1

A comparison of single-phase and phase-gated average verification plans for proton

radiotherapy
Katelyn Knoepke, BS, R.T.(R)(T), Jennifer DeWeese, BS, R.T.(R)(T), Joseph Spencer, BS,
R.T.(R)(T)(CT), Nishele Lenards, PhD, CMD, R.T.(R)(T), FAAMD, Ashley Hunzeker, MS,
CMD, Jedediah E. Johnson, PhD
Medical Dosimetry Program at the University of Wisconsin-LaCrosse, WI
ABSTRACT
To address challenges and enhance the efficiency of online adaptive radiation therapy,
advancements in automation are pivotal. The problem is that the creation of routine weekly
verification plans for phase-gated treatments requires the creation of a new phase-gated average
scan which is time-consuming and incompatible with current workflows utilizing automated
software. Therefore, the purpose of this study was to compare clinical target volume (CTV)
coverage between a single, full exhale phase verification plan and a phase-gated average
verification plan to determine whether a single-phase verification is an acceptable surrogate. For
this study, target coverage was specified as the percentage of the target volume receiving 95% of
the prescription dose (V95% [%]). Researchers hypothesized that the target coverage of the rigid,
deformable, and physician-modified CTVs on a single-phase verification will be within ± 5% of
the target coverage on a phase-gated average verification for the comprehensive cohort of
patients studied (H1A), also within the studied lung (H2A), liver (H3A) and esophageal (H4A)
patient cohorts. Additionally, researchers hypothesized that the single-phase and phase-gated
average verification comparison of target coverage will differ by no more than ± 5% for the
patient subgroups of both clinically acceptable verification plans and those that triggered a
subsequent replan (H5A). Quantitative analysis of the target coverage metric demonstrated a
difference of less than ± 5% between the phase-gated average verification plan and the single-
phase verification plan. This similarity in target coverage extended across lung, liver, and
esophagus patients, highlighting clinical viability. Qualitative analysis further revealed consistent
clinical decisions, with minor discrepancies noted, especially in esophagus cases. Researchers
suggest that single-phase verification plans can be acceptable surrogates for phase-gated
verification plans in most clinical scenarios, improving efficiency in proton therapy practice.

Keywords: Proton therapy; 4DCT; verifications; interplay; adaptive radiation therapy; phase-
gated
 2

Introduction
The advantages of proton pencil beam radiotherapy over conventional x-ray radiotherapy
have led to a growing interest in its application. Proton treatments generally deliver less integral
dose to surrounding healthy organs, resulting in better treatment outcomes.1,2 However, the
primary challenge of proton pencil beam treatments lies in the sensitivity of the planned dose
distribution to changes in proton range, making these plans vulnerable to degradation due to
changes in patient anatomy.3,4,5 Daily variations in patient setup and anatomical changes can alter
the dose distribution, affecting both target coverage and organ at risk (OAR) sparing. 3,6 To
manage these uncertainties and ensure the ongoing safety and effectiveness of the proton therapy
treatments, acquiring routine CT verification scans is essential.6 The CT verification is
performed under the same scanning parameters as the CT simulation. The treatment plan is
recalculated on the CT verification image set, allowing for a quantitative assessment of the dose
on current patient anatomy. These regular scans help assess any deviations in the current dose
distribution from the initial treatment plan, enabling clinical interventions such as the creation of
a modified treatment plan.7,8,9 This replanning may be necessary through the course of treatment,
especially beyond 4 weeks, emphasizing the importance of an efficient verification and
replanning process to maintain plan quality.4,6,8,10
Another significant challenge of proton pencil beam therapy is the impact of respiratory
motion, which can introduce interplay effects that produce suboptimal dose distributions. 3,5,7,11
The interplay effect occurs because of the relative motion between a dynamic treatment delivery
and a moving target.5 Some spots are placed closer together than intended, while others are
pulled further apart, increasing dose heterogeneity.7 Furthermore, respiratory motion can also
lead to tissue changes upstream of the intended target, causing corresponding changes in the
proton range and affecting the resulting delivered dose to the target.7,12
Utilization of four-dimensional computed tomography (4DCT) imaging is a standard
technique for motion evaluation and treatment planning for mobile targets using pencil beam
proton therapy.7,10,12 Four-dimensional image sets are created by tracking the position of a
surrogate marker and correlating this signal with an oversampled CT image set that captures the
full respiratory cycle at each anatomical location. This 4D reconstruction results in 10 separate
three-dimensional computed tomography (3DCT) data sets, each representing a portion of the
breathing cycle and allowing for characterization of target motion.7,10 If this motion amplitude
 3

results in a treatment plan with an unacceptably large volume of healthy tissue irradiation and/or
interplay effect, a respiratory-gated technique can be used. In a phase-gated approach, only a
subset of the breathing phases surrounding full exhale are averaged together and used for
treatment planning.7,10,11 The corresponding treatment is only delivered during these breathing
phases by actively gating the beam using the breathing surrogate signal.7,10 While essential to
high quality, safe treatment plans, integrating these phase-gating processes can add to treatment
complexities and creates challenging workflows.
In modern radiation therapy, the demand for streamlined and efficient workflows is
paramount, particularly when managing phase-gated patients and the ever-advancing online
adaptive radiation therapy (ART). When a verification scan is performed on a phase-gated
patient, a new phase-gated data set must be generated. The manual process of creating a new
phase-gated image set involves a full 4D reconstruction and customized averaging of the
individual breathing phases. With clinical efficiency in proton clinics at a premium, this presents
an opportunity for further process optimization. This is especially important in the motivation
toward automation in online ART, which involves real-time dose assessment and subsequent
modification of the treatment plan to maximize target dose and minimize normal tissue
dosage.4,6,9,13 Online ART is performed in the treatment room immediately prior to treatment
delivery and is particularly suitable for treatment areas with anticipated adaption needs, such as
intra-abdominal sites.7,9 Efficient workflows are crucial for implementing online adaptive
protocols in radiotherapy practices, which involve complex and labor-intensive tasks such as
imaging, assessment, replanning, and quality assurance.9,13 Decreased efficiency can lead to
targeting inaccuracies due to changes between initial imaging and beam delivery. 7
To address these challenges and enhance the efficiency of online adaptive radiation
therapy, advancements in automation are pivotal. The problem is that the verification process for
phase-gated treatments requires the creation of a new phase-gated average scan which is time-
consuming and incompatible with current workflows utilizing automated software. Therefore,
the purpose of this study was to compare clinical target volume (CTV) coverage between a
single, full exhale phase verification plan and a phase-gated average verification plan to
determine whether a single-phase verification is an acceptable surrogate. For this study, target
coverage metric, specified as the percentage of the target volume receiving 95% of the
prescription dose (V95% [%]), was considered. Researchers hypothesized that the target coverage
 4

of the rigid, deformable, and physician-modified CTVs on a single-phase verification will be

within ± 5% of the target coverage on a phase-gated verification for the comprehensive cohort of
patients studied (H1A), also within the studied lung (H2A), liver (H3A) and esophageal (H4A)
patient cohorts. Additionally, researchers hypothesized that the single-phase and phase-gated
average verification comparison of target coverage will differ by no more than ± 5% for the
patient subgroups of both clinically acceptable verification plans and those that triggered a
subsequent replan (H5A).

Methods and Materials

Patient Selection
This study included datasets of patients that had received phase-gated intensity-
modulated proton therapy (IMPT) treatment and completed at least one 4D verification scan
throughout the treatment course. In each case, initial tumor motion was assessed during a 4D
simulation process and was found to be greater than 10.0 mm, which is an indication for phase-
gated treatment in our clinic. A member of the physics team reviewed the scans and determined
the phase range across which to create the phase-gated average scan that was used during
treatment planning. Anatomic treatment sites included in this study were lung, liver, and
esophagus. Excluded from this study were datasets that were not within the included treatment
sites as well as those not utilizing phase-gated treatment delivery. The selection of verification
scans was carried out through a random sampling method, with the aim of capturing instances of
scans that were either replanned due to inadequate target coverage or retained without any
alterations due to sufficient target coverage. The final study population included 18 patients with
a site breakdown of 7 esophagus, 6 lung, and 5 liver patients.
Verification Process
For each patient selected, an identical verification process was completed on both the
phase-gated average dataset and the single-phase dataset. This resulted in a phase-gated average
verification along with a single-phase verification for each patient. Each patient in this study
received a weekly 4DCT verification scan, with one of these weekly scans designated for this
analysis. If the patient required a replan throughout the treatment course, the verification that
indicated a need for replanning was selected. If the patient did not require a replan at any time, a
verification was randomly selected. The 4D image set was sub-divided into 10 respiratory
phases. For the phase-gated verification a phase-gated average scan was created utilizing the
 5

same phase selection from initial treatment planning. For this study, the single-phase verification
data set included only the 50-phase from the 4D data set. The 50-phase was chosen because it
corresponds to full-exhale, and the phase-gated average data set generally averages the breathing
phases surrounding full-exhale.
Each data set was individually sent to MIM Maestro (MIM Software Inc.) for processing.
A MIM workflow, which included a manual registration process and the propagation of contours
necessary for plan evaluation, was performed on each data set. Registration was based on the
daily image guided radiation therapy (IGRT) matching instructions which were patient
dependent and provided by the physician. This process resulted in a verification plan that
accurately represented treatment conditions. The original CTV contours were both rigidly and
deformably transferred from the original simulation scan to the verification scan. The rigid
contour was a direct copy of the original, while the deformable contour was modified through the
MIM workflow and is an attempt to adjust for changes in patient anatomy from one scan to
another. If the patient had multiple target volumes, a rigid and deformable CTV contour was
created for both the high and low dose CTV. The verification scan and contours were transferred
from MIM and imported into treatment planning software Eclipse 15.6 (Varian Medical
Systems). A verification plan was completed by calculating the original treatment plan on the
new verification data set. Each plan was then verified by a physicist for accuracy and
subsequently reviewed by the physician.
Physician Review
In addition to the rigid and deformed CTVs, a physician-modified CTV contour was also
created by the physician to accurately delineate the target on both the original phase-gated
average data set as well as the single-phase data set. This process was completed for lung and
esophagus patients. A physician-modified CTV contour was not generated for liver patients due
to the lack of magnetic resonance imaging (MRI) necessary to delineate updated target volumes.
These contours were created to address the accuracy limitations associated with deformable
contour propagation. The physician-modified CTV contour from the phase-gated average data
set was also copied to the single-phase image to allow for another method of target coverage
comparison.
Following CTV modifications, the physician performed a side-by-side evaluation of the
phase-gated and single-phase verification for each patient. The physician evaluated anatomical
 6

changes impacting target coverage as well as doses to critical structures. Any significant
differences between the 2 verification plans were noted. The physicians reviewed the contours on
the phase-gated average and single-phase verification plans and provided researchers with a
hypothetical recommendation of clinical acceptability.
Data Collection and Statistical Analysis
To assess target coverage between the phase-gated and single-phase scans, the V95% [%]
was evaluated for the rigid, deformable, and physician-modified contours for both the high and
low dose CTV on both the single-phase and phase-gated average verification plan for each
patient. To compare the target coverage between the single-phase and phase-gated average
verification, a dependent t-test was performed. The mean difference in target coverage between
the single-phase and phase-gated average verification was assessed along with the P-value (<
0.05) and 95% confidence interval.
Results
Comprehensive Cohort Comparison
When analyzing the comprehensive cohort of treatment sites, the mean difference in
target coverage (V95% [%]) between the phase-gated average verification plan and single-phase
verification plan was assessed for the rigid, deformable, physician-modified phase-gated, and
physician-modified single-phase CTV structures (Table 1). The mean difference in target
coverage for the rigid CTV contour between the phase-gated average verification and the single-
phase verification (n=30) was - 0.46% ± 1.1% (P=0.030) with a 95% CI [- 0.87, - 0.05]. The
mean difference in target coverage for the deformable CTV contour between the phase-gated
average verification and the single-phase verification (n=30) was - 0.13% ± 1.7% (P=0.683) with
a 95% CI [- 0.77,0.51]. The mean difference in target coverage for the physician-modified phase-
gated CTV contour between the phase-gated average verification and the single-phase
verification (n=20) was - 0.63% ± 1.3% (P=0.471) with a 95% CI [- 1.26, - 0.01]. The mean
difference in target coverage between the physician-modified phase-gated CTV contour on the
phase-gated verification and the physician-modified single-phase CTV contour on the single-
phase verification (n=20) was - 0.45% ± 1.3% (P=0.139) with a 95% CI [- 1.07,0.16]. Despite P-
value significance, the mean difference in target coverage between the phase-gated average
verification and the single-phase verification was within ± 5% for each contour evaluated when
 7

considering the comprehensive cohort of treatment sites (Figure 1). Therefore, the first null
hypothesis (H10) was rejected.
Lung Patient Comparison
The mean difference in target coverage (V95% [%]) between the phase-gated average
verification and single-phase verification was assessed for the rigid, deformable, physician-
modified phase-gated, and physician-modified single-phase CTV structures was also assessed for
each treatment site individually. The lung patient population had a mean difference in target
coverage for the rigid CTV contour between the phase-gated average verification and the single-
phase verification (n=7) of - 1.72% ± 1.8% (P=0.043) with a 95% CI [- 3.36, - 0.07]. The mean
difference in target coverage for the deformable CTV contour between the phase-gated average
verification and the single-phase verification (n=7) was - 1.13% ± 2.2% (P=0.220) with a 95%
CI [- 3.15, 0.89]. The mean difference in target coverage for the physician-modified phase-gated
CTV contour between the phase-gated average verification and the single-phase verification
(n=7) was - 1.67% ± 1.9% (P=0.057) with a 95% CI [- 3.41, 0.07]. The mean difference in target
coverage between the physician-modified phase-gated CTV contour on the phase-gated
verification and the physician-modified single-phase CTV contour on the single-phase
verification (n=7) was - 1.08% ± 2.2%. (P=0.234) with a 95% CI [- 3.08, 0.92]. Despite P-value
significance, the mean difference in target coverage between the phase-gated average verification
and the single-phase verification was within ± 5% for each contour evaluated for the lung patient
cohort (Figure 2). Therefore, the second null hypothesis (H20) was rejected.
Liver Patient Comparison
The liver patient population had a mean difference in target coverage (V95% [%]) for the
rigid CTV contour between the phase-gated average verification and the single-phase
verification (n=10) of 0.03% ± 0.2% (P =0.593) with a 95% CI [- 0.11, 0.17]. The mean
difference in target coverage for the deformable CTV contour between the phase-gated average
verification and the single-phase verification (n=10) was 0.94% ± 1.3% (P=0.052) with a 95%
CI [- 0.01, 1.88]. This patient population did not have the CTV recontoured on the verification
data sets due to inability to delineate target volumes in absence of more advanced imaging.
Despite P-value significance, the mean difference in target coverage between the phase-gated
average verification and the single-phase verification was within ± 5% for each contour
 8

evaluated for the liver patient cohort (Figure 3). Therefore, the third null hypothesis (H30) was
rejected.
Esophagus Patient Comparison
The esophagus patient population had a mean difference in target coverage (V95% [%]) for
the rigid CTV contour between the phase-gated average verification and the single-phase
verification (n=13) of - 0.16% ± 0.3% (P=0.053) with a 95% CI [- 0.32, 0]. The mean difference
in target coverage for the deformable CTV contour between the phase-gated average verification
and the single-phase verification (n=13) was - 0.41% ± 1.3% (P=0.288) with a 95% CI [- 1.21,
0.39]. The mean difference in target coverage for the physician-modified phase-gated CTV
contour between the phase-gated average verification and the single-phase verification (n=13)
was - 0.07% ± 0.3% (P=0.328) with a 95% CI [- 0.22, 0.08]. The mean difference in target
coverage between the physician-modified phase-gated CTV contour on the phase-gated
verification and the physician-modified single-phase CTV contour on the single-phase
verification (n=13) was - 0.12% ± 0.3 (P=0.124) with a 95% CI [- 0.27, 0.04]. Despite P-value
significance, the mean difference in target coverage between the phase-gated average verification
and the single-phase verification was within ± 5% for each contour evaluated for the esophagus
patient cohort (Figure 4). Therefore, the fourth null hypothesis (H40) was rejected.
Replan Status Comparison
Verification plans were divided into 2 separate cohorts depending on whether the initial
phase-gated verification did or did not indicate the need for a replan. The mean difference in
target coverage (V95% [%]) was assessed within these cohorts to determine if this distinction
made a difference in target coverage between the phase-gated verification and single-phase
verification. The verification plans that required a replan had a mean difference in target
coverage for the rigid CTV contour between the phase-gated average verification and the single-
phase verification (n=10) of - 1.07% ± 1.72% (P=0.080) with a 95% CI [- 2.3, 0.16]. The mean
difference in target coverage for the deformable CTV contour between the phase-gated average
verification and the single-phase verification (n=10) was - 1.15% ± 2.25% (P=0.140) with a 95%
CI [- 2.77,0.46]. The mean difference in target coverage for the physician-modified phase-gated
CTV contour between the phase-gated average verification and the single-phase verification
(n=8) was - 1.34% ± 1.9% (P=0.079) with a 95% CI [- 2.89, 0.21]. The mean difference in target
coverage between the physician-modified phase-gated CTV contour on the phase-gated
 9

verification and the physician-modified single-phase CTV contour on the single-phase

verification (n=8) was - 0.65% ± 2.0%. (P=0.379) with a 95% CI [- 2.3, 0.99]. Despite P-value
significance, the mean difference in target coverage between the phase-gated average verification
and the single-phase verification was within ± 5% for each contour evaluated for the
verifications requiring a replan cohort (Figure 5).
The verification plans that did not require a replan had a mean difference in target
coverage (V95% [%]) for the rigid CTV contour between the phase-gated average verification and
the single-phase verification (n=20) of - 0.15% ± 0.4% (P=0.088) with a 95% CI [- 0.33, 0.03].
The mean difference in target coverage for the deformable CTV contour between the phase-
gated average verification and the single-phase verification (n=20) was 0.38% ± 1.1% (P=0.138)
with a 95% CI [- 0.13, 0.9]. The mean difference in target coverage for the physician-modified
phase-gated CTV contour between the phase-gated average verification and the single-phase
verification (n=12) was - 0.16% ± 0.5% (P=0.313) with a 95% CI [- 0.49, 0.17]. The mean
difference in target coverage between the physician-modified phase-gated CTV contour on the
phase-gated verification and the physician-modified single-phase CTV contour on the single-
phase verification (n=12) was - 0.32% ± 0.7%. (P=0.137) with a 95% CI [- 0.76, 0.12]. Despite
P-value significance, the mean difference in target coverage was within ± 5% for each contour
evaluated for the sample of verifications not resulting in re-planning (Figure 6). Therefore, the
fifth null hypothesis (H50) was rejected.
Discussion
Quantitative Analysis
The results of the quantitative analysis demonstrated that the mean difference in target
coverage (V95% [%]) between the phase-gated average verification plans and single-phase
verification plans was within ± 5% for all contours evaluated, regardless of treatment site or
replanning status. The statistical significance indicated by the P-value varied amongst cohorts
and the contour used for evaluation. However, the 95% confidence interval validated that the
mean difference in target coverage between a phase-gated average verification and a single-phase
verification is almost certainly within ± 5%. This finding is important as it supports the
hypothesis that single-phase verification plans are generally acceptable surrogates for phase-
gated average verification plans, which has clinical implications for our proton therapy practice.
 10

Of the treatment sites included in this research, the lung patient cohort demonstrated the
largest mean difference in target coverage and contained outliers close to or exceeding the ± 5%
threshold. The small size of these treatment volumes, the location near moving heterogeneities,
and the increased mobility of the target may be causative factors for this observation.14 This
indicates a need for further investigation of this treatment site in particular to determine clinical
acceptability. The esophagus treatment site cohort demonstrated the smallest mean difference in
target coverage. The larger treatment volumes generally associated with this site may result in
the smaller relative differences in target coverage noted between a single-phase and phase-gated
average verification.
Analysis between patient subgroups of both clinically acceptable verification plans and
those that triggered a subsequent replan showed minor differences in results. The mean
difference in target coverage was smaller for clinically acceptable verifications. Verifications that
triggered a replan most often displayed an exaggeration of the decrease in target coverage on the
single-phase verification plan in comparison to the decrease in coverage on the phase-gated
average verification plan. This suggests that clinical decisions to replan would generally not have
been reversed.
The mean differences in target coverage were generally small, with the 95% confidence
interval falling well within the ± 5% threshold further underscoring the clinical viability of
single-phase verification plans. However, there may be specific cases in which the clinical goals
require a tighter degree of correspondence, at the discretion of the attending physician.
Furthermore, this data set included outliers which exceeded the ± 5% threshold, suggesting that
there may be case-specific considerations which may be contraindications for a single-phase
verification surrogate. These include anatomical location of the treatment volume, specific
motion characteristics, and adjacent moving heterogeneities.7,10,14
By using a single-phase verification protocol, proton therapy clinics can potentially
reduce the time and resource requirements associated with phase-gated scans and streamline the
treatment process. This is particularly pertinent in the context of online adaptive radiation
therapy, where real-time adjustments to treatment plans are essential.13 These findings are
particularly relevant for lung, liver, and esophagus patients who often require phase-gated
treatment due to respiratory motion.7,11 The results show that single-phase verification plans
generally provide clinically acceptable representations of the target coverage in phase-gated
 11

plans for these patients, potentially streamlining the treatment process and reducing the need for
resource-intensive processing of phase-gated image sets.
Qualitative Analysis
Although there is value in analyzing a target coverage metric to determine clinical
acceptability of a verification plan, this analysis does not capture the intricacies of plan
evaluation and the clinical decision-making process. To address this limitation, a physician
expert in each disease site group represented in this study reviewed both the original phase-gated
verification along with the newly generated single-phase verification and informed researchers
on whether encountering either version would lead to a different clinical decision. These
decisions included reconsidering the need for a replan, introducing an extra verification scan, or
conveying specific instructions to the radiation therapists regarding the setup process. Any
significant differences between the verifications were noted. With this approach, the researchers
were able to assess the use of a single-phase verification using a qualitative assessment to
complement the more quantitative dose volume histogram (DVH) based analysis.
The qualitative analysis revealed overall consistency in clinical decisions between the
single-phase and phase-gated average verification plans, indicating that a single-phase
verification could often serve as a clinically acceptable surrogate. In many cases, the single-
phase verification plans supported the same clinical decisions as the phase-gated average
verification plans, even in scenarios where there was a difference in target coverage. There were
a few instances where the single-phase verification plans led to differing clinical decisions.
These cases did not correlate with larger than average differences in target coverage, highlighting
the intricacies of plan evaluation. A total of 3 cases led to differing clinical decisions. Of these
cases, 2 were lung patients and the third was a liver patient. Two of these cases had treatment
volumes located near the diaphragm, indicating that the anatomical location of the treatment site
and motion characteristics may impact clinical acceptability. These results suggest that target
volumes near mobile heterogeneities may show greater discrepancies between a single-phase and
phase-gated verification. Also, the assertion that a mean difference in target coverage within ±
5% corresponds to a blanket statement of clinical acceptability is an oversimplification of a more
complex clinical reality, as even minor dosimetric variations (including regions of increased
radiation dose not captured by a V95% [%] target coverage metric) could potentially impact
management decisions.
 12

Esophagus verifications resulted in consistently small differences in target coverage

between the phase-gated average and single-phase verification. The qualitative analysis also
showed consistent clinical decisions for the entirety of this cohort. This indicates that for this
particular treatment site, single-phase verifications may be an appropriate option with less case-
specific caveats.
Conclusion
Proton pencil beam radiotherapy is gaining popularity due to its superior sparing of
healthy organs compared to conventional x-ray radiotherapy. However, it is vulnerable to
changes in patient anatomy and the impact of respiratory motion, necessitating routine CT
verification scans in phase-gated plans. The problem is that the verification process for phase-
gated treatments in our clinic requires the creation of a new phase-gated average scan which is
time-consuming and incompatible with current workflows utilizing automated software.
Therefore, the purpose of this study was to compare CTV coverage between a single, full exhale
phase verification plan and a phase-gated average verification plan to determine whether a
single-phase verification is an acceptable surrogate. Both quantitative and qualitative analyses
were conducted to evaluate the compatibility of single-phase verification plans. The results
suggest that single-phase verification plans offer a clinically viable and efficient alternative to
phase-gated plans in many clinical scenarios, with potentially some contraindications in lung and
liver proton treatment plans which require further investigation.
The limitations of this study included a relatively small sample size and a focus on
specific treatment sites, potentially limiting the generalizability of the results. Future research
should expand the patient population to include a broader range of treatment sites, investigate the
impact of varying motion characteristics on verification plan suitability, and explore automated
processes for generating single-phase verification plans. These endeavors can further enhance the
efficiency and accessibility of proton therapy while addressing the identified limitations of this
study.
Acknowledgements
The authors would like to thank Douglas Baumann and the UW-La Crosse Statistical Consulting
Center for guidance with data analysis and display of statistical results for the study. However,
any errors in statistics or interpretation of data are the sole responsibility of the authors.
 13

References
1. Cheng JY, Liu CM, Wang YM, et al. Proton versus photon radiotherapy for primary
hepatocellular carcinoma: a propensity-matched analysis. Radiat Oncol. 2020;15(1):159.
https://doi.org/10.1186/s13014-020-01605-4
2. Suh YG, Noh JM, Lee DY, et al. Proton Beam Therapy versus Photon Radiotherapy for
Stage I Non-Small Cell Lung Cancer. Cancers (Basel). 2022;14(15):3627.
https://doi.org/10.3390/cancers14153627
3. Knäusl B, Lebbink F, Fossati P, Engwall E, Georg D, Stock M. Patient breathing motion and
delivery specifics influencing the robustness of a proton pancreas irradiation. Cancers.
2023;15(9):2550. https://doi.org/10.3390/cancers15092550
4. Hu YH, Harper, RH, Deiter NC, et al. Analysis of the rate of re-planning in spot-scanning
proton therapy. Int J of Part Ther. 2022;9(2):49-58. https://doi.org/10.14338/IJPT-21-
00043.1
5. Smolders A, Hengeveld AC, Both S, et al. Inter- and intrafractional 4D dose accumulation
for evaluating ΔNTCP robustness in lung cancer. Radiother Oncol. 2023;182:109488.
https://doi.org/10.1016/j.radonc.2023.109488
6. Deiter N, Chu F, Lenards N, Hunzeker A, Lang K, & Mundy D. Evaluation of replanning in
intensity-modulated proton therapy for oropharyngeal cancer: Factors influencing plan
robustness. Med Dosim. 2020;45(4):384-392. https://doi.org/10.1016/j.meddos.2020.06.002
7. Tryggestad EJ, Liu W, Pepin MD, Hallemeier CL, & Sio TT. Managing treatment-related
uncertainties in proton beam radiotherapy for gastrointestinal cancers. J of Gastrointest
Oncol. 2020;11(1):212-224. https://doi.org/10.21037/jgo.2019.11.07
8. Evans JD, Harper RH, Petersen M, et al. The importance of verification CT-QA scans in
patients treated with IMPT for head and neck cancers. Int J of Part Ther. 2020;7(1):41-
53. https://doi.org/10.14338/IJPT-20-00006.1
9. Green OL, Henke LE, & Hugo GD. Practical clinical workflows for online and offline
adaptive radiation therapy. Semin in Radiat Oncol. 2019;29(3):219-
227. https://doi.org/10.1016/j.semradonc.2019.02.004
10. Gelover E, Deisher AJ, Herman MG, Johnson J E, Kruse JJ, & Tryggestad EJ. Clinical
implementation of respiratory‐gated spot‐scanning proton therapy: an efficiency analysis of
 14

active motion management. J of Appl Clin Med Phys. 2019;20(5):99-

108. https://doi.org/10.1002/acm2.12584
11. Gut P, Krieger M, Lomax T, Weber DC, & Hrbacek J. Combining rescanning and gating for
a time-efficient treatment of mobile tumors using pencil beam scanning proton therapy.
Radiother Oncol. 2021;160: 82-89. https://doi.org/10.1016/j.radonc.2021.03.041
12. Taasti VT, Hattu D, Vaassen F, et al. Treatment planning and 4D robust evaluation strategy
for proton therapy of lung tumors with large motion amplitude. Med Phys. 2021;48(8):4425-
4437. https://doi.org/10.1002/mp.15067
13. Paganetti H, Botas P, Sharp GC, Winey B. Adaptive proton therapy. Phys in Med & Biol.
2021;66(22). https://doi.org/10.1088/1361-6560/ac344f
14. Chang JY, Zhang X, Knopf A, et al. Consensus guidelines for implementing pencil-beam
scanning proton therapy for thoracic malignancies on behalf of the PTCOG thoracic and
lymphoma subcommittee. Int J of Radiat Oncol*Biol*Phys. 2017;99(1):41-50.
https://doi.org/10.1016/j.ijrobp.2017.05.014
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Figures

Figure 1. Difference in target coverage (V95% [%]) for the comprehensive treatment site cohort
for the rigid, deformable, physician-modified phase-gated, and physician-modified phase-gated
versus single-phase contours.
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Figure 2. Difference in target coverage (V95% [%]) for the lung cohort for the rigid, deformable,
physician-modified phase-gated, and physician-modified phase-gated versus single-phase
contours.

Figure 3. Difference in target coverage (V95% [%]) for the liver cohort for the rigid and
deformable contours.
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Figure 4. Difference in target coverage (V95% [%]) for the esophagus cohort for the rigid,
deformable, physician-modified phase-gated, and physician-modified phase-gated versus single-
phase contours.
 18

Figure 5. Difference in target coverage (V95% [%]) for the cohort initially requiring a replan
between the rigid, deformable, physician-modified phase-gated, and physician modified phase-
gated versus single-phase contours.
 19

Figure 6. Difference in target coverage (V95% [%]) for the cohort not initially requiring a replan
between rigid, deformable, physician modified phase-gated, and physician-modified phase-gated
versus single-phase contours.
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Tables
Table 1. Mean Difference in Target Coverage (V95% [%]).
Mean Standard 95% P-value
Difference Deviation Confidence
(%) Interval
All Sites
Rigid Contour -0.46 1.1 [-0.87, -0.05] 0.030
Deformable Contour 0.13 1.7 [-0.77, 0.51] 0.683
Physician-modified Phase-gated contour -0.63 1.3 [-1.26, -0.01] 0.471
Physician-modified Phase-gated vs. -0.45 1.3 [1.07, 0.16] 0.139
Single-phase contour

Lung
Rigid Contour -1.72 1.8 [-3.36, -0.07] 0.043
Deformable Contour -1.13 2.2 [-3.15, 0.89] 0.220
Physician-modified Phase-gated contour -1.67 1.9 [-3.41, 0.07] 0.057
Physician-modified Phase-gated vs. -1.08 2.2 [-3.08, 0.92] 0.234
Single-phase Contour

Liver
Rigid Contour 0.03 0.2 [-0.11, 0.17] 0.593
Deformable Contour 0.94 1.3 [-0.01, 1.88] 0.052

Esophagus
Rigid Contour -0.16 0.3 [-0.32, 0] 0.053
Deformable Contour -0.41 1.3 [-1.21, 0.39] 0.288
Physician-modified Phase-gated contour -0.07 0.3 [-0.22, 0.08] 0.328
Physician-modified Phase-gated vs. -0.12 0.3 [-0.27, 0.04] 0.124
Single-phase Contour

Replanned Cases
Rigid Contour -1.07 1.7 [-2.3, -0.16] 0.080
Deformable Contour -1.15 2.3 [-2.77, 0.46] 0.140
Physician-modified Phase-gated contour -1.34 1.9 [-2.89, 0.21] 0.079
Physician-modified Phase-gated vs. -0.65 2.0 [-2.3, 0.99] 0.379
Single-phase Contour

Cases Not Replanned

Rigid Contour -0.15 0.4 [-0.33, 0.03] 0.088
Deformable Contour 0.38 1.1 [-0.13, 0.9] 0.138
Physician-modified Phase-gated contour -0.16 0.5 [-0.49, 0.17] 0.313
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Physician-modified Phase-gated vs. -0.32 0.7 [-0.76, 0.12] 0.137

Single-phase Contour