International Journal of

Radiation Oncology
biology physics

www.redjournal.org

Physics Contribution

Quantification of Proton Dose Calculation Accuracy

in the Lung
Clemens Grassberger, MSc,*,y Juliane Daartz, PhD,* Stephen Dowdell, PhD,*
Thomas Ruggieri,* Greg Sharp, PhD,* and Harald Paganetti, PhD*
*Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts; and yCenter for Proton Radiotherapy, Paul Scherrer Institute, Villigen, Switzerland

Received Sep 20, 2013, and in revised form Feb 6, 2014. Accepted for publication Feb 14, 2014.

Summary Purpose: To quantify the accuracy of a clinical proton treatment planning system
We report on the assessment (TPS) as well as Monte Carlo (MC)ebased dose calculation through measurements
of the dose calculation ac- and to assess the clinical impact in a cohort of patients with tumors located in the lung.
curacy for lung treatments Methods and Materials: A lung phantom and ion chamber array were used to measure
with proton beams. A clini- the dose to a plane through a tumor embedded in the lung, and to determine the distal
cally used treatment plan- fall-off of the proton beam. Results were compared with TPS and MC calculations. Dose
ning system and Monte distributions in 19 patients (54 fields total) were simulated using MC and compared to the
Carlo algorithm were TPS algorithm.
compared with experiments Results: MC increased dose calculation accuracy in lung tissue compared with the TPS
in a heterogeneous lung and reproduced dose measurements in the target to within 2%. The average difference
phantom. The clinical impact between measured and predicted dose in a plane through the center of the target was
of the differences was 5.6% for the TPS and 1.6% for MC. MC recalculations in patients showed a mean dose
analyzed in a cohort of 19 to the clinical target volume on average 3.4% lower than the TPS, exceeding 5% for small
patients. The results demon- fields. For large tumors, MC also predicted consistently higher V5 and V10 to the normal
strate that the clinical dose lung, because of a wider lateral penumbra, which was also observed experimentally. Crit-
calculation algorithm over- ical structures located distal to the target could show large deviations, although this effect
estimates the dose to the was highly patient specific. Range measurements showed that MC can reduce range uncer-
target, particularly if the tainty by a factor of w2: the average (maximum) difference to the measured range was 3.9
tumor is small and centrally mm (7.5 mm) for MC and 7 mm (17 mm) for the TPS in lung tissue.
located. Conclusion: Integration of Monte Carlo dose calculation techniques into the clinic would
improve treatment quality in proton therapy for lung cancer by avoiding systematic over-
estimation of target dose and underestimation of dose to normal lung. In addition, the abil-
ity to confidently reduce range margins would benefit all patients by potentially lowering
toxicity. Ó 2014 Elsevier Inc.

Reprint requests to: Clemens Grassberger, MSc, Massachusetts General AcknowledgmentsdThe authors acknowledge Dr Henning Willers for
Hospital, Francis H. Burr Proton Therapy Center, 30 Fruit St, Boston, MA fruitful discussions concerning clinical relevance, Dr Ben Clasie for
02114. Tel: (617) 724-1202; E-mail: [email protected]. sharing his experimental expertise, Judy Adams and Nick Depauw for
edu sharing their knowledge about treatment planning, and Dr Jon Jackson and
Supported by National Cancer Institute grant R01CA111590. Partners Research Computing for maintenance of the computing cluster.
Conflict of interest: none.

Int J Radiation Oncol Biol Phys, Vol. 89, No. 2, pp. 424e430, 2014
0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2014.02.023
Volume 89  Number 2  2014 Proton dose calculation in lung 425

Introduction To compare to a site with less complex patient geometry,

an additional set of 10 liver fields from 5 cases, with similar
Proton therapy is a rapidly growing treatment modality and water-equivalent ranges (108-194 mm) and field sizes to the
continues to be investigated for new treatment sites, lung cohort was included.
because of its ability to provide superior dose distributions
in many cases. Non-small cell lung cancer (NSCLC) has a Treatment planning and dose calculation
high incidence rate with relatively poor patient outcomes algorithms
and limited scope for dose escalation using conventional
techniques (1). All patients underwent planning and treatment with
Proton therapy has only relatively recently been inves- passively scattered proton therapy. The treatment planning
tigated as a treatment modality for lung cancer (2). Various system used was XiO (Computerized Medical System) with
studies have reported promising results in terms of lower an analytical algorithm based on Hong et al (7). The pa-
toxicity (3). A randomized phase 2 trial is underway tients underwent planning according to clinical protocols,
(NCT00915005, clinicaltrials.gov), and more studies are either developed at our institution (8) or methods used in
currently recruiting (eg, NCT01770418). The results of multi-institutional trials (9).
these ongoing studies and upcoming clinical trials will For recalculation, the plans were exported from the TPS
determine the future role of proton therapy in the treatment to the MC system TOPAS (TOol for PArticle Simulation)
of lung cancer (4). (10). Both TPS and MC dose calculations were based on
For photon dose calculations, it has long been known identical Hounsfield units to relative stopping power
that equivalent-path-length (EPL) algorithms severely relationships.
overestimate the dose to the target (5, 6). This has been the
motivation for the development of alternative methods,
Phantom study
such as convolution/superposition and Monte Carlo (MC)
algorithms and their introduction into the clinic over the
past decade (5). The adequacy of current clinical dose Experiments were conducted at the Proton Therapy Center at
calculation algorithms for protons in this challenging ge- Massachusetts General Hospital. The Wellhofer I’mRT
ometry needs to be ensured. This deserves special attention, phantom consisted of 10-mm slabs of cedar wood with a
as the finite range of protons and the lower number of relative stopping power (SP) to water of 0.33, according to
incident beam angles in proton compared to photon therapy the HU-SP conversion curve used by the TPS. The tumor
leave less margin for error. (202020 mm3, SPZ1.15) is divided into 2 halves and
Our aims were the following: (1) to assess a clinical TPS embedded in 2 thicker slabs (20-mm), to enable measure-
and a MC dose calculation algorithm through measurements ments in a plane within the target. Figure 1A shows the
in a lung phantom, focusing on the dose to the target and on experimental setup. The structure placed on top of the
range uncertainties at the distal fall-off; and (2) to analyze 2-dimensional array of ionization chambers (I’mRT
the difference between the TPS and MC in a cohort of 19 MatriXX, Ion Beam Applications) is the middle part of the
patients treated with passively scattered proton therapy. phantom, a computed tomography (CT) scan of which is
shown in Figure 1B. For all experiments, we used the beam’s-
eye-view x-ray system, reducing the setup uncertainty to <1
Methods and Materials mm. The uncertainty in dose measurement was assumed to
be 1.5% according to vendor specifications, and the statisti-
Patient cohort cal uncertainty of the MC simulations was <1%, because of
the high number of protons (108) simulated per field.
All patients undergoing proton therapy to treat tumors in We used the TPS to plan a treatment with a prescribed
the lung at our institution dating from July 2011 to July dose of 1 Gy (relative biological effectiveness [RBE]) to
2013 (nZ18) were included in the study. In addition, 1 the clinical target volume (CTV), defined as 8-mm expan-
patient who had undergone planning with protons but was sion of the gross tumor volume (GTV). Subsequently, we
randomized to the photon arm of an ongoing clinical trial delivered the treatment to the experimental setup (Fig. 1A)
was also included. and measured the dose distribution across a plane in the
As this study focused on the accuracy of clinical dose middle of the target.
calculations in the lung, the specific tumor histology did not For the range measurements, we modified the homoge-
have an impact on the study design. Prescribed doses and neous phantom by including an artificial chest wall (Fig. 1C),
fractionation schemes varied; the patient cohort included 6 consisting of Lucite (20 mm thickness) embedded with bone-
stereotactic cases, 2 boost plans complementing photon equivalent “ribs.” These ribs have a diameter of 11 mm and
plans, and 11 fractionated schedules. To account for these vary in spacing from 5 to 20 mm to simulate the human rib
variations, all deviations are given in percentages of the cage with its increasing distance between the more inferiorly
prescribed dose. Tumor sizes ranged from 2 to 318 cc, with located ribs. Following clinical protocols, we developed a
clinical stages from IA to IV. single-field treatment plan (range/modulation 9.1/4.4 cm) to
426 Grassberger et al. International Journal of Radiation Oncology  Biology  Physics

Fig. 1. Experimental setup and results. (A) Lung slabs (cedar wood) and chest wall (Lucite) positioned on the 2-dimensional
array of ionization chambers. (B) Computed tomogram of the phantom with gross tumor volume (GTV; full) and clinical target
volume (CTV; dashed) contours. (C) Modified phantom with chest wall simulating a human rib cage, showing also the 2 halves
of the embedded tumor in red. (D) Line profile through the central axis of the tumor, with magnifications for target periphery (E)
and penumbra (F). Error bars for measurement 1.5%, for Monte Carlo 1% (shaded blue). A color version of this figure is
available at www.redjournal.org.

cover the target. A total of 64 ionization chambers of the A similar effect is observed in MC recalculations of
detector-array were located within the field. By gradually patient treatment plans, shown in Figure 2A. The mean
adding lung slabs (water-equivalent thickness 3 mm) to the dose difference predicted by MC and TPS is plotted as a
setup, we were able to measure the dose at each of these 64 function of size of the aperture opening. The crosses
points with increasing depth, allowing us to calculate the represent the 54 fields from the 19 treatment plans, and the
range in the phantom. We chose Range50, that is the range circles correspond to the 10 liver fields. The MC algorithm
where the dose has fallen to 50% of the prescribed dose, to consistently predicts a lower target dose, and the effect is
compare the measured and predicted ranges. higher in the lung compared to liver. The average
(maximum) mean dose loss is 2.3% (5.4%) for all 54
Results fields. The measurement results from the experiment in
Figure 1D are also indicated in Figure 2A, corresponding
Dose to target and normal lung well to the Monte Carlo prediction. The minimum target
dose for a specific field decreases by up to 7.6%. The
Figures 1D to 1F show the experimental results, obtained average (maximum) mean dose loss per patient is 2.2%
with the setup in Figures 1A and 1B, together with the (4.1%), as the effect averages out over multiple fields.
predictions of the TPS and MC along a profile through the Figure 2B demonstrates the effect of the calculation al-
center of the target. The measurements in the periphery of gorithm on the dose to normal lung, showing that MC predicts
the high-dose region (Fig. 1E) are consistently lower than a lower dose to normal lung for small targets and a higher
planned by the TPS, within measurement uncertainty of the dose for large ones. The difference (MCTPS) in mean lung
MC prediction. In the low-dose penumbra (Fig. 1F) mea- dose (MLD) and the volumes receiving greater than 5
surements and MC coincide as well, showing a higher dose Gy(RBE) (V5) and 10 Gy(RBE) (V10) were between 5 and
than predicted by the TPS. Across the measurement plane þ12%, 1 and þ22%, and 4 and þ13%, respectively.
within the target, the average difference between mea- Figures 2C to 2F show the results for 1 field of a lung
surement and MC is 1.6% of prescribed dose, compared patient, that is, a single data point in Figure 2A. The TPS and
with 5.6% for the TPS. MC predictions and their dose-volume histograms (DVHs)
The reason for the lower dose in the periphery, and are shown in Figures 2C, 2D, and 2E, respectively. The dose
conversely higher dose in the penumbra, is that protons difference in Figure 2F highlights the lower target dose
interacting in the chest wall are scattered further out of field predicted by MC. Readers should note the increasingly
because of the low-density lung tissue that follows. The lower dose toward the CTV edges in Figure 2F, which re-
mechanism will be further discussed below. sembles the experimental results shown in Figure 1E.
Volume 89  Number 2  2014 Proton dose calculation in lung 427

Fig. 2. Summary of the patient study. (A) Mean target dose difference (Monte Carlo [MC]treatment planning system
[TPS]) plotted against the size of the aperture opening. The measurement (green square) represents the average of
(measurement-TPS) across the center of the CTV. (B) Changes in mean lung dose (MLD), V5, and V10 in percentage of
planned values as a function of tumor volume; x-axis is broken for better visualization. (C-F) Example field: TPS dose (C),
MC dose (D), dose-volume histograms (DVHs) (E), and dose difference (FZCD). All color bars are percentages of
prescribed dose, transparent below 0.1%. Orange/blue contours represent the gross tumor volume (GTV)/clinical target
volume (CTV). A color version of this figure is available at www.redjournal.org.

Proton range uncertainties can have. The increased range in the superior
part of the field leads to a marked increase in dose to the spinal
Figures 3A and 3B show the predictions of the TPS and the cord, which clearly alters the DVH.
MC algorithms in the modified lung phantom that included
an artificial chest wall. The difference between the 2 al- Discussion
gorithms (MCTPS) is shown in Figure 3C, with red and
blue areas indicating higher doses in MC and TPS, The experiments confirm that the dose delivered to pe-
respectively. The histograms in Figure 3D demonstrate the ripheral regions of a target embedded in low-density tissue
results, displaying the differences in Range50. Each entry is lower than expected by the TPS and can be correctly
represents the difference between predicted and measured predicted by MC simulations. The reason lies in the
range in 1 of the 64 measurement points on the distal degradation of the lateral penumbra, which increases as a
surface. The average (maximum) range differences were function of depth to a greater extent than is predicted by the
3.9 mm (7.5 mm) and 7 mm (17 mm) for MC and TPS, TPS. XiO, as well as other treatment planning systems
respectively. Readers should note that the range differences based on analytical algorithms (7, 11-13), assume that the
in Figure 3D are given in lung tissue, that is, they are penumbral width is a function of water-equivalent depth
magnified by a factor of w3 compared to soft tissue. only. However, after scattering in the chest wall, the beam
These differences are caused by inaccuracies in the diverges over a longer distance, because of the higher
modeling of multiple Coulomb scattering in the TPS algo- geometric range of the beam in low-density tissue. The
rithm, which accounts only for the material along each pen- implication for the target dose is visualized in Figure 5A,
cil’s central axis (11, 12). This effect is prominent when which shows the dose profile as predicted by TPS and MC
heterogeneities are along the beam path, which is the case for for the patient shown in Figures 2C and 2D, replicating the
most lung patients because of rib-lung interfaces. Figure 4 phantom results presented in Figures 1D to 1F.
shows the dose distribution calculated by the TPS, MC, their This effect is related to the well-known field size effect
difference (MCTPS) and the DVHs of target and the spinal (14), which is exacerbated in low-density lung tissue. This
cord (from left to right). This patient was ultimately treated is demonstrated by the liver fields also shown in Figure 2A,
with photons; however, the data show the impact that range which exhibit a similar size and range compared to the lung
428 Grassberger et al. International Journal of Radiation Oncology  Biology  Physics

Fig. 3. Experimental verification of proton range using a heterogeneous lung phantom (shown in Fig. 1C): prediction of
treatment planning system (TPS) (A), Monte Carlo (MC) (B), and difference between them (MCTPS) (C). All color bars
are percentages of prescribed dose, transparent below 0.1%. (D) Histograms representing the difference in measured Range50
compared to MC (top, blue) and the TPS (bottom, red). Vertical lines represent range margins discussed by Paganetti (20):
2.4%þ1.2 mm (solid blue), 4.6%þ1.2 mm (solid red), and 3.5%þ1 mm (dashed red). A color version of this figure is
available at www.redjournal.org.

fields, yet do not show degradation in a mean dose greater aperture size, the distance between tumor and chest wall
than 1%. This discrepancy of MC and analytical algorithms also significantly correlates (Spearman PZ.004) with lower
in lung compared to liver targets has already been noted in dose. The range of the field also has a significant correlation
a recent study (15). (Spearman PZ.0001) to lower dose, although only for fields
of similar size (>20 cm2). Therefore, fields with a large
Impact of MC dose calculation on dose to target tumorechest wall distance and a high range are most at risk
and critical structures for delivering lower target doses than predicted by the TPS.
As shown in the results, analytical dose calculation
The dose reduction measured in the phantom (Fig. 1D) is methods in the lung can lead to a mean dose loss of more
similar to the in-patient effect predicted by MC (Figs. 2C- than 5% for small targets, whereas the lung V5 can increase
2F). The MC dose is slightly reduced compared to the TPS by more than 20%. Not accounting for these deviations
in the center, whereas toward the edge of the target the could inherently introduce bias into randomized clinical
reduction becomes substantial (>5%), exceeding the dose trials comparing photon and proton therapies for lung cancer.
tolerance typically required in the clinic. First, because of the steep dose-response curve of most
As visible in Figure 2A, there is a significant correlation lung cancer cell lines (16), a lower mean target dose can
between the loss of mean target dose and the aperture size have a significant effect on outcome, as shown in previous
(Spearman PZ.0002). The spread among the values in clinical studies (17). As Figure 5 demonstrates, the TPS
Figure 2A for the same aperture size suggests additional underestimates the dose specifically in the CTV periphery,
confounding factors to the field size (14). In addition to the a region that has been linked to increased cancer stem cell

Fig 4. Example of underestimated range in a patient by an analytical dose calculation algorithm. All color bars are per-
centages of prescribed dose. Contours shown are the gross tumor volume (GTV; pink), clinical target volume (CTV; green),
and spinal cord (red). A color version of this figure is available at www.redjournal.org.
Volume 89  Number 2  2014 Proton dose calculation in lung 429

Fig 5. (A) Dose profile of treatment planning system (TPS) and Monte Carlo (MC) along the horizontal axis of the dose
distribution in Figure 2C and 2D. (B) Visualization of the impact of tissue density on the range margin (cyan area). Both
fields have the same (water-equivalent) range and therefore range margin, indicated in cyan, yet the margin of the superior
field is enlarged by a factor of w3. A color version of this figure is available at www.redjournal.org.

density (18). Consequently, the effect on local control could calculation uncertainty could be reduced from 4.6%þ1.2
be higher than the mean dose loss initially suggests. It has mm to 2.4%þ1.2 mm (20), represented by the solid lines in
also been shown in clinical studies that prescription of dose Figure 3D. The results of this work indicate that the latter is
to isocenter, leading to lower peripheral tumor doses, is an adequate margin for dose calculation uncertainty,
linked to decreased local control (17). although additional margins certainly have to be added to
Second, as the MC algorithm predicts consistently account for other uncertainties encountered in patient
higher doses to the normal lung for large targets, conclu- treatments. The lower histogram in Figure 3D suggests that
sions regarding the toxicity of protons could be adversely 4.6%þ1.2 mm is a necessary margin for the current TPS.
affected. This would especially concern trials designed Furthermore, applying a margin of 3.5%þ1 mm, a
around iso-toxic dose escalation strategies (19). commonly used value for proton range uncertainty (20), is
not sufficient in this inhomogeneous geometry. Acknowl-
Impact of MC dose calculation on range uncertainty edging this, we currently use additional range margins at
and associated margins our institution for lung treatments.
The reduction in range uncertainty margins by 2.2%,
that is, from 4.6% to 2.4%, can make a sizable difference if
The second area in which MC algorithms can have an
in lung tissue. For example, at 20-cm range, MC algorithms
impact on clinical practice is through reduced range un-
could decrease the distal range margin by 4.4-mm water-
certainty margins. The impact will be greatest for large
equivalent range, which corresponds to approximately 15
targets located in the lung, because the range margin is
mm of lung tissue.
defined as an increase in the water-equivalent range. If the
distal fall-off occurs in low-density tissue, as shown on the
right side of Figure 5, the volume of normal tissue irradi- Consequences and future directions
ated is increased compared to other soft-tissue sites.
It has been proposed that, by using MC algorithms for A possible short-term solution could be to triage patients to
treatment planning, range margins associated with dose specific risk groups, as shown in Figure 6. The left side of the

Fig 6. Possible mitigation approach applied to 54 treatment fields. (Left) Treatment fields divided into 3 risk groups, as
described in the text. (Right) Treatment fields simulated with increased monitor units (high risk þ4%, intermediate risk þ3%,
low risk þ2%).
430 Grassberger et al. International Journal of Radiation Oncology  Biology  Physics

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