1

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
There are multiple challenges in intensity modulated proton therapy (IMPT) lung
planning that can impact plan robustness, such as respiratory motion near the target, patient setup
variations, and inter-fraction anatomy changes. Previous research has shown improvement in
proton plan robustness by using Hounsfield Unit (HU) overrides to the target volume. The
purpose of this study was 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, -200, or 0
would increase robustness of proton lung planning (H1A, H2A, and H3A respectively) and
maintain inter-fraction clinical target volume (CTV) coverage (H4A, H5A, and H6A respectively).
Fifteen patients were selected for this retrospective study. Plans were compared with and without
an HU override applied to an optimization structure that was created to specifically cover the
CTV and lung overlap region. When evaluating robustness of the original plans, utilization of the
HU optimization structure did not demonstrate a significant increase in robustness. When
comparing weekly verification scans, the HU optimization structure did demonstrate sufficient
evidence to indicate an increase in inter-fraction robustness. Overall, researchers discovered that
the use of an HU optimization structure offers a practical option to increase inter-fraction plan
robustness and should be considered for lung proton treatment planning.
Keywords: lung cancer, IMPT, robustness, HU planning override, optimization
Introduction
Prior to proton therapy, 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 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
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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 to maintain planned 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 prescribing dose to the target within the overlapping tumor and
lung region. Electron densities from the planning CT scan are represented by Hounsfield Unit
(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 prevents range or set-up errors resulting in increased dose to OAR or 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,
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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 of the healthy tissue and
nearby OAR. Mobile target volumes can also cause 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 for proton plans includes the
use of an 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 al10 utilized an HU override to a whole target structure to attempt to increase 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 problem is maintaining robust target coverage between the target volume
and lung overlap region due to inter-fraction tumor and anatomy changes. The potential of an
HU override to increase IMPT inter-fraction robustness in lung planning, without exceeding dose
constraints to OAR, requires further research. Therefore, the purpose of this study was 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, -200, and 0 would increase original plan
robustness of the clinical target volume (CTV) such that 95% of the volume received at least
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100% or more of the prescribed dose (D95% ≥ 100%) for all robustness curves (H1A, H2A, and H3A
respectively) and maintain inter-fraction CTV coverage D95% ≥ 95% (H4A, H5A, and H6A
respectively). 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 (cc). Each patient had 5 verification scans
completed throughout treatment and was planned with a prescribed dose of 60 Gy in 30 fractions
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
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 2.0 mm slice thickness, and
tumor motion was evaluated using MIM software to ensure the target moved less than 1.0 cm in
all directions.
Contouring
After completion of a 4DCT simulation, datasets were imported into the Eclipse
treatment planning system (TPS) for contouring and any secondary image registrations. The
radiation oncologist defined a CTV labeled CTV6000 for all 15 patients following departmental
guidelines for lung cancer. Planning target volumes were not created as the typical expansion for
a PTV 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
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addition to OAR, an optimization structure was created that specifically covered the CTV and
lung overlap region (Figure 1).
Treatment Planning
After completion of target and OAR delineation, retrospective planning commenced,
employing the Varian Eclipse external beam 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, meaning that each beam was optimized individually for dose contribution. 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 through all HU optimization structure comparisons.
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 -400, -200, and 0 respectively. During the planning process, dose volume
histogram (DVH) curves were created for isocenter shifts in 6 directions and positive or negative
range uncertainty. The least desirable of these curves demonstrated the greatest deviation in
target coverage in the given direction from the original DVH. Original plans were normalized to
ensure that the least desirable robustness curve maintained D95% ≥ 95% per department standards,
in addition to meeting OAR constraints from RTOG 0617.
Plan Evaluation
Overall, plan robustness was evaluated for all 4 plans for each patient. Robustness
calculations consisted of 6 directional error tests that assessed isocenter shifts of 5.0 mm in
positive and negative x, y, and z directions per departmental standards. Also, an RLSP
calibration curve error test reviewed a 5% positive and negative uncertainty for range error for a
total of 8 DVH curves. 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 D 95% ≥ 95% was used to evaluate plan robustness per department standards.
Final dose to CTV6000 and OAR were compared on all plans. The values obtained were
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recorded and used for statistical analysis between each plan created with and without an HU
optimization structure for target plan robustness evaluation.
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 - 400, - 200, and 0 original plans
increased robustness from the original plan without the optimization structure, the paired T-test
was first implemented. The inter-fraction robustness was also evaluated by taking the average of
the 5 verification robustness values per patient to determine if the HU -400, -200, and 0
verifications increased the robustness compared to the original verification robustness using a
non-parametric Wilcoxon Signed Rank (WSR) test. The 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 -400, -200, and 0. A 5% level of significance was used
for each test.
Results
Original plans with and without an HU optimization structure were reviewed to assess
initial plan robustness of percentage of CTV6000 receiving 60 Gy. The paired T-test was
performed to compare the original plan average without an HU override (100.61%) to the
original plan average of each hypothesized HU override plan. Verification scans performed
throughout treatment were then considered to assess inter-fraction robustness in terms of
percentage of CTV6000 receiving 60 Gy. The WSR test was performed to compare the
verification plan average without an HU override (96.53%) to the verification plan average using
an HU override.
-400 HU Results
The original plan with an HU override value of -400 resulted in the percentage of
CTV6000 receiving 60 Gy averaging 100.51% after plan normalization to ensure the least
desirable robustness curve maintained D95% ≥ 95% (Figure 2). There was no significant
difference between the original plan using an HU override value of -400 to the original plan
without an HU optimization structure (p = 0.45, 95% CI [-0.35, 0.16]). The original plan using an
HU override value of -400 suggested the existing null hypothesis (H10) failed to be rejected.
Regarding the verification scans, the percentage of CTV6000 receiving 60 Gy averaged 97.54%
with an HU override value of -400 (Figure 3). These results indicated that there was sufficient
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and significant evidence to determine an increase in inter-fraction robustness using an HU

override value of -400 (p = 0.012). The inter-fraction robustness using an HU override value of -
400 suggested the existing null hypothesis (H40) was rejected.
-200 HU Results
The original plan with an HU override value of -200 resulted in the percentage of
CTV6000 receiving 60 Gy averaging 100.33% after plan normalization to ensure the least
desirable robustness curve maintained D95% ≥ 95% (Figure 2). There was no significant
difference between the original plans using an HU override value of -200 (p = 0.067, 95% CI [-
0.57, 0.02]). The original plan using an HU override value of -200 suggested the existing null
hypothesis (H20) failed to be rejected. Regarding the verification scans, the percentage of
CTV6000 receiving 60 Gy for the HU override value of –200 averaged 97.94% (Figure 3). The
results indicated that there was sufficient and significant evidence to determine an increase in
inter-fraction robustness using an HU override value of -200 (p = 0.011). The inter-fraction
robustness using an HU override value of -200 suggested the existing null hypothesis (H50) was
rejected.
0 HU Results
The original plan with an HU override value of 0 resulted in the percentage of CTV6000
receiving 60 Gy averaging 100.31% after plan normalization to ensure the least desirable
robustness curve maintained D95% ≥ 95% (Figure 2). The implication was significant in that
original plans with an HU override value of 0 marginally lowered plan robustness yet remained
within clinically acceptable target coverage of D95% ≥ 100% (p = 0.021, 95% CI [-0.053, -0.05]).
The original plan using an HU override value of 0 suggested the existing null hypothesis (H30)
failed to be rejected. Regarding the verification scans, the percentage of CTV6000 receiving 60
Gy averaged 97.97% with an HU override value of 0 (Figure 3). The results indicated that there
was sufficient and significant evidence to determine an increase in inter-fraction robustness using
an HU override value of 0 (p = 0.012). The inter-fraction robustness using an HU override value
of 0 suggested the existing null hypothesis (H60) was rejected.
Discussion
Result Analysis
After reviewing all plans, there was not a statistically significant increase in plan
robustness to CTV6000 when comparing the original plans with no HU override to the original
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plans with an HU override of -400, -200, or 0. However, it should be noted that there was not a
significant decrease in plan robustness to the original plans with an HU override of - 400 or -200,
and these original plans using an HU override of - 400 and -200 remained well above the 95%
clinically acceptable dose constraint (average CTV6000 D95% = 100.51% and 100.33%
respectively). While the original plan with an HU override of 0 decreased slightly in plan
robustness, the percentage of CTV6000 receiving 60 Gy averaged 100.31%, again well above the
95% clinically acceptable dose constraint.
Current findings support research by Tryggestad et al9 regarding the clinical gain in
dosimetric robustness with the utilization of an HU override in air-filled cavities near the target
volume. Although the current findings highlight the gain in robustness for targets within the
lung, Tryggestad et al 9 focused largely on air-filled cavities near abdominal targets. Results from
a single patient in the current study research population demonstrated that the first complete plan
with no HU override did not meet inter-fraction evaluation criteria (D95% ≥ 95%) on the final
verification scan with only 94.2% coverage (Figure 4). Contrastingly, each associated plan
created with an HU optimization structure appeared to maintain robustness throughout the full
course of treatment. The HU optimization structure appears to be a valuable tool in maintaining
and significantly increasing inter-fraction CTV coverage. Another consideration while increasing
planning robustness involves theoretically increasing dose to healthy tissue near the target
volume. In all instances of this study population, dose to all nearby OAR remained well within
departmental plan evaluation criteria of all originally approved plans.
Implications for Medical Dosimetry
With the utilization of weekly 4DCT verification scans evaluating tumor motion and
inter-fraction anatomy changes, it has been found that plan robustness was improved for inter-
fraction IMPT planning when utilizing an HU optimization structure with the value of -400, -
200, or 0. Of these HU override values, there was no superior value found for inter-fraction
robustness. There was a negligible increase in dose to OAR that remained well within
departmental guidelines. These findings agree with earlier findings by Botas et al5 and Liu et al11
concluding that plans using an HU optimization structure can increase proton plan inter-fraction
robustness while maintaining no significant increase to nearby OAR.
Conclusion
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Ultimately, finding dosimetric improvements to proton lung planning continues to be a

problem in 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 was to
determine the value of an HU optimization structure covering the target volume and lung overlap
region that would increase proton plan robustness and maintain inter-fraction target coverage.
The frequency of replanning may decrease when planning with a HU optimization structure that
utilizes an override value of -400, -200, or 0 leading to improved planning accuracy and clinical
efficiency. It is vital that physicians are cognizant of original CTV coverage in planning to limit
the potential for replanning. This may suggest that a change in practice may be sensible to
tighten CTV robustness acceptance or consistently evaluate the percentage of coverage
compared to robustness.
A limitation to this study was the range of the sample population. The current study
sample size was limited to 15 patients due to selective inclusion and exclusion criteria. Another
limitation was that this study was performed at a single institution utilizing a single TPS and
dose calculation algorithm. A multi-institution approach could be beneficial in finding
differences per TPS practices as well as calculation algorithms leading to potential findings in
proton lung replanning and inter-fraction robustness evaluation.
Future researchers should increase the number of patients as well as expand the inclusion
criteria. This criterion may include more mobile target volumes near the diaphragm as well as
patients that require lung volume re-irradiation with associated anatomy changes due to their
advanced tumor burden within the body. Additionally, a more thorough review of nearby dose to
OAR should be explored to fully evaluate the increase in dose to OAR for statistical significance
based on each original plan as well as associated inter-fraction verification plans with and
without the use of an HU override. This would include a closer evaluation of inter-fraction dose
to critical OAR structures such as the heart, healthy lung tissue, and esophagus.
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
statistical results of the data; however, any errors of fact or interpretation remain the sole
responsibility of the authors.
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10. Kang Y, Zhang X, Chang J, et al. 4D Proton treatment planning strategy for mobile lung
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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 indicated by a striped arrow represents a CTV volume delineated by the
physician (A). The magenta color indicated by a solid black arrow represents the HU
optimization structure along the lung and tissue interface created for this study (B), given an HU
override value of either -400, -200, or 0.
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Figure 2. 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 white. Original
plans using an HU optimization structure with an override value of -400 are shown as vertical
stripes, -200 are shown as dots, and 0 are shown as horizontal stripes.
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Figure 3. 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 white. Verification plans using an HU optimization structure with an
override value of -400 are shown as vertical stripes, -200 are shown as dots, and 0 are shown as
horizontal stripes.
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Figure 4. Values obtained for statistical analysis without and with an HU optimization structure
for target plan robustness evaluation are shown above for one patient within the research
population. Original plans are shown first with a thick black border (white representing no
override, vertical stripes representing an override using HU -400, dots representing an override
using HU -200, and horizontal stripes representing an override using HU 0). Five associated
verification plans follow their corresponding original plan. Solid black represents any
verification plan that fell below robustness evaluation criteria.