Men2012 PDF
Men2012 PDF
Men2012 PDF
a r t i c l e i n f o abstract
Available online 31 October 2011 Intensity modulated radiation therapy (IMRT) is one of the most widely used delivery modalities for
Keywords: radiation therapy for cancer patients. A patient is typically treated in daily fractions over a period of 59
Interfraction motion weeks. In this paper, we consider the problem of accounting for changes in patient setup location and
IMRT treatment planning internal geometry between the treatment fractions, usually referred to as interfraction motion. The
Stochastic models conventional method is to add a margin around the clinical tumor volume (CTV) to obtain a planning
target volume (PTV). A uence map optimization (FMO) model is then solved to determine the optimal
intensity proles to deliver to the patient. However, a margin-based method may not adequately model
the changes in dose distributions due to the random nature of organ motion. Accounting for
interfraction motion in the FMO model essentially transforms the deterministic optimization problem
into a stochastic one. We propose a stochastic FMO model that employs convex penalty functions to
control the treatment plan quality and uses a large number of scenarios to characterize interfraction
motion uncertainties. Some effects of radiotherapy are impacted mainly by the dose distribution in a
given treatment fraction while others tend to manifest themselves over time and depend mostly on the
total dose received over the course of treatment. We will therefore formulate an optimization model
that explicitly incorporates treatment plan evaluation criteria that apply to the total dose received over
all treatment fractions and ones that apply to the dose per fraction. Particularly when many structures
fall into the former category, this can lead to signicant reductions in the dimension of the optimization
model and therefore the time required to solve it. We test an example of our model on ve clinical
prostate cancer cases, showing the efcacy of our approach. In particular, compared to a traditional
margin-based treatment plan, our plans exhibit signicantly improved target dose coverage and
clinically equivalent critical structure sparing at only a modest increase in computational effort.
& 2011 Elsevier Ltd. All rights reserved.
0305-0548/$ - see front matter & 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cor.2011.10.020
1780 C. Men et al. / Computers & Operations Research 39 (2012) 17791789
Traditionally, the design and evaluation of IMRT treatment the MIGA approach may not be large enough to capture all
plans (i.e., the FMO model) is based on a static patient model interfraction motion uncertainties, and signicantly increasing
obtained using a single planning CT image set. During the course of the number of scenarios may make the optimization model
a fractionated radiation therapy the patient geometry may deviate intractable. Secondly, while properties of a treatment plan that
from the geometry observed in the image on which a treatment depend on aggregate dose distribution are accurately assessed by
plan is based. These deviations are caused by, for example, (i) an considering the expected or average dose delivered per fraction,
inability to setup the patient in an identical location with respect to other properties that rely more heavily on the dose distribution
the radiation source on each day of the treatment, (ii) movement delivered in a single treatment fraction are ignored by the MIGA
and shape changes of tumor as well as soft tissues and organs, and approach. As McShan et al. [21] point out: Clearly, to believe that
(iii) patient weight loss or gain. Such changes in patient geometry the MIGA optimization is going to be clinically useful in this case,
between fractions are generally referred to as interfraction motion. the cost function for the optimization should be modied to
(This distinguishes these sources of uncertainty to those caused by either (1) force dose/fraction constraints as well as the total dose
intrafraction motion, which refers to internal organ motion occur- costs, or (2) specically include dose/fraction corrections into the
ring during the actual radiation treatment due to breathing, optimization through the use of linear/quadratic model estimates
swallowing, etc.; see, e.g., [15].) of a bioeffect. In this paper, we will take the former approach.
To account for organ motion, the conventional approach is to In this paper, we will therefore introduce a new stochastic
add a margin around the clinical tumor volume (CTV) to obtain a model for FMO that accurately captures interfraction motion
planning target volume (PTV) (see, e.g., [12,13]). The CTV contains uncertainties while remaining computationally tractable. Our
an area including and immediately surrounding the gross tumor goals in this paper are to
volume (GTV) that is at high risk for clinical extension of the
tumor. The PTV is an expansion of the CTV with a margin propose a new stochastic FMO model accounting for interfrac-
accounting for both interfraction and intrafraction motion. tion motion;
Several studies (see, e.g., [2,33,34,24]) have empirically derived empirically evaluate the ability of this model to nd high-
expressions for the required margin size. However, these quality treatment plans when the model is used to account for
margin-based methods suffer from the fact that the margin may setup errors in particular;
not adequately model the changes in dose distribution due to the develop a new and appropriate way to evaluate treatment plan
uncertain deviations caused by interfraction and intrafraction evaluation criteria that depend on the dose distribution in a
organ motion; in particular, it may not be necessary or appro- single treatment fraction.
priate to use a uniform margin for the entire CTV. Therefore, the
use of margins for treatment planning may lead to underdosing of
the CTV and/or overdosing of critical structures, causing reduced
cure rates or increased side-effects of treatment. Moreover, the 2. Incorporating interfraction motion
aggregate dose distribution received by those targets and critical
structures for which dose per fraction is important does not 2.1. Deterministic FMO model
accurately capture treatment plan quality. Although the cumula-
tive dose over the course of treatment is evaluated, the actual Our stochastic FMO model is based on a traditional determi-
dose received in each of the treatment fractions may signicantly nistic FMO model that we will rst introduce. We denote the set
differ from the planned (or clinically prescribed) one. of beamlets (which discretize a pre-determined and xed set of
Because of these problems associated with margin-based beams from different directions) by N and the associated decision
methods, attention has shifted to the development of alternative variables representing the intensity of these beamlets by xi (iA N).
methods. It is expected that explicitly accounting for the uncer- Furthermore, we denote the set of voxels by V, and associate a
tainties of interfraction motion will lead to improved treatment decision variable zj with each voxel j A V that measures the dose
plans by implicitly identifying patient-dependent and non- received by that voxel. We make the standard approximation that
uniform margins to optimally hedge against geometry changes. expresses the vector of voxel doses as a linear function of the
Hence, the conicting goals of tumor dose coverage and critical intensities of the apertures through the so-called dose deposition
structure sparing can be balanced more effectively. One approach coefcients Dij : the dose received by voxel j A V in a given fraction
is to post process the static planned dose distribution by convol- from beamlet iA N at unit intensity. Finally, we assume that the
ving it with a probability density function which describes the clinician or physician has identied a collection of treatment plan
motion uncertainties (see, e.g., [19,20]). This dose-convolution evaluation criteria given by the convex functions G : R9V9 -R
method assumes shift invariance of the dose distribution. ( A L) as well as associated criteria weights w ( A L). Then our
However, internal inhomogeneities and surface curvature may deterministic FMO model can be written as
lead to violations of this assumption (see [7,8]). In order to
X
overcome these drawbacks, Chu et al. [6] propose a robust minimize w G z
optimization model. However, their model not only views the AL
dose to the voxels as independent random variables, whereas in
practice there will be a strong dependence between these, but it subject to
also focuses on the aggregate delivered dose over the entire X
course of treatment. Alternatively, McShan et al. [21] proposed zj Dij xi for j A V
iAN
the multiple instance geometry approximation (MIGA) technique.
In this approach, a relatively small number of scenarios (typically
about seven) for the patient geometry are selected and a full dose xi Z 0 for i A N
calculation is performed for each of these scenarios. A treatment
plan is then determined based on the average or expected dose (see, e.g., [28]). Of course an FMO model may also contain
distribution delivered to the patient in these scenarios. This constraints on certain treatment plan evaluation criteria. Our
approach, although very promising, suffers from two potentially approach can be extended to such models, but for ease of
serious drawbacks. Firstly, the number of scenarios that is used in exposition we will not consider this explicitly in this paper.
C. Men et al. / Computers & Operations Research 39 (2012) 17791789 1781
Table 1
Model dimensions (full resolution; between parentheses: after downsampling).
Radiation Oncology. This data was then imported into the we identify the bixels for which the dose deposition coefcient Dij
University of Florida Optimized Radiation Therapy (UFORT) treat- associated with at least one target voxel is nonzero in any of the
ment planning system and used to generate the data required by scenarios. For all cases we generated a voxel grid with voxels of
the models described above (see, e.g., [28]). size 4 4 4 mm3 for the targets and critical structures. Dempsey
For all ve cases, we design plans using nine equispaced et al. [9] performed a Fourier analysis of required voxel resolution
60
Co-beams (note that this does not affect the optimization for the case of 6 MV photon beams. Our resolution in this paper
algorithm, which is, without modication, applicable to high- was based on a similar (but unpublished) analysis of 60Co-beams.
energy x-ray beams as well; see, for example, [28] for results with Moreover, this resolution is a typical choice for prostate cancer
6 MV photon beams). The nine beams are evenly distributed cases in clinical settings due to (i) the typical tumor size, and (ii)
around the patient with angles 01, 401, 801, 1201, 1601, 2001, the relatively regular shape of the prostate (for other sites a
2401, 2801, 3201, respectively. The nominal size of each beam is different resolution may be required). For the optimization model,
40 40 cm2. The beams are discretized into bixels of size we downsampled the voxels in normal tissue to a voxel grid of
1 1 cm2, yielding on the order of 1600 bixels. The coefcients 8 8 8 mm3. However, the treatment quality of the obtained
Dij are then obtained using a pencil beam model with a correction plans was always evaluated on the full resolution voxel grid. There
for nonhomogeneous tissue densities. We then reduce the set of is one target (prostate), with a prescription dose 73.8 Gy delivered
beamlets that actually need to be considered in the optimization in 41 daily fractions. Moreover, there are three critical structures:
by using the fact that the actual volume to be treated is usually bladder, rectum, and femoral heads, in addition to normal tissue.
signicantly smaller. That is, for each beam, we identify a mask Table 1 shows the problem dimensions for the ve cases.
consisting of only those bixels that can help treat the targets, i.e., Both our deterministic and stochastic FMO models employ
treatment plan evaluation criteria that are quadratic one-sided
voxel-based penalty functions. Denoting the collection of targets
Table 2 by T and the collection of critical structures by C, these penalty
Criteria for prostate cancer.
functions are
Rectum Bladder Femoral heads 1 X 2
Gt z a
t maxf0,T
t zj g t AT 1
9V t 9 j A V
r 15% receives Z 75 Gy r 15% receives Z 80 Gy r 10% receives Z 52 Gy t
100 100
80 80
% Scenarios
% Scenarios
60 60
40 40
20 20
Scenarios 1-25 Scenarios 1-50
Scenarios 101-200 Scenarios 101-200
0 0
70 75 80 85 90 95 100 70 75 80 85 90 95 100
% Volume % Volume
100 100
80 80
% Scenarios
% Scenarios
60 60
40 40
20 20
Scenarios 1-75 Scenarios 1-100
Scenarios 101-200 Scenarios 101-200
0 0
70 75 80 85 90 95 100 70 75 80 85 90 95 100
% Volume % Volume
Fig. 1. The probability that a specied percentage of the target received the prescription dose for case 1: (a) 25, (b) 50, (c) 75, and (d) 100 scenarios.
C. Men et al. / Computers & Operations Research 39 (2012) 17791789 1783
where T
t and T t are underdosing and overdosing thresholds and voxels is associated with a dose/fraction effects (i.e., lack of
at and at are criteria weights). For illustration purposes, our adequate tumor cell kill), while overdosing of voxels is associated
experiments deal with an example where underdosing of target with total dose effects (side-effects of treatment). That is, we
included overdosing-related penalties in the set Ltotal and under-
Table 3 dosing-related criteria in the set Lfx , i.e., Lfx T and Ltotal T [ C.
CPU running time (seconds). Since our model explicitly accounts for interfraction motion,
our target is the CTV with margins added for intrafraction motion;
Case Traditional model Stochastic model (100 scenarios)
we will denote the corresponding expanded CTV by CTV . In
1 45 271 order to compare the results of our stochastic model with a more
2 42 149 traditional margin-based approach, we also create a PTV by
3 71 375 expanding the CTV with a setup margin. Empirically, the setup
4 67 246
5 89 251
errors in each direction have been found to be approximately
normally distributed with a standard deviation of 3 mm (see, e.g.,
Case 1 Case 2
100 100
80 80
% Scenarios
% Scenarios
60 60
40 40
Case 3 Case 4
100 100
80 80
% Scenarios
% Scenarios
60 60
40 40
Case 5
100
80
% Scenarios
60
40
20 Traditional Model
Stochastic Model
0
70 75 80 85 90 95 100
% Volume
Fig. 2. The probability that a specied percentage of the target received the prescription dose: (a) case 1, (b) case 2, (c) case 3, (d) case 4, and (d) case 5.
1784 C. Men et al. / Computers & Operations Research 39 (2012) 17791789
[10,4,25,35]). Following Antolak and Rosen [2], we therefore set are not well-established, we used the most strict criteria that we
the width of the setup error margin to about 1.65 times the found in the literature [3]. For the traditional deterministic FMO
standard deviation and formed the PTV by adding a margin of model, we required that (i) at least 95% of the PTV receives the
5 mm in each direction to the CTV . Clinical DVH criteria and prescribed dose of 73.8 Gy, (ii) at least 99% of the PTV receives
constraints were established to keep toxicity at acceptable levels, 93% of the prescribed dose, and (iii) no more than 10% of the PTV
and our optimized treatment plans were evaluated with respect receives 110% of the prescribed dose. Formalizing these criteria
to these criteria. In particular, we used the RTOG [26] criteria for yields a non-convex optimization model. Moreover, quantifying
rectum and bladder (see Table 2) which are commonly used by the trade-off between these criteria is highly subjective. We
physicians and researchers [27,5,23]. While femoral head criteria therefore chose to use the convex penalty-function based model
as described above without explicit incorporation of the DVH
Table 4 criteria. We tuned the problem parameters of this model by
Target hotspot (% of volume exceeding 110% of the prescribed dose). manual adjustment, taking the clinical DVH criteria into account
as well as the physicians clinical subjective trade-offs. This
Case Traditional model Stochastic model
process was applied to a single patient case, and these parameters
1 1.65 2.07 were then used for all other cases as well. The performance of the
2 3.63 4.75 obtained treatment plans with respect to the clinical DVH criteria
3 6.41 4.70 is taken as evidence of the effectiveness of this approach.
4 1.97 1.46
5 3.00 2.17
We next generated 200 scenarios by perturbing the location of
the patient according to a normal distribution with a mean of
Case 1 (traditional)
100
80
60
% Volume
40
20
0
0 10 20 30 40 50 60 70 80
Dose (Gy)
Case 1 (stochastic)
100
90
80
70
60
% Volume
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80
Dose (Gy)
Fig. 3. DVH clouds for the CTV for case 1: (a) traditional model and (b) stochastic model.
C. Men et al. / Computers & Operations Research 39 (2012) 17791789 1785
Case 1 Case 2
(Traditional: dot; Stochastic: solid) (Traditional: dot; Stochastic: solid)
100 100
Femoral Head Femoral Head
Rectum Rectum
80 80
Normal tissue Normal tissue
% Volume
% Volume
Bladder Bladder
60 60
40 40
20 20
0 0
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
Dose (Gy) Dose (Gy)
Case 3 Case 4
(Traditional: dot; Stochastic: solid) (Traditional: dot; Stochastic: solid)
100 100
Femoral head Femoral head
Rectum Rectum
80 80
Normal tissue Normal tissue
% Volume
% Volume
Bladder
60 60 Bladder
40 40
20 20
0 0
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
Dose (Gy) Dose (Gy)
Case 5
(Traditional: dot; Stochastic: solid)
100
Femoral head
Rectum
80
Normal tissue
% Volume
Bladder
60
40
20
0
0 10 20 30 40 50 60 70 80
Dose (Gy)
Fig. 4. DVHs for critical structures (stochastic vs. traditional model: (a) case 1, (b) case 2, (c) case 3, (d) case 4, and (d) case 5).
1786 C. Men et al. / Computers & Operations Research 39 (2012) 17791789
3.2.2. Target coverage, hot spots, and cold spots @75 Gy @70 Gy @65 Gy @60 Gy
Fig. 2 shows the target coverage curves for all ve cases for both (r 15%) (r 25%) (r 35%) (r 50%)
the treatment plan obtained with the traditional model and the one
1 Traditional 8.37 11.91 14.78 17.40
obtained with the stochastic model using scenarios 1100, in both
Stochastic 9.29 12.35 15.16 16.92
cases evaluated on scenarios 101200. It is clear from these gures 2 Traditional 3.99 6.22 8.45 11.09
that, in general, the stochastic model obtains a much better target Stochastic 10.65 13.43 16.64 20.08
dose coverage than the traditional model does. Taking case 1 as an 3 Traditional 2.70 14.13 17.17 22.85
example, the probability of 95% target coverage is 99% for the Stochastic 2.77 9.69 16.06 20.49
4 Traditional 13.79 20.15 25.82 30.86
stochastic model as opposed to 91% with the traditional model. Stochastic 10.56 17.98 22.95 27.40
Besides estimating the probability that a specied percentage 5 Traditional 11.20 19.52 25.41 29.57
of the target receive the prescription dose, we would like to check Stochastic 8.21 15.46 20.29 25.60
another two important criteria: target coldspots (underdosing)
and hotspots (overdosing) which refer to the volume of target
which receives less than 93% and more than 110% of prescription
Table 6
dose, respectively. Table 4 shows the averaged hotspots for all ve DVH criteria for bladder and femoral heads (%).
cases. In most of the scenarios, 100% of the target receives at least
93% of the prescription dose for all ve cases, so there are no Case Model Bladder Femoral
unacceptable coldspots. heads
@80 Gy @75 Gy @70 Gy @65 Gy @52 Gy
A more traditional way of evaluating the dose distribution for ( r 15%) (r 25%) ( r 35%) (r 50%) ( r 10%)
structures for which dose/fraction effects are important is to use
so-called DVH clouds, i.e., a DVH for each potential fraction 1 Traditional 0.57 6.09 9.51 12.30 0.06
scenario. In our case, the optimization model only concerns itself Stochastic 0.68 10.47 15.06 17.97 1.21
2 Traditional 0.82 6.88 8.45 10.09 0
with individual fractions when evaluating the dose distribution in
Stochastic 7.7 13.12 16.57 20.16 5.44
the target, so we limit ourselves to DVH clouds for the CTV. Fig. 3 3 Traditional 0.79 11.36 16.82 24.95 0.20
conrms that the stochastic model achieves more consistent Stochastic 0 2.58 9.52 14.48 0.59
target coverage than the traditional model. It is interesting to 4 Traditional 0.42 4.65 6.87 8.71 0
note that this gain in target coverage does not seem to come at Stochastic 0.54 3.21 5.60 7.13 0
5 Traditional 0.29 4.45 6.93 8.99 0
the expense of additional hotspots: the upper tails of both DVH Stochastic 0.14 2.63 4.90 6.96 0.59
clouds appear very similar.
C. Men et al. / Computers & Operations Research 39 (2012) 17791789 1787
Case 1, scenario 135 (traditional: dot; stochastic: solid) stochastic model, evaluated using the scenarios). To assess this
100 effect, we compared the perceived DVHs reported from the
traditional model with the actual DVHs that take into account
CTV+ the uncertainty using the 200 scenarios from the interfraction
80
Femoral head motion model. The results indicate that the perceived DVHs for
critical structures are very close to the actual ones (see examples
Rectum
% Volume
20
3.2.6. Expected dose vs. aggregate dose over all fractions
Finally, note that an essential assumption that we make in our
0 model is that the aggregate dose delivered over 41 fractions
0 10 20 30 40 50 60 70 80
Dose (Gy)
(which is uncertain) can accurately be approximated by the
expected dose delivered over these 41 fractions. In order to
Fig. 5. DVHs for case 1 in Scenario 135 (stochastic vs. traditional model). validate this assumption, we simulated the optimized treatment
Femoral head
Rectum
80
Normal tissue
60 Bladder
% Volume
40
20
0
0 10 20 30 40 50 60 70 80
Dose (Gy)
Femoral head
Rectum
80
Normal tissue
60 Bladder
% Volume
40
20
0
0 10 20 30 40 50 60 70 80
Dose (Gy)
Fig. 6. Perceived and actual DVHs for critical structures for (a) case 1 and (b) case 2.
1788 C. Men et al. / Computers & Operations Research 39 (2012) 17791789
Case 1 Case 2
100 100
Actual Perceived
Perceived Actual
80 80
60 60
% Volume
% Volume
40 40
20 20
0 0
65 67 69 71 73 75 77 79 81 83 85 65 67 69 71 73 75 77 79 81 83 85
-20 -20
Dose (Gy) Dose (Gy)
Case 3 Case 4
100 100
Perceived Perceived
Actual Actual
80 80
% Volume
% Volume
60 60
40 40
20 20
0 0
65 67 69 71 73 75 77 79 81 83 85 65 67 69 71 73 75 77 79 81 83 85
-20 -20
Dose (Gy) Dose (Gy)
Case 5
100
Perceived
Actual
80
60
% Volume
40
20
0
65 67 69 71 73 75 77 79 81 83 85
-20
Dose (Gy)
Fig. 7. Perceived and actual DVHs for the target: (a) case 1, (b) case 2, (c) case 3, (d) case 4, and (d) case 5.
plans over a collection of ve sample random treatments of 41 in each treatment fraction and evaluate the per-fraction DVHs,
fractions each, and plotted the corresponding realized DVHs. while for total dose effects we consider the aggregate DVHs over
Fig. 8 shows that, for case 1, the differences between the ve all treatment fractions. We illustrate the model by including dose/
simulated treatments were clinically indistinguishable from one fraction criteria for target coverage while including total dose
another. The results for the other four cases were similar. criteria for all targets and critical structures. Note, however, that
our proposed methodology applies equally well to other settings,
as long as the distribution of interfraction motion can accurately
4. Concluding remarks and future research directions be characterized. We show that robust treatment plans can be
obtained using only a modest number of scenarios. In particular,
We propose a new stochastic optimization model for IMRT the target dose coverage obtained with the stochastic model is far
treatment planning that accounts for interfraction motion and superior to that obtained by a traditional model using xed
distinguishes explicitly between total dose and dose/fraction interfraction motion margins. Clearly, the quality of our results
effects. For dose/fraction effects, we penalize the doses received depend on the correctness of the assumed organ motion model, so
C. Men et al. / Computers & Operations Research 39 (2012) 17791789 1789