radiation e.g. due to
scheduled (or unscheduled) breaks such as
holidays.

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 40

Repopulation/
Regeneration
 Also normal tissue repopulate - this is an
important mechanism to reduce acute side
effects from e.g. the irradiation of skin or
mucosa
 Radiation schedules must allow sufficient
regeneration time for acutely reacting tissues.

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 41

The 4 Rs of radiotherapy: Influence on
time between fractions, t, and overall
treatment time, T

 Reoxygenation  Need minimum T

 Need minimum t
 Redistribution
 Need minimum t for
 Repair normal tissues
 Repopulation (or  Need to reduce T for
Regeneration) tumour

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 42

The 4 Rs of radiotherapy: Influence on
time between fractions, t, and overall
treatment time, T

 Reoxygenation  Need minimum T

 Need minimum t
 Redistribution
 Need minimum t for
 Repair normal tissues
 Repopulation (or  Need to reduce T for
Regeneration) tumor

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 43

4. Time, dose and fractionation
 Need to optimize fractionation schedule
for individual circumstances
 Parameters:
 Total dose
 Dose per fraction
 Time between fractions
 Total treatment time

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 44

Extension of LQ model to include
time:
E = - ln S = n * d (α + βd) - γT

 γ equals ln2/Tp with Tp the potential doubling

time
 note that the γT term has the opposite sign to
the α + βd term indicating tumour growth
instead of cell kill

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 45

The potential doubling time
 the fastest time in which a tumour can
double its volume
 depends on cell type and can be of the order
of 2 days in fast growing tumours
 can be measured in cell biology
experiments
 requires optimal conditions for the tumour
and is a worst case scenario

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 46

Extension of LQ model to include
time:
E = - ln S = n * d (α + βd) - γT

Including Tk ("kick off time") which allows for

a time lag before the tumour switches to the
fastest repopulation time:

BED = (1 + d / (α/β)) * nd - (ln2 (T - Tk)) / αTp

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 47

Evidence for “kick off” time

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 48

Use of the LQ model in
external beam radiotherapy:
 Calculate ‘equivalent’ fractionation
schemes
 Determine radiobiological parameters
 Determine the effect of treatment
breaks
 e.g. Do we need to give extra dose for the
long weekend break?

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 49

Calculation of equivalent
fractionation schemes
 Assume two fractionation schemes are
identical in biological effect if they
produce the same BED
BED = (1+d1/(α/β))n1d1 = (1+d2/(α/β))n2d2
This is obviously only valid for one
tissue/tumour type with one set of
alpha, beta and gamma values
 Example at the end of the lecture

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Brachytherapy
 Typically not a homogenous dose
distribution
 Low dose rate treatment possible
 High dose rate treatments are typically
given with larger fractions than external
beam radiotherapy
 Pulsed dose rate somewhere in between

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 51

LQ model can be extended to
brachytherapy
 HDR with short high dose fractions can
be handled very similarly to external
beam radiotherapy
 However, the dose inhomogeneities
inherent in brachytherapy (compare
parts 6 and 11 of the course) make a
good calculation difficult.

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 52

LDR brachytherapy
 An extension of the LQ model to cover
low dose rates with significant repair
occurring during treatment
 Mathematics developed by R Dale
(1985)
 Too complex for present course…

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 53

Brachytherapy
 LQ model allows BED calculation for
brachytherapy
 comparison possible for external beam and
brachytherapy
 adding of biologically effective doses
possible
 Brachytherapy has the potential to
minimize the dose to normal structures -
probably still the most important factor
is good geometry of an implant
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 54
However, caution is necessary
 All models are just models
 The radiobiological parameters are not
well known
 Parameters for a population of patients
may not apply to an individual patient

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 55

A note on different radiation
qualities
 Not only in radiation protection is there
a different effectiveness of different
radiation types - however:
 The effect of concern is different
 The Relative Biological Effectiveness (RBE
values) is different - e.g. for neutrons in
therapy RBE is about 3
 The effect of fractionation may be VERY
different

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 56

Adapted from Marco Zaider (2000)
Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 57
Comparison of dose response of
neutrons and photons

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 58

Summary
 Radiobiology is essential to understand the
effects of radiotherapy
 It is also important for radiation protection of
the patient as it allows minimization of the
radiation effects in healthy tissues
 There are models which allow to estimate the
effect of a given radiotherapy schedule
 Caution is necessary when applying a model
to an individual patient - clinical judgement
should not be overruled

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 59

Where to Get More
Information
 Other sessions
 References:
 Steel G (ed): Radiobiology, 2nd ed. 1997
 Hall E: Radiobiology for the radiologist, 3rd
ed. Lippincott, Philadelphia 1988
 Withers R. The four Rs of radiotherapy.
Adv. Radiat. Biol. 5: 241-271; 1975

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 60

Any questions?
 Question:

Please calculate the dose per fraction in a five fraction

treatment for a palliative radiotherapy treatment which
results in the same biologically effective dose to the
tumour as a single fraction of 8Gy (assume a/b = 20Gy
(tumour) or 2Gy (spinal cord)).
Answer (part 1)
 Assuming no time effects (i.e. time between fractions
is large enough to allow full repair and the overall
treatment time is short enough to prohibit significant
repopulation during the treatment) the biologically
effective dose (BED) of the treatment schedules can
be calculated as
 BED = nd (1 + d/(a/b)) with n number of fractions, d
dose per fraction and a/b the alphabeta ratio
 BED (tumour, single fraction) = 1 * 8 (1 + 8/20) =
11.2Gy

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 63

Answer (part 2)
 to get a similar BED in five fractions for the tumour,
one needs to deliver 2Gy per fraction (BED = 11Gy)
 BED (spinal cord, single fraction) = 1 * 8 (1 + 8/2) =
40Gy
 to get a similar BED in five fractions for the spinal
cord, one needs to deliver 3.1Gy per fraction (BED =
39.5Gy)
 This example illustrates how much more sensitive late
reacting normal tissue is to fractionation. The single
dose of 8Gy is nearly 4 times more toxic to spinal
cord than to a tumour.

Radiation Protection in Radiotherapy Part 3, lecture 2: High doses in radiation therapy 64