Errors and Margins in Radiotherapy

Marcel van Herk

Clinical radiotherapy procedures aim at high accuracy.
However, there are many error sources that act during
treatment preparation and execution that limit the ac-
curacy. As a consequence, a safety margin is required
to ensure that the planned dose is actually delivered to
the target for (almost) all patients. Before treatment
planning, a planning computed tomography scan is
made. In particular, motion of skin with respect to the
internal anatomy limits the reproducibility of this step,
introducing a systematic setup error. The second im-
portant error source is organ motion. The tumor is
imaged in an arbitrary position, leading to a systematic
organ motion error. The image may also be distorted
because of the interference of the scanning process and
organ motion. A further systematic error introduced
during treatment planning is caused by the delineation
process. During treatment, the most important errors
are setup error and organ motion leading to day-to-day
variations. There are many ways to dene the margins
required for these errors. In this article, an overview is
given of errors in radiotherapy and margin recipes,
based on physical and biological considerations. Respi-
ration motion is treated separately.
2004 Elsevier Inc. All rights reserved.
T
he treatment process of external beam ra-
diotherapy of solid tumors inherently intro-
duces geometrical uncertainties. The main
sources of uncertainty are tumor delineation in-
accuracies of the gross tumor volume (GTV),
unknown extent of microscopic tumor, organ po-
sitional variation within the patient, and setup
variations. Recently, much attention has been
paid to measurement and reduction of geometri-
cal errors. However, residual uncertainties al-
ways remain. In conformal radiotherapy, these
uncertainties are generally handled by a safety
margin. The purpose of this article is to summa-
rize error sources in radiotherapy, describe meth-
ods for quantifying the errors, and describe the
impact that these errors have on the dose deliv-
ered to the clinical target volume (CTV). Next,
we will discuss treatment margins based on phys-
ical and biological considerations. Finally, a num-
ber of controversies concerning errors and mar-
gins will be discussed.
Errors in Radiotherapy
High geometrical accuracy is a prerequisite for a
safe clinical application of conformal radiother-
apy. Several factors contribute to the overall
treatment accuracy.
1
In this article, we will use
the word error to describe any deviation be-
tween planned and executed treatment, however
small it is. Gross errors, which should be caught
using quality assurance procedures, are outside
the scope of this article. Usually, it is possible to
reduce the magnitude of small errors at an
increase of workload (eg, by implementing portal
imaging or on-line image-guided radiotherapy).
At present, one expands the CTV with a safety
margin to obtain the planning target volume
(PTV). The PTV is given a high dose to ensure
that the CTV receives adequate dose despite
small geometrical errors.
Several geometrical uncertainties are involved
in the delineation process of the GTV. First, the
imaging modalities have a limited resolution, in
particular perpendicular to the slice planes caus-
ing the partial volume effect.
2
Then, there is
observer noise (ie, when the same observer is
asked to delineate the target volume twice, the
answer will not be the same, intraobserver vari-
ation).
3,4
Interpretation differences between ob-
servers or image modalities are also important.
4-8
If different or unclear guidelines are used for
target volume delineation, this will have a major
impact on the consistency of delineated struc-
tures.
9-11
Delineation uncertainty is a purely sys-
tematic error; it will inuence all treatment frac-
tions in an identical way through the treatment
planning process.
According to International Commission on Ra-
diation Units and Measurements (ICRU) Report
50,
12
the CTV is dened as the GTV plus the
regions with suspected microscopic tumor. This
CTV may be the GTV plus a margin or it may
include nodal regions as well. For prostate can-
From the Department of Radiotherapy, The Netherlands Cancer
Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Nether-
lands.
Address reprint requests to Marcel van Herk, PhD, Department of
Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwen-
hoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The
Netherlands.
2004 Elsevier Inc. All rights reserved.
1053-4296/04/1401-0007$30.00/0
doi:10.1053/j.semradonc.2003.10.003
52 Seminars in Radiation Oncology, Vol 14, No 1 ( January), 2004: pp 52-64
cer, a combination of clinical ndings and other
tumor characteristics (like the prostate-specic
antigen level and Gleason score) are used to
estimate the probability of microscopic capsular
invasion and involvement of the seminal vesi-
cles.
13-16
These estimations are based on pathol-
ogy of resected prostates. A statistical atlas of
tumor spread in the prostate was presented by
Chen et al.
17
Kestin and colleagues,
18
among oth-
ers, gathered statistics of tumor spread in the
seminal vesicles. Also, for head and neck and
nonsmall-cell lung cancer, surgical resection
specimens have been analyzed to provide infor-
mation on the probabilities of microscopic tumor
deposits.
19
Numerous authors have presented data on
setup accuracy.
20-22
With careful immobilization
or well-designed setup protocols,
23-26
a setup ac-
curacy for each axis of 2-mm SD or better can be
achieved for prostate irradiation. For other treat-
ment sites, such as the head and neck, smaller
setup errors are achieved by routinely applying
rigid immobilization.
27
For the lung, setup errors
in the order of 2 to 4 mm have been reported.
28
Setup error has both a random and a systematic
component. In particular, motion of skin with
respect to the internal anatomy limits the repro-
ducibility of the patient setup on the computed
tomography (CT) scanner, introducing a system-
atic setup error.
Another important source of uncertainty is
organ motion.
29-33
The motion of the prostate
during treatment has been investigated by im-
planting markers and measuring their posi-
tion relative to the bony anatomy using portal
imaging or under uoroscopy.
34,35
Alternatively,
repeat CT scans have been used to study the
movement of organs during the course of radio-
therapy.
30,36-38
For example, we observed that a
translation (mainly in the anterior-posterior di-
rection) and a rotation (mainly around the left-
right axis) could describe the combined motion of
prostate and seminal vesicles.
39
These results are
in good agreement with ndings of other au-
thors.
21,34,36,38
In the lung, in particular for le-
sions close to the diaphragm, tumor movement
with 2- to 3-cm amplitude is possible.
20,29,40
To
precisely plan and treat lung tumors, it is there-
fore important to reduce this movement.
33
Organ
motion causes both systematic and random er-
rors. Even though no movement occurs as such in
the CT scan, the organ movement is frozen by
the action of taking the CT image (ie, the beam
will be targeted at the arbitrary position the
moving organ had during the scan).
Specication and Computation of Errors
In the overview of errors in radiotherapy, errors
were classied as random and systematic. Sup-
pose that we have measured an error on a daily
basis for a number of patients and fractions.
Figure 1 shows how these data are analyzed to
determine the SD of the random error, , the SD
of the systematic error, , and the overall mean
(or group systematic) error, M. Mean and SD of
the daily measurements are rst obtained per
patient. The group systematic error is just the
mean of all means. One expects this error to be
small. However, M often deviates signicantly
from zero because of imprecision in the equip-
ment (lasers) and procedure. The SD of the
means per patient is an estimator for the SD of
the systematic error. It described how reproduc-
ible the treatment preparation is performed. The
individual SDs give the SD of the random error
for each patient. When the number of measure-
ments per patient is limited, differences between
individual patients are difcult to prove. There-
fore, in general, group means of the SD of the
random error are presented. The correct way to
determine this group mean is to determine the
root mean square of the SDs of all patients.
Besides errors that vary from patient to patient
or from fraction to fraction, there are also move-
ments that occur within a single fraction. In par-
ticular, respiration motion and peristaltic motion
Fig 1. Estimation of the SD of random and systematic
errors based on measurements in a population of pa-
tients. The numbers in this table could represent, for
instance, a shift of the patient in millimeters in the
left-right direction determined using electronic portal
imaging. For each patient, the mean and SD of mea-
surements of several fractions is determined. Different
combinations of these values give an estimate of the
errors for a population of patients.
Errors and Margins in Radiotherapy 53
have a time scale that is shorter than the delivery
time of a single fraction.
Table 1 gives an example overview of uncer-
tainties during radiotherapy of the prostate (ran-
dom and systematic translations and rotations)
measured in our institute. In general, uncertain-
ties that are introduced during treatment prep-
aration (ie, once) are larger than day-to-day
variation during treatment execution. The mag-
nitude of all uncertainties is similar. This means
that all uncertainties should be addressed to sig-
nicantly reduce the overall uncertainty. Rota-
tional errors are signicant in some cases.
38,39,41
Effect of Errors on the Dose
The effect of random and systematic errors on
the dose is different.
42,43
Random errors blur the
dose distribution,
44
whereas systematic errors
cause a shift of the cumulative dose distribution
relative to the target. The blurring can be de-
scribed as a convolution of the dose distribution
with the probability distribution function of the
random error.
45
This method is not completely
correct but is quite accurate in practice.
46-49
It
was found that the error in convolution follows a
Gaussian distribution with a width equal to the
SD of the random deviations divided by the
square root of the number of fractions.
47-49
Breathing motion can be handled similarly.
45,47,50
Whereas the blurring of the dose distribution
because of random errors and respiration over a
large number of fractions is predictable, the ef-
fect if the systematic error will be unknown for
each individual patient (insofar it has not been
measured and corrected) and it must be treated
statistically. Two procedures for this purpose
have been described in the literature. Stroom et
al
51
showed that a convolution of a binary image
of the target leads to a coverage probability map
that can be used to determine the average dose-
volume histogram over a patient population. van
Herk et al
43
derived cumulative probability dis-
tributions of the dose delivered to the CTV for a
given treatment plan and called these distribu-
tions dose-population histograms. Analytically, it
was possible to derive dose-population histo-
grams for a spherical symmetry for the minimum
dose delivered to the CTV (Fig 2). In later work,
a Monte Carlolike method was used to evaluate
probability distributions of dosimetric and bio-
Table 1. Overview of Prostate Treatment Uncertainties (SDs of Translations and Rotations) as Obtained by
Different Studies at the Netherlands Cancer Institute
Execution (random) Errors Preparation (Systematic) Errors
LR SI AP LR SI AP
Target volume delineation
8
1.7 mm 2..3.5 mm* 2 mm
Organ motion (translation)
39
0.9 mm 1.7 mm 2.7 mm 0.9 mm 1.7 mm 2.7 mm
Organ motion (rotation)
39
4.0 dg 1.3 dg 2.1 dg 4.0 dg 1.3 dg 2.1 dg
Setup error (translation)
23
2.0 mm 1.8 mm 1.7 mm 2.6 mm 2.4 mm 2.4 mm
Setup error (rotation)
41
1.1 dg 0.6 dg 0.5 dg 1.1 dg 0.6 dg 0.5 dg
Abbreviations: LR, left-right; SI, superior-inferior; AP, anterior-posterior.
*These values are because of the larger uncertainty in target volume delineation near the apex and the seminal vesicles.
These values are estimates of the preparation (systematic) error in case no portal imaging with a correction protocol would have
been applied.
Fig 2. Example of dose-population histograms for dif-
ferent margins (0, 6, and 12 mm) for the minimum in
the total dose delivered to the CTV over 36 fractions
based on the error statistics of Table 1. There is a
dramatic drop in the probability level of reaching an
acceptable minimum dose as the margin is reduced.
When there is zero margin, the probability of giving a
high dose to the target is zero because the dose distri-
bution will completely t around the CTV, such that
only a zero error will lead to a high dose, whereas the
probability of zero error is extremely small.
54 Marcel van Herk
logic parameters.
52
Besides translations and ro-
tations, tumor and normal tissue shape variations
occur that require more complex strategies to
take them into account.
53,54
Incorporation of Uncertainties Into
Treatment Planning: Margins
According to ICRU Reports 50
12
and 62,
55
setup
and organ positional uncertainties should be in-
corporated into the treatment planning process
by taking a margin around the CTV, thereby
dening the PTV. How these margins should be
dened as a function of the distribution of organ
position and setup errors was not specied. In the
Northern Association of Clinical Physics recom-
mendation,
56
separate margins were proposed for
positioning uncertainty and for organ motion,
called the setup margin and the internal margin,
respectively. This concept of separate margins
suggests that a linear separation of the internal
errors (organ motion) and setup errors can be
made. However, because external error sources
and internal error sources are generally not cor-
related, a linear addition of their standard devi-
ations is, in general, not correct.
43,49
Several margin recipes have been published,
however, with little supporting data for the clin-
ical impact of the given recipe and often ignoring
preparation (systematic) errors. Austin-Seymour
et al
57
dened an anisotropic margin for setup
and organ position errors by a cylindrical expan-
sion of the CTV. By targeted interviews of phy-
sicians, it was found that recorded PTV margins
corresponded to a nominal probability of 75%.
Hunt et al
58
showed that the required margin for
random errors depends on treatment technique
and eld design. Bel et al
59
showed, through sim-
ulation, that a margin for random deviations of
0.7 times their SD is adequate to keep a 95% dose
coverage. This number of 0.7 depends on the
particular beam arrangement.
60
Aaltonen et al
56
derived a margin for random errors of 0.5 to 0.7
times the SD based on biological modeling. The
impact of preparation (systematic) errors was
tested by computing DVHs for a few possible
shifts, which conrmed that systematic errors are
much more important than random errors.
61
Extensive numerical simulations of prostate
radiotherapy have been performed by Killoran et
al.
62
These authors introduced the concept of
probability of prescription dose, which can be
described for each part of the anatomy. The
beam margin was iterated to ensure coverage up
to a given dose for a given fraction of the patient
population. Fontenla et al
63
described a method
to include the target shape into a quantitative
optimization process to derive treatment margins
explicitly accounting for uncertainties in the po-
sition of target and organs at risk.
A number of groups
49,51,64
explored the use of
coverage probability matrices to derive margins.
With this method, it is easy to include rotations
and the CTV shape of individual patients. In
addition, coverage probabilities can be used to
take organs at risk into account.
64
Stroom et al
51
provide the following margin recipe based on
coverage probability. A margin should be used
that is 2 times the total SD of systematic errors
plus 0.7 times the total SD of random errors to
ensure that, on average, 99% of the target volume
receives 95% of the prescribed dose or more. A
fundamental problem of coverage probabilities is
that they tend to undervalue sharp tumor exten-
sions, which are smeared out to very low proba-
bility levels and will not be included in the mar-
gin. Craig et al
49
described the relation between
the geometrical measure of CTV coverage and
tumor control probability (TCP) for random er-
rors and some systematic errors.
van Herk et al
43
used the minimum cumula-
tive CTV dose as a gauge for geometrical
misses. Based on the dose population histograms
as shown in Figure 2, they derived a margin
recipe to guarantee that 90% of patients in the
population receive a minimum cumulative CTV
dose of at least 95% of the prescribed dose. This
margin is approximately 2.5 times the total SD of
systematic plus 0.7 times the total SD of random
errors.
Lo f et al
65
accounted for both measured and
nonmeasured (random) positioning uncertainties
using a planning algorithm based on a combina-
tion of dynamic and stochastic optimization tech-
niques. Their formulation explicitly describes the
dependence of the treatment outcome on the
incident uence distribution, the patient geome-
try, the radiobiological properties of the patient,
and the fractionation schedule. However, they
consider that all systematic errors are measur-
able and correctable.
Errors and Margins in Radiotherapy 55
Margins: Biological Considerations
Goitein discussed the difference between random
and systematic errors using a simple biological
consideration in this issue. He found that the
slope of the dose-effect curve affects the impor-
tance of random and systematic errors. This
thought experiment is, however, an oversimpli-
cation because in practice, errors will often lead
only to a partial underdosage of the target and
not to a complete miss. A more detailed analysis
of the biological effects of random and systematic
errors was performed by van Herk et al.
52
We
evaluated realistic treatment plans in terms of
equivalent uniform dose (EUD) and TCP in the
presence of execution (random) and preparation
(systematic) geometrical errors. We found that a
margin of 10 mm between CTV and PTV is ad-
equate for 3-eld prostate treatments given the
accuracy level of our department, taking rota-
tional errors into account (ie, the TCP in a pop-
ulation of patients, TCP
pop
, is reduced less than
1% because of geometrical errors). When reduc-
ing the margin to 6 mm, the dose must be in-
creased from 80 to 87 Gy to maintain the same
TCP
pop
(Fig 3). Only in regions with a high-dose
gradient such a margin reduction leads to a de-
crease in normal tissue dose for the same TCP
pop
.
We also found a rough correspondence of the 84%
minimum dose with the 98% EUD. Based on this
correspondence, a margin recipe was dened to
give 90% of patients at least 98% EUD, a margin
of 2.5 0.7 3 mm must be used. This recipe
corresponds accurately with 1% TCP
pop
loss for
prostate plans with clinically reasonable values of
and . Amer at al
66
used similar Monte Carlo
based analyses to determine the effect of differ-
ent correction strategies on TCP.
66
Both studies
excluded simulation of biological fractionation
effects. Van Herk et al
47
showed that, because of
biological fractionation effects, the effective total
dose distribution becomes slightly wider: 0.4 mm
for / 1 Gy and a random error SD of 3 mm,
whereas the widening increased with random error.
Remaining biological issues are the effect of
tumor cell density distribution and the effect of
unknown tumor cell presence on margin require-
ment.
67
These effects can be studied through
simulations, but clinical data are scarce. The ad-
vent of biological imaging, such as positron emis-
sion tomography (PET), promises more biological
information on a patient by patient basis.
68
How-
ever, validation of the different imaging tech-
niques (eg, by correlation with pathology) re-
mains to be done. Recently, we performed
simulation studies including different tumor cell
density distributions.
69
When the tumor cell den-
sity is concentrated on one side of the CTV (typ-
ical for prostate), the TCP
pop
loss decreases. This
effect is caused by the effective larger margin on
the side with the lower cell density. The effect
stabilizes when the ratio of tumor cell densities
exceeds 1,000, at a TCP
pop
loss that is about 30%
of the TCP
pop
loss for a uniform cell density. A
similar reduction in TCP
pop
loss may be reached
by a 2-mm increase in margin. When there is a
5-mm shell of reduced tumor cell density (simu-
lating the region between GTV and CTV), the
TCP
pop
loss because of geometrical errors also
Fig 3. Effect of geometrical
errors on TCP
pop
as function
of dose in a population of
patients, TCP
pop
, for differ-
ent margins. The computa-
tion includes effects of geo-
metrical errors, as specied
in Table 1. There is a thresh-
old margin, below which the
TCP
pop
will start to decrease
sharply. In this case, a re-
duction of the margin from
10 mm to 6 mm will lead to
a 10% TCP
pop
loss and re-
quires about 10% dose esca-
lation to compensate.
56 Marcel van Herk
decreases. This effect stabilizes at a cell density
ratio of 10,000, indicating that the penumbral
dose is adequate to eradicate such a low tumor
cell density when it is moved outside the high-
dose region due to the presence of geometric
errors.
Effect of Respiration
Respiration motion during imaging has 2 ef-
fects.
70
First, the image is blurred (approxi-
mately) over the time and space corresponding to
a single slice. Second, the image is distorted be-
cause of the relative speed of motion and scan-
ning. If the scanning time is very short with
respect to the respiration cycle, the tumor is
imaged in an arbitrary respiration phase, leading
to a systematic organ motion error. In practice,
the image is distorted due to the interference of
the scanning process and the respiration. The SD
of the distortion is just given by the SD of the
respiration motion, which is typically about one
third of the peak-peak amplitude.
47
Respiration
motion during treatment causes an asymmetric
deviation in the shape of the total dose distribu-
tion. Please note that irrespective of the shape of
the probability distributions, SDs will add in
quadrature. With a random error SD of 3 mm
and respiration amplitude of 1 cm or less (SD
0.36 cm), the asymmetry is negligible.
47
For res-
piration motion in excess of 1 cm in amplitude,
isodose lines shift in a distinctly asymmetric fash-
ion and asymmetric margins need to be used.
Applying a common margin recipe (2.5 SD of
systematic errors plus 0.7 SD of random errors)
to respiration motion only, the total margin that
is required is about the peak-peak amplitude.
This nding is not surprising because such a
margin ensures that the period motion is always
covered. However, it is a nice illustration of the
validity of this common margin recipe that was
derived for normally distributed errors, even in
the case of an explicit nonnormal distribution
because of respiration. Because movements be-
cause of respiration and movement of the beam
are on the same time scale, there may be some
interference between both variations leading to
hot and cold spots delivered in a single fraction.
71
Bortfeld et al
72
also discuss these effects.
Our ndings are in contradiction with sugges-
tions by McKenzie
50
that argue that respiration
motion should not be treated as Gaussian and
that it should be combined linearly with other
errors instead of in quadrature as other error
sources. Our results agree with those in Engels-
man et al
73
in that respiration motion with clin-
ical relevant amplitude has a small impact on the
dose compared with other errors that may occur
in clinical practice.
Note that in a study by van Herk et al
47
a zero
systematic error is assumed. In practice that
means that a representative CT scan has to be
available showing the tumor exactly in the aver-
age position. Methods to obtain representative
CT scans are slow scanning,
74
respiration corre-
lated CT,
75,76
or fast 4-dimensional magnetic res-
onance imaging.
77
In a slow scanning method, the
CT scanner is run slowly and/or multiple CT
scans are averaged such that multiple respiration
phases are recorded per slice. A disadvantage of
slow CT scan methods is the loss of the resolution
because of motion. It has been suggested that
PET, which inherently performs slow scanning, is
also a good solution to estimate the motion path
of a tumor.
78
However, also for PET motion re-
sults in blurring of the object and respiration
gated PET may be a better option. The most
promising solution to obtain high quality CT data
in presence of respiration motion is respiration
correlated CT.
75,76
Here 4-dimensional data are
acquired that can be analyzed to determine the
mean tumor position.
Discussion
How Should Errors Be Added?
As seen from the tumor, there is almost no dif-
ference between organ motion, setup error and
delineation error. All of these errors lead to a
shift of the high dose region away from the CTV
and these errors should therefore be treated
equally. This means that for an individual pa-
tient, all these errors must be added linearly. In
terms of SDs, this means that the SDs must be
added in quadrature. There is, however, a
marked difference between random and system-
atic errors if multiple fractions are delivered.
Importance of Systematic Errors
All fractions are inuenced the same by the sys-
tematic errors, whereas random errors will point
in different directions for different fractions
this results, in general, in a much smaller dose
Errors and Margins in Radiotherapy 57
effect of random errors than of systematic errors.
This difference is reected in the margin recipes
by Stroom et al
51
and van Herk et al.
43
The
blurring effect of the random errors leads to
small decrease of dose at the edge of the high-
dose region that will moderately affects all pa-
tients. The systematic errors, on the other hand,
lead to a shift of the dose that will strongly affect
some patients (ie, when the shift is such that the
CTV moves outside the high-dose region). When
allowing a xed reduction of the minimum cumu-
lative dose (ie, to 95%), the margin for random
errors is small (ie, 0.7 ). As mentioned in the
biological effects of errors section, the relative
effect of this dose reduction compared with the
effect of geometrical misses caused by systematic
errors depends on the slope of the dose-effect
relation. This effect can also be observed in the
work of van Herk et al,
52
in which nomograms
were presented of TCP
pop
loss as function of mar-
gin, random error, and systematic error. In Fig-
ure 4, similar data are shown; the required mar-
gin follows elongated elipses where random
errors are approximately half as important as
systematic errors, whereas the impact of group
systematic errors is small (Fig 4B). These gures
are consistent with the slope of the dose-related
curves, which is about 0.5 in the relevant dose
range (Fig 3).
Will Errors Ever Be Zero?
One might consider that because of modern de-
velopments in image-guided radiotherapy, it is
possible to eliminate all geometrical errors and it
may become safe to reduce the margin to zero.
However, in my opinion, it is impossible to com-
pletely eliminate all geometrical errors. For in-
stance, even if the treatment is completely accu-
rate, there will still be uncertainties in GTV and
CTV denition. Then, online systems for image-
guided radiotherapy will not be perfectly accu-
rate because of detection or observer errors in
the imaging system. Then there will always be
some delay between imaging and treatment lead-
ing to uncertainties because of short-term organ
movement. Then, there will be limits on the ac-
curacy of correction procedures. Finally, when
using indirect methods for detection of the tumor
position, there will still be the possibility of rela-
tive movement of the structure of reference and
the tumor.
What Dose Should Be Used to Evaluate a
Treatment Plan?
Because of geometrical errors, the planned dose
in PTV or CTV is not representative of the actual
dose delivered. Only in a very classical situation,
in which a homogeneous dose is planned for the
Fig 4. Nomogram of TCP
pop
loss as function of margin, random error SD (), and systematic error SD () with
a group systematic error (M) of 0 and 2 mm.
58 Marcel van Herk
PTV and large margins are used, is it to be
expected that the dose planned in the PTV will
be representative for the delivered dose in the
CTV. In a study by Stroom and Heijmen,
79
a
method is described to improve the representa-
tion of the dose delivered to the CTV by dening
what they call a representative target volume,
RTV, which is the CTV plus an adequate margin
according to a margin recipe. The dose that is
planned using a PTV with smaller margins, to
spare normal tissues, is then evaluated using the
RTV. For instance, the percentage volume in the
RTV that receives a smaller dose than, for exam-
ple, 95% of the dose in the specication point is
an indication of the probability of adequate CTV
coverage. An even better solution would be to
incorporate a Monte Carlolike evaluation sys-
tem in the planning system, allowing computa-
tion of probability distributions of the dose in the
CTV. In that case, it becomes possible to cor-
rectly evaluate the risk of a smaller margin ver-
sus the gain in normal tissue damage. However,
without reliable biological models, this tradeoff
remains difcult. We used the minimum dose as
a gauge for geometrical misses and found a rea-
sonable one-to-one relation between minimum
dose to the CTV and EUD and TCP. A com-
pletely different question from evaluation of the
dose to the CTV given geometrical errors is how
to obtain a reliable estimate of the dose that will
be received by the CTV given only the planned
dose distribution. In that case, the mean dose
may be more useful than the minimum dose.
Levegrun et al
79
found that the minimum dose of
the PTV did not correspond with local control as
established by core biopsies, whereas the mean
dose did. However, in this study, outcome was
correlated with the planned dose distribution
without taking possible geometrical errors into
account.
How Should Margins Be Added?
Although the SD of different geometrical errors
should be added in quadrature, random and sys-
tematic often result in different margins, and
how these should be added may not always be
clear. The simplest situation is when the margin
is dened as a probability level of the minimum
dose. In that case, the PTV margin is generated
using a rst margin for systematic errors that
ensures a certain percentage coverage, followed
by adding a margin for random errors that en-
sures coverage of the rst margin up to a given
dose. However, such a linear addition of margins
is not valid for margins based on probabilities
and/or biological effects. When margins are de-
ned based on probability levels, they should be
added in quadrature because the margins repre-
sent the width of probability distributions. Simi-
larly, one may expect an interaction between
CTV and PTV margins when both are based on
probability levels. Such an interaction has, how-
ever, not yet been investigated.
Comparison of Margin Recipes
Most published margin recipes ignore systematic
errors or fail to differentiate between random
and systematic errors. The published margin rec-
ipes that do differentiate between random and
systematic errors can often be written as a linear
combination of the SD of the random and the SD
of the systematic errors (Table 2). Filling in an
identical random and systematic error SD, the
recipes of van Herk et al
43
and Stroom et al
51
result in a margins of about 2.3
total
for the van
Herk et al
43
study and 1.9
total
for the Stroom et
al
51
study. In general, the margins proposed by
others that do not differentiate random and sys-
tematic errors are somewhat smaller (ie, the
older margin recipes underestimate the effect of
the systematic errors). The trend that is visible in
Table 2 is a reduction of the required margin
when going from physical to biological consider-
ations. However, it should be noted that the bio-
logical effects of geometrical errors depend on
the model parameters used. Because these pa-
rameters are often doubtful at best, it is currently
safer to base oneself on physics considerations,
leading to larger margins.
Besides the magnitude of the errors, the fol-
lowing factors potentially affect the margin:
1. Probability of tumor presence (CTV margin):
when there is a smaller likelihood of tumor
cell presence for part of the tumor, only a
(unknown) fraction of the patient population
will require treatment of that part of the tu-
mor (ie, the margin for that part of the tumor
is less critical).
2. Tumor cell density: when the tumor cell den-
sity is lower, the local dose required to kill all
cells is lower and the margin for that part of
the tumor is again less critical.
Errors and Margins in Radiotherapy 59
3. Tumor cell viability: it is possible that tumor
cells in part of the tumor are more viable or have
a different dose response because of environ-
ment variables such as oxygenation and nutri-
ents supply. The more viable parts of the tumor
must be treated to a higher dose and the mar-
gins requirements are more critical. It is quite
possible that tumor cells at the edge of the CTV
are actually more viable in some situations.
4. Fringe dose: when there is a background dose
(eg, because of other beams), the effect of
geometrical errors on dose is reduced (the
plan is less conformal) and somewhat less
margin may be used.
5. Presence of normal tissues: when normal tis-
sues need to be spared there is a good incen-
tive to reduce the local margin. However, such
reduction should be carefully weighed against
the risk of missing the target. For instance, a
zero margin at one side of the tumor will lead
to a very high change that part of the tumor
there is underdosed. In practice, this means
that zero margins should only be used for
boost doses that can (partly) be missed with-
out incurring disaster.
These factors should be addressed in new stud-
ies. However, the required clinical data is often
missing, so that it is of utmost importance that
biological models are improved.
How to Deal With Respiration
When the imaging of a moving tumor is well
addressed (ie, the time-averaged position of the
Table 2. Summary of Published Margin Recipes for Target, Respiration (Target) and Organs of Risk
Author Application Recipe Assumptions
Bel et al,
1996b
59
Target 0.7 Random errors only (linear approximation)
Monte Carlo
Antolak and
Rosen, 1999
81
Target 1.65 Random errors only, block margin?
Stroom et al,
1999
51
Target 2 0.7 95% dose to on average 99% of CTV tested
in realistic plans
Van Herk et al,
2000
43
Target 2.5 0.7 or (more
correct):
2.5 1.64 (
p
)
Minimum dose to CTV is 95% for 90% of
patients. Analytical solution for perfect
conformation
McKenzie et al,
2000
60
Target 2.5 (
p
) Extension of van Herk et al for fringe dose
due to limited number of beams
Parker et al,
2002
82
Target (
2

2
) 95% minimum dose and 100% dose for
95% of volume. Probability levels not
specied
Van Herk et al,
2002
52
Target 2.5 0.7 3 mm or
(more correct):
2.7
2

2
1.6
2

2
2.8
mm
Monte Carlo based test of 1% TCP loss
due to geometrical errors for prostate
patients
Van Herk et al,
2003
69
Target M 2 mm
M 5 mm
Correction for nonuniform cell density
Ten Haken
et al, 1997
83
and
Engelsman
et al, 2001
84
Respiration (liver
and lung)
0 A No margin for respiration but
compensation by dose escalation to iso-
NTCP, reducing target dose homogeneity
constraints
McKenzie et al
2000
50
Respiration A Margin for respiration on top of other
margins when respiration dominates
other errors
van Herk et al,
2003
47
Respiration
(lung)
0.25 A (caudally)
0.45 A (cranially)
Margin for (random) respiration combined
with 3 mm random SD, when respiration
dominates other errors (A 1 cm)
McKenzie et al,
2002
85
OAR 1.3 / 0.5 Margins for small and/or serial organs at
risk in low () or high () dose region
Abbreviations: , SD of systematic errors; , SD of random errors;
p
, describes width of beam penumbra tted to a Gauss
function; A, peak-peak amplitude of respiration; M, margin before adjustment for described effect.
60 Marcel van Herk
tumor is well known), the required margin for
respiration is small. In studies by Ten Haken et
al
83
and Englesman et al,
84
it is therefore sug-
gested to use zero margin and compensate with a
small dose escalation. van Herk et al
47
suggest to
treat respiration with a peak-peak amplitude of
less than 1 cm the same as random errors (the
corresponding SD of respiration motion is about
0.3 A) and use a nonuniform margin of 0.25A to
0.45A when the respiration exceeds 1 cm. In the
Material and Methods section, we showed that
when both random and systematic respiration
motion is present (eg, when no measures have
been taken to obtain representative imaging),
the margin for respiration is A, which corre-
sponds well with the study of McKenzie et al.
50
Margin for Normal Tissues
Systematic geometrical errors bring OAR closer
or further away from the high-dose region. When
complications are acceptable (eg, for the rec-
tum), this means that 50% of patients get more
and 50% get less dose. This means that, on aver-
age, the net effect is zero and no margin is re-
quired. For some organs (eg, the spinal cord),
complications because of geometrical error are
unacceptable and the margin recipe in the study
by McKenzie et al
84
may be used. Computing the
margin using typical error values for the spinal
cord, a 5-mm margin seems appropriate. Such a
margin actually corresponds with the width of the
spinal canal, which is normally delineated instead
of the actual spinal cord.
Conclusions
Random errors introduced by organ motion and
setup error have a similar magnitude. Systematic
errors introduced by target volume delineation,
organ motion, and setup errors have a similar
magnitude and should be reduced by clear delin-
eation protocols, multimodality imaging, correct
CT scan procedures, and electronic portal imag-
ing with decision rules. The SD of random errors
must be added quadratically to obtain the total
error. The SD of systematic errors must also be
added quadratically to obtain the total error. Sys-
tematic errors require 3 to 4 times more margin
than random errors. Large systematic errors
cause geographical misses. Biological margin rec-
ipes are more forgiving than recipes based on
physical considerations.
References
1. Urie MM, Goitein M, Doppke K, et al: The role of un-
certainty analysis in treatment planning. Int J Radiat
Oncol Biol Phys 21:91-107, 1991
2. Links JM, Beach LS, Subramaniam B, et al: Edge com-
plexity and partial volume effects. J Comput Assist To-
mogr 22:450-458, 1998
3. Dubois DF, Prestidge BR, Hotchkiss LA, et al: Intraob-
server and interobserver variability of MR imaging- and
CT-derived prostate volumes after transperineal intersti-
tial permanent prostate brachytherapy. Radiology 207:
785-789, 1998
4. Fiorino C, Reni M, Bolognesi A, et al: Intra- and inter-
observer variability in contouring prostate and seminal
vesicles: Implications for conformal treatment planning.
Radiother Oncol 47:285-292, 1998
5. Ten Haken RK, Thornton AFJ, Sandler HM, et al: A
quantitative assessment of the addition of MRI to CT-
based, 3-D treatment planning of brain tumors. Ra-
diother Oncol 25:121-133, 1992
6. Leunens G, Menten J, Weltens C, et al: Quality assess-
ment of medical decision making in radiation oncology:
Variability in target volume delineation for brain tu-
mours. Radiother Oncol 29:169-175, 1993
7. Weltens C, Menten J, Feron Bellon E, et al: Interobserver
variations in gross tumor volume delineation of brain
tumors on CT and impact of MRI. Radiother Oncol 48:14,
1998
8. Rasch C, Barillot I, Remeijer P, et al: Denition of the
prostate in CT and MRI: A multi-observer study. Int J
Radiat Oncol Biol Phys 43:57-66, 1993
9. Valley JF, Mirimanoff RO: Comparison of treatment
techniques for lung cancer. Radiother Oncol 28:168-173,
1993
10. Ketting CH, Austin-Seymour M, Kalet I, et al: Auto-
mated planning target volume generation: An evaluation
pitting a computer-based tool against human experts. Int
J Radiat Oncol Biol Phys 37:697-704, 1997
11. Nowak P, van Dieren E, van Sornsen de Koste J, et al:
Treatment portals for elective radiotherapy of the neck:
An inventory in The Netherlands. Radiother Oncol 43:
81-86, 1997
12. ICRU Report 50. Prescribing, Recording and Reporting
Photon Beam Therapy. International Commission on Ra-
diation Units and Measurements, Bethesda, MD, 1993
13. Marks LB, Anscher MS: Radiotherapy for prostate can-
cer: Should the seminal vesicles be considered target ? Int
J Radiat Oncol Biol Phys 24:435-440, 1992
14. Kleer E, Larson-Keller JJ, Zincke H, et al: Ability of
preoperative serum prostate specic antigen value to pre-
dict pathologic stage and DNA ploidy. Urology 41:207-
216, 1993
15. Partin AW, Yoo J, Carter HB, et al: The use of prostate
specic antigen, clinical stage and Gleason score to pre-
dict pathological stage in men with localized prostate
cancer. J Urol 150:110-114, 1993
16. Diaz A, Roach M III, Marquez C, et al: Indications for and
the signicance of seminal vesicle irradiation during con-
formal radiotherapy for localized prostate cancer. Int J
Radiat Oncol Biol Phys 30:323-329, 1994
Errors and Margins in Radiotherapy 61
17. Chen ME, Johnston DA, Tang K, et al: Detailed mapping
of prostate carcinoma foci: Biopsy strategy implications.
Cancer 89:1800-1809, 2000
18. Kestin L, Goldstein N, Vicini F, et al: Treatment of
prostate cancer with radiotherapy: Should the entire sem-
inal vesicles be included in the clinical target volume? Int
J Radiat Oncol Biol Phys 54:686-697, 2002
19. Giraud P, Antoine M, Larrouy A, et al: Evaluation of
microscopic tumor cell extension in non-small-cell lung
cancer for three-dimensional conformal radiotherapy
planning. Int J Radiat Oncol Biol Phys 48:1015-1024, 2000
20. Ekberg L, Holmberg O, Wittgren L, et al: What margins
should be added to the clinical target volume in radio-
therapy treatment planning for lung cancer. Radiother
Oncol 48:71-77, 1998
21. Tinger A, Michalski JM, Cheng A, et al: A critical evalu-
ation of the planning target volume for 3-D conformal
radiotherapy of prostate cancer. Int J Radiat Oncol Biol
Phys 42:213-221, 1998
22. Hurkmans CW, Remeijer P, Lebesque JV, et al: Set-up
verication using portal imaging; review of current clin-
ical practice. Radiother Oncol 58:105-120, 2001
23. Bel A, Vos PH, Rodrigus PT, et al: High-precision pros-
tate cancer irradiation by clinical application of an ofine
patient setup verication procedure, using portal imag-
ing. Int J Radiat Oncol Biol Phys 35:321-332, 1996
24. Creutzberg CL, Althof VGM, De Hoog M, et al: A quality
control study of the accuracy of patient positioning in
irradiation of pelvic elds. Int J Radiat Oncol Biol Phys
34:697-708, 1996
25. Hanley J, Lumley MA, Mageras GS, et al: Measurement
of patient positioning errors in three-dimensional confor-
mal radiotherapy of the prostate. Int J Radiat Oncol Biol
Phys 37:435-444, 1997
26. Yan D, Wong JW, Vicini F, et al: Adaptive modication of
treatment planning to minimize the deleterious effects of
treatment setup errors. Int J Radiat Oncol Biol Phys
38:197-206, 1997
27. Weltens C, Kesteloot K, Vandevelde G, et al: Comparison
of plastic and Ort masks for patient head xation during
radiotherapy: Precision and costs. Int J Radiat Oncol Biol
Phys 33:499-507, 1995
28. De Boer HCJ, van So rnsen de Koste JR, Senan S, et al:
Analysis and reduction of 3D systematic and random
setup errors during the simulation and treatment of lung
cancer patients with CT-based external beam radiother-
apy dose planning. Int J Radiat Oncol Biol Phys 49:857-
868, 2001
29. Ross CS, Hussey DH, Pennington EC, et al: Analysis of
movement of intrathoracic neoplasms using ultrafast
computerized tomography. Int J Radiat Oncol Biol Phys
18:671-677, 1990
30. Roeske JC, Forman JD, Mesina CF, et al: Evaluation of
changes in the size and location of the prostate, seminal
vesicles, bladder, and rectum during a course of external
beam radiation therapy. Int J Radiat Oncol Biol Phys
33:1321-1329, 1995
31. Beard CJ, Kijewski P, Bussiere M, et al: Analysis of
prostate and seminal vesicle motion: implications for
treatment planning. Int J Radiat Oncol Biol Phys 34:451-
458, 1996
32. Antolak JA, Rosen II, Childress CH, et al: Prostate target
volume variations during a course of radiotherapy. Int J
Radiat Oncol Biol Phys 42:1661-672, 1998
33. Armstrong JG: Target volume denition for three-dimen-
sional conformal radiation therapy of lung cancer. Br J
Radiol 71:587-594, 1998
34. Balter JM, Sandler HM, Lam K, et al: Measurement of
prostate movement over the course of routine radiother-
apy using implanted markers. Int J Radiat Oncol Biol
Phys 31:113-118, 1995
35. Nederveen A, Lagendijk J, Hofman P: Detection of du-
cial gold markers for automatic on-line megavoltage po-
sition verication using a marker extraction kernel
(MEK). Int J Radiat Oncol Biol Phys 47:1435-1442, 2000
36. Melian E, Mageras GS, Fuks Z, et al: Variation in pros-
tate position quantitation and implications for three-di-
mensional conformal treatment planning. Int J Radiat
Oncol Biol Phys 38:73-81, 1997
37. Dawson LA, Mah K, Franssen E, et al: Target position
variability throughout prostate radiotherapy. Int J Radiat
Oncol Biol Phys 42:1155-1161, 1998
38. Stroom JC, Koper PCM, Korevaar GA, et al: Internal
organ motion in prostate cancer patients treated in prone
and supine treatment position. Radiother Oncol 51:237-
248, 1999
39. van Herk M, Bruce A, Kroes AP, et al: Quantication of
organ motion during conformal radiotherapy of the pros-
tate by three dimensional image registration. Int J Radiat
Oncol Biol Phys 33:1311-1320, 1995
40. Seppenwoolde Y, Shirato H, Kitamura K, et al: Precise
and real-time measurement of 3D tumor motion in lung
due to breathing and heartbeat, measured during radio-
therapy. Int J Radiat Oncol Biol Phys 53:822-834, 2002
41. Remeijer P, Geerlof E, Ploeger L, et al: 3-D portal image
analysis in clinical practice: An evaluation of 2-D and 3-D
analysis techniques as applied to 30 prostate cancer pa-
tients. Int J Radiat Oncol Biol Phys 46:1281-1290, 2000
42. Bijhold J, Lebesque JV, Hart AAM, et al: Maximizing
setup accuracy using portal images as applied to a con-
formal boost technique for prostatic cancer. Radiother
Oncol 24:261-271, 1992
43. van Herk M, Remeijer P, Rasch C, et al: The probability
of correct target dosage: Dose-population histograms for
deriving treatment margins in radiotherapy. Int J Radiat
Oncol Biol Phys 47:1121-1135, 2000
44. Leong J: Implementation of random positioning error in
computerised radiation treatment planning systems as a
result of fractionation. Phys Med Biol 32:327-334, 1987
45. Lujan AE, Larsen EW, Balter JM, et al: A method for
incorporating organ motion due to breathing into 3D dose
calculations. Med Phys 26:715-720, 1999
46. Cho BC, van Herk M, Mijnheer BJ, et al: The effect of
set-up uncertainties, contour changes, and tissue inhomo-
geneities on target dose-volume histograms. Med Phys
29:2305-2318, 2002
47. van Herk M, Witte M, van der Geer J, et al: Biological and
physical fractionation effects of random geometrical er-
rors. Int J Radiat Oncol Biol Phys 57:1460-1471, 2003
48. McCarter SD, Beckham WA: Evaluation of the validity of
a convolution method for incorporating tumour move-
ment and set-up variations into the radiotherapy treat-
ment planning system. Phys Med Biol 45:923-931, 2000
62 Marcel van Herk
49. Craig T, Battista J, Moiseenko V, et al: Considerations for
the implementation of target volume protocols in radia-
tion therapy. Int J Radiat Oncol Biol Phys 49:241-250,
2001
50. McKenzie AL: How should breathing motion be com-
bined with other errors when drawing margins around
the clinical target volumes? Br J Radiol 73:973-977, 2000
51. Stroom JC, de Boer HCJ, Huizinga H, et al: Inclusion of
geometrical uncertainties in radiotherapy treatment
planning by means of coverage probability. Int J Radiat
Oncol Biol Phys 43:905-919, 1999
52. van Herk M, Remeijer P, Lebesque JV: Inclusion of geo-
metric uncertainties in treatment plan evaluation. Int J
Radiat Oncol Biol Phys 52:1407-1422, 2002
53. Mageras GS, Kutcher GJ, Leibel SA, et al: A method of
incorporating organ motion uncertainties into three-di-
mensional conformal treatment plans. Int J Radiat Oncol
Biol Phys 35:333-342, 1996
54. Yan D, Jaffray DA, Wong JW: A model to accumulate
fractionated dose in a deforming organ. Int J Radiat
Oncol Biol Phys 44:665-675, 1999
55. ICRU Report 62. Prescribing, Recording and Reporting
Photon Beam Therapy (supplement to ICRU Report. 50)
International Commission on Radiation Units and Mea-
surements, Bethesda, MD, 1999
56. Aaltonen P, Brahme A, Lax I, et al: Specication of dose
delivery in radiation therapy. Recommendation by the
Nordic Association of Clinical Physics (NACP). Acta On-
col 36:1-32, 1997 (suppl)
57. Austin-Seymour M, Kalet I, McDonald J, et al: Three
dimensional planning target volumes: A model and a
software tool. Int J Radiat Oncol Biol Phys 33:1073-1080,
1995
58. Hunt MA, Kutcher GJ, Burman C, et al: The effect of
setup uncertainties on the treatment of nasopharynx can-
cer. Int J Radiat Oncol Biol Phys 27:437-447, 1993
59. Bel A, van Herk M, Lebesque JV: Target margins for
random geometrical treatment uncertainties in confor-
mal radiotherapy. Med Phys 23:1537-1545, 1996
60. McKenzie AL, van Herk M, Mijnheer B: The width of
margins in radiotherapy treatment plans. Phys Med Biol
45:3331-3342, 2000
61. MacKay RI, Graham PA, Moore CJ, et al: Animation and
radiobiological analysis of 3D motion in conformal radio-
therapy. Radiother Oncol 52:43-49, 1999
62. Killoran JH, Kooy HM, Gladstone DJ, et al: A numerical
simulation of organ motion and daily setup uncertainties:
Implications for radiation therapy. Int J Radiat Oncol
Biol Phys 37:213-221, 1997
63. Fontenla E, Pelizzari CA, Chen GT: Implications of 3-di-
mensional target shape and motion in aperture design.
Med Phys 23:1431-1441, 1996
64. Mageras GS, Fuks Z, Leibel SA, et al: Computerized
design of target margins for treatment uncertainties in
conformal radiotherapy. Int J Radiat Oncol Biol Phys
43:437-445, 1999
65. Lo f J, Lind BK, Brahme A: An adaptive control algorithm
for optimization of intensity modulated radiotherapy con-
sidering uncertainties in beam proles, patient set-up
and internal organ motion. Phys Med Biol 43:1605-1628,
1998
66. Amer AM, Mackay RI, Roberts SA, et al: The required
number of treatment imaging days for an effective off-
line correction of systematic errors in conformal radio-
therapy of prostate cancerA radiobiological analysis.
Radiother Oncol 61:143-150, 2001
67. Goitein M, Schultheiss TE: Strategies for treating possi-
ble tumor extension: Some theoretical considerations. Int
J Radiat Oncol Biol Phys 11:1519-1528, 1985
68. Ling CC, Humm J, Larson S, et al: Towards multidimen-
sional radiotherapy (MD-CRT): Biological imaging and
biological conformality. Int J Radiat Oncol Biol Phys 47:
551-560, 2000
69. van Herk M, Witte M, van der Geer J, et al: Modeling the
effect of treatment uncertainties in radiotherapy on tu-
mor control probability for different tumor cell density
congurations. Int J Radiat Oncol Biol Phys 55:447(ab-
str), 2003
70. Balter JM, Ten Haken RK, Lawrence TS, et al: Uncer-
tainties in CT-based radiation therapy treatment plan-
ning associated with patient breathing. Int J Radiat Oncol
Biol Phys 36:167-174, 1996
71. Yu CX, Jaffray DA, Wong JW: The effects of intra-frac-
tion organ motion on the delivery of dynamic intensity
modulation. Phys Med Biol 43:91-104, 1998
72. Bortfeld T, Jokivarsi K, Goitein M, et al: Effects of intra-
fraction motion on IMRT dose delivery: Statistical anal-
ysis and simulation. Phys Med Biol 47:2203-2220, 2002
73. Engelsman M, Damen EM, De Jaeger K, et al: The effect
of breathing and set-up errors on the cumulative dose to
a lung tumor. Radiother Oncol 60:95-105, 2001
74. Lagerwaard FJ, Van Sornsen de Koste JR, Nijssen-Visser
MR, et al: Multiple slow CT scans for incorporating
lung tumor mobility in radiotherapy planning. Int J Ra-
diat Oncol Biol Phys 51:932-937, 2001
75. Ford EC, Mageras GS, Yorke E, et al: Respiration-corre-
lated spiral CT: A method of measuring respiratory-in-
duced anatomic motion for radiation treatment planning.
Med Phys 30:88-97, 2003
76. Vedam SS, Keall PJ, Kini VR, et al: Acquiring a four-
dimensional computed tomography dataset using an
external respiratory signal. Phys Med Biol 48:45-62,
2003
77. Shimizu S, Shirato H, Aoyama H, et al: High-speed
magnetic resonance imaging for four-dimensional
treatment planning of conformal radiotherapy of mov-
ing body tumors. Int J Radiat Oncol Biol Phys 48:471-
474, 2000
78. Caldwell CB, Mah K, Skinner M, et al: Can PET provide
the 3D extent of tumor motion for individualized internal
target volumes? A phantom study of the limitations of CT
and the promise of PET. Int J Radiat Oncol Biol Phys
55:1381-1393, 2003
79. Stroom JC, Heijmen BJ: Geometrical uncertainties, ra-
diotherapy planning margins, and the ICRU-62 report.
Radiother Oncol 64:75-83, 2002
80. Levegrun S, Jackson A, Zelefsky MJ, et al: Analysis of
biopsy outcome after three-dimensional conformal radia-
tion therapy of prostate cancer using dose-distribution
variables and tumor control probability models. Int J
Radiat Oncol Biol Phys 47:1245-1260, 2000
Errors and Margins in Radiotherapy 63
81. Antolak JA, Rosen II: Planning target volumes for radio-
therapy: How much margin is needed? Int J Radiat Oncol
Biol Phys 44:1165-1170, 1999
82. Parker BC, Shiu AS, Maor MH, et al: PTV margin deter-
mination in conformal SRT of intracranial lesions. J Appl
Clin Med Phys 3:176-189, 2002
83. Ten Haken RK, Balter JM, Marsh LH, et al: Potential
benets of eliminating planning target volume ex-
pansions for patient breathing in the treatment of liver
tumors. Int J Radiat Oncol Biol Phys 38:613-617,
1997
84. Engelsman M, Remeijer P, van Herk M, et al: Field size
reduction enables iso-NTCP escalation of tumor control
probability for irradiation of lung tumors. Int J Radiat
Oncol Biol Phys 51:1290-1298, 2001
85. McKenzie A, van Herk M, Mijnheer B: Margins for geo-
metric uncertainty around organs at risk in radiotherapy.
Radiother Oncol 62:299-307, 2002
64 Marcel van Herk