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Increasing inter-fraction target robustness in intensity-modulated proton radiotherapy for

lung cancer using a planning HU optimization structure
Carissa Rivinius BS, RT(R)(T); Kristen Dezell BS, RT(R)(T); Brittni McKane BS, RT(R)(T);
Nishele Lenards, PhD, CMD, RT(R)(T), FAAMD; Ashley Hunzeker, MS, CMD; Alan Kraling,
CMD, RT(T)
Medical Dosimetry Program at the University of Wisconsin-La Crosse, WI
Abstract
Keywords: lung cancer, IMPT, robustness, HU planning override, optimization
Introduction
Traditionally, radiation therapy for the treatment of lung cancer was performed with
conformal photon beams and then evolved into photon intensity modulated radiation therapy
(IMRT).1,2 As advancements continued, proton therapy became an enticing modality due to the
relative stopping power and ensuing decreased dose to nearby healthy tissue.1,2 Protons deposit
the majority of dose at a certain depth known as a “Bragg peak,” and the associated rapid dose
fall off results in greater sparing of nearby organs at risk (OAR) compared to traditional photon
radiation therapy techniques. Consequently, protons are much more sensitive to anatomic
changes, such as target depth variation and organ motion, within the beam path. Intensity
modulated proton therapy (IMPT) is the latest advancement in proton treatments, allowing for
even more conformal and precise dose distributions. There are many benefits to IMPT, although
there are also many challenges. In proton lung planning, these challenges include accounting for
respiratory motion and other daily set-up variations that have larger implications in proton
planning than photon planning. Additionally, heterogeneity differences and inter-fraction
anatomic changes can significantly impact the dose distribution in proton lung planning. These
challenges can impact the robustness of a plan, or the ability of a plan to maintain dose while
managing these uncertainties.3
A major consideration when evaluating a proton plan is whether it maintains robustness
throughout the course of treatment. An uncertainty that can influence robustness within a proton
plan is heterogeneity differences. Inherent low electron densities exist within the lung, therefore;
it is well known that proton radiation travels further in lung parenchyma due to this low tissue
density.1 However, tumor density is typically much higher, resulting in overall target volume
heterogeneities and difficulty of dose robustness to the target within the overlapping tumor and
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lung region. Electron densities from the planning CT scan are represented by HU values, which
are used to determine relative linear stopping power (RLSP) and the associated dose.1 The RLSP
can vary by 5% or more based on the assigned HU, leading to potential proton range errors.1
Besides target volume heterogeneities, several other factors play a role in IMPT lung planning
robustness such as tumor motion from breathing or cardiac motion and tumor inter-fraction
shrinkage or growth.3,4
To improve proton plan robustness related to tumor motion and inter-fraction changes,
enhanced imaging technology such as 4DCT allows for 4D dose evaluation, leading to improved
proton plan robustness.5 Additional enhancements in imaging technology, such as on-board
imaging and CT gantry capabilities, have provided additional opportunities to improve IMPT
robustness. Robust optimization builds a framework into proton plans to work against geometric
uncertainties and ensure that range or set-up errors do not result in increased dose to OAR nor
under-coverage of the target.6 Traditional 3D volume CT imaging reduced many set-up errors
but could not account for or monitor tumor motion. Advanced CT scanners can now perform a
functional, real-time 4D scan that monitors respiration and tumor motion, which is critical in the
thoracic region.
The 4DCT scans aid physicians in targeting the tumor volume by requiring a smaller
target volume expansion from gross disease, therefore sparing more healthy tissue and nearby
OAR. Mobile target volumes can also cause something called an interplay effect, where the
small spots of the proton pencil beam can miss the target due to intra-gate motion, leading to
greater dosimetric uncertainty. To combat this effect, layer-based repainting combined with 4D
motion analyses can drastically improve overall plan robustness.5,7,8 Repainting involves
subdividing a treatment plan and delivering multiple iterative layers over the moving target,
ultimately smoothing the dose by reducing potential for misplaced proton spot delivery.7
Layer-based repainting along with 4D planning has been effective in increasing
robustness in IMPT lung planning. Even so, previous department specific experience
demonstrated that maintaining robustness throughout a full course of proton lung treatment was a
challenge. One option to further increase inter-fraction robustness includes the use of a
Hounsfield Unit (HU) override. Tryggestad et al9 discussed the gain in dosimetric robustness
when utilizing an HU override in air-filled cavities using relative HU values from nearby
structures. Kang et al 10 utilized an HU override to a whole target structure to try to increase
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robustness, such as overriding the entire planning target volume (PTV) or internal target volume
(ITV). Botas et al5 and Wei et al11 discovered a significant increase in plan robustness and target
coverage by overriding the entire ITV, but the surrounding OAR also received a greater dose.
Protons provide an opportunity for increased dose conformality as a result of protons
RLSP and the Bragg peak. These factors and the associated plan robustness are directly
influenced by uncertainties such as tumor motion, anatomical changes, and tissue
heterogeneities. The potential of an HU override to increase IMPT inter-fraction robustness in
lung planning, without exceeding dose constraints to OAR, needs further research. The problem
is maintaining robust target coverage between the target volume and lung overlap region due to
inter-fraction tumor and anatomy changes. The purpose of this study is to determine the value of
an HU optimization structure covering the target volume and lung overlap region that will
increase proton plan robustness and maintain the inter-fraction target coverage. The research
hypotheses were that HU values of -400 (H1A), -200 (H2A), and 0 (H3A) would increase
robustness of proton lung planning and maintain inter-fraction CTV coverage that 95% of the
volume received at least 100% or more of the prescribed dose (D95% ≥ 100%). Inter-fraction CTV
coverage was analyzed using D95% ≥ 100% ± 5% per departmental protocol. Researchers
examined statistically significant associations between HU values and increased robustness, and
OAR such as the heart, lungs, and esophagus were reviewed to ensure recommended dose
constraints were not exceeded.
Methods and Materials
Patient Selection and Setup
This was a retrospective study from a single institution performed on 15 patients who
were treated for primary lung cancer using IMPT. Inclusion criteria was IMPT left lung targets
with air in the CTV overlap ≥ 50 cubic centimeters (ccs), each patient had 5 verification scans
completed throughout treatment, and each patient was planned with a prescribed dose of 60 Gy
to the primary target. Patients who had right sided lung cancer or previous radiation treatment to
the same area were excluded from this study.
Each patient was simulated in a head-first, supine position. Depending on the patient’s
positional abilities and tumor location in the lung, immobilization varied slightly. For 7 patients,
immobilization included a 5-point mask, Klarity neck rest, and arms down by their sides with
indexed handles for shoulder reproducibility. The remaining 8 patients were positioned with their
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arms up and indexed in a custom upper Vac-Lok. All patients had a 4DCT simulation completed
on a Siemens CT scanner with a scan range through the lungs using 2 mm slice thickness, and
tumor motion was evaluated using MIM software to ensure the target moved less than 1 cm in all
directions.
Treatment Planning
After completion of a 4DCT simulation, datasets were imported into the Eclipse
treatment planning system for contouring and any secondary image registrations. The radiation
oncologist defined a clinical target volume (CTV) labeled CTV6000 for all 15 patients following
departmental guidelines for lung cancer. Planning target volumes were not created as the typical
expansion that a PTV would provide was indirectly achieved through robust optimization of the
CTV.9 Delineation of OAR were completed on the planning scan by the physician, medical
resident, and medical dosimetrist per clinical departmental contouring guidelines; including the
heart, esophagus, and lungs referencing the Radiation Therapy Oncology Group (RTOG) 0617
study constraints.12 In addition to OAR, each patient had an optimization structure created that
specifically covered the CTV and lung overlap region (Figure 1).
After completion of target and OAR delineation, retrospective planning commenced,
employing the Varian Eclipse external beam Treatment Planning System (TPS), Version 15.6.8.
The plans were created using Proton Convolution Superposition and Nonlinear Universal Proton
Optimizer (NUPO) algorithms, Version 15.6.06. Each plan utilized a single field optimization
(SFO) repaint vac machine, resulting in independent field optimization as information was not
shared between fields. The vac machine delivers a range of energy that adjusts layer by layer
based on the depth of the beam as it traverses tissue. The optimal beam arrangement for each
patient was created using 2 posterior oblique fields with an optional anterior field depending on
anteroposterior target location. Each patients’ beam arrangement remained unchanged across all
associated plans with and without the HU optimization structure.
Each patient was planned 4 times to evaluate target robustness; the first plan did not
incorporate an HU override value, and the next 3 plans utilized the optimization structure with an
HU override value of 0, -200, and -400 respectively. The prescription was 60 Gy in 30 fractions
to CTV6000. Plan normalization was based on target coverage and OAR constraints from RTOG
0617. The least desirable robustness DVH curves created during the planning process showed the
least acceptable treatment scenario range based on changes in target volume and isocenter shifts
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in 6 directions. Least desirable robustness curves were evaluated and normalized to ensure that ≥
95% of the dose coverage was to ≥ 95% of the target volume.
Plan Evaluation
Overall, plan robustness was evaluated for all 4 plans for each patient. Robustness
calculations consisted of a 6 directional error test that assessed isocenter shifts of 5 mm in
positive and negative x, y, and z directions per departmental standards. Also, an HU to relative
linear stopping power (RLSP) calibration curve error test reviewed a 5% positive and negative
uncertainty for range error. Extreme inspiration or expiration phases were also considered when
evaluating plan robustness from the 4DCT planning scan and were within departmental
standards. All robustness curves were evaluated and verified with each patient’s weekly
verification 4DCT scan. These 4DCT verification scans overlaid the dose from the 4 original
plans. The CTV6000 D95% ≥ 95% within ± 5% was used to evaluate plan robustness.
Final dose to CTV6000 and OAR were compared on all plans. The values obtained were
recorded and used for statistical analysis between each plan created without and with an HU
optimization structure for target plan robustness evaluation. Figure 2 shows these values
collected for one patient for each plan.
Statistical analysis
The data pertaining to target robustness and OAR dose was evaluated to determine the
best method for statistical analysis. To determine if the HU 0, -200, and -400 original plans
increased robustness from the original plan without the optimization structure, the paired T-test
was first implemented. Second, the inter-fraction robustness was evaluated by taking the average
of the 5 verification robustness values per patient to determine if the HU 0, -200, and –400
verifications increased the robustness compared to the original verification robustness using a
non-parametric Wilcoxon Signed Rank (WSR) test. Third, OAR values were reviewed to verify
dose constraints were not exceeded and determine on average the difference between the OAR
original values and the values using HU 0, -200, and -400. A 5% level of significance was used
for each test.
Results
HU values and Target Coverage
Original plans without and with an HU optimization structure were reviewed to assess
initial plan robustness. The percentage of CTV6000 receiving 60 Gy averaged 100.61% for the
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original plan with no HU override, 100.51% for the original plan with an HU override value of –
400, 100.33% for the original plan with an HU override value of –200, and 100.31 for the
original plan with an HU override value of 0 (Figure 3). The Paired T-test was performed to
compare the original plan average without an HU override to the original plan average using an
HU override. The results revealed that there was no significant difference between the original
plans using an HU override value of -400 (p = 0.45, 95% CI [-0.35, 0.16]) or an HU override
value of -200 (p = 0.067, 95% CI [-0.57, 0.02]). This resulted in the rejection of hypotheses H1A
and H2A as neither HU -400 nor HU -200 significantly increased robustness of proton lung
planning. The original plan with an HU override value of 0 had sufficient significant results
implying that it lowered plan robustness (p = 0.021, 95% CI [-0.053, -0.05]), again resulting in
the rejection of hypothesis H3A. It is worth noting that while all hypotheses were rejected, all
original plans without and with an HU optimization structure override had clinically acceptable
coverage of D95% ≥ 100%.
Verification scans performed throughout treatment were then considered to assess inter-
fraction robustness. The percentage of CTV6000 receiving 60 Gy averaged 96.53% for the
verification plans with no HU override, 97.54% for the verification plans with an HU override
value of –400, 97.94% for the verification plans with an HU override value of –200, and 97.97%
for the verification plans with an HU override value of 0 (Figure 4). The Wilcoxon Signed Rank
test was performed to compare the verification plan average with no HU override to the
verification plan average using an HU override value. The results indicated that there was
sufficient and significant evidence to determine an increase in inter-fraction robustness using an
HU override value of -400 (p = 0.012), an HU override value of -200 (p = 0.011), and an HU
override value of 0 (p = 0.012). While hypotheses H1A, H2A, H3A were rejected based on the
original plans, it is important to highlight that all verification plans did maintain and significantly
increase inter-fraction CTV coverage that 95% of the volume received ≥ 100% ± 5% of the
prescribed dose.
Discussion
Conclusion
Acknowledgements
The authors would like to thank Dr. Sherwin Toribio from the University of Wisconsin –
La Crosse Statistical Consulting Center for assistance in statistical analysis and interpretation of
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statistical results of the data; however, any errors of fact or interpretation remain the sole
responsibility of the authors.
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Figures

Figure 1. This image shows a sample visual representation of a CTV volume without (A) and
with (B) an HU optimization structure in the axial (top), coronal (middle), and sagittal views
(bottom). The cyan color represents a CTV volume delineated by the physician. The magenta
color along the lung and tissue interface represents the HU optimization structure created for this
study, given an HU override value of either -400, -200, or 0.
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Figure 2. Values obtained for statistical analysis without and with an HU optimization structure
for target plan robustness evaluation are shown above for one patient within our research
population. Original plans are shown in a dark color (blue representing no override, green
representing an override using HU -400, yellow representing an override using HU -200, and red
representing an override using HU 0). Five associated verification plans are shown in a lighter
color following their corresponding original plan. In the first complete plan without an HU
override (blue), the final verification scan (black) would not have met our target robustness
evaluation criteria of D95% ≥ 100% ± 5% as it resulted in 94.2% coverage, below the lower 95%
threshold. On the other hand, each associated plan created with an HU optimization structure
would have maintained robustness ± 5% throughout the full course of treatment.
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Figure 3. Target coverage of original plans without and with HU override values of -400, -200,
and 0. Original plans without an HU optimization structure are represented by dark blue.
Original plans using an HU optimization structure with an override value of –400 are shown in
green, -200 are shown in yellow, and 0 are shown in red.
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Figure 4. Target coverage of verification plans to assess inter-fraction robustness without and
with HU override values of -400, -200, and 0. Verification plans without an HU optimization
structure are represented in light blue. Verification plans using an HU optimization structure with
an override value of –400 are shown in light green, -200 are shown in light yellow, and 0 are
shown in light red.