1

A comparison of single-phase and phase-gated average verification planning 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
The purpose of this study was to investigate the possibility of using single-phase verification
plans in place of phase-gated verification plans for proton pencil beam radiotherapy, aiming to
streamline the treatment process. Quantitative analysis revealed that, for lung, liver, and
esophagus patients, the mean difference in target coverage between phase-gated and single-phase
verification was within 5%, supporting the hypothesis. Specific differences were small,
underlining clinical viability. Qualitative analysis showed that single-phase verification often led
to consistent clinical decisions. While minor discrepancies were observed, particularly for lung
and liver patients, the majority of clinical decisions remained unchanged. The study suggests that
single-phase verification plans can be acceptable surrogates for phase-gated plans, improving
efficiency in proton therapy practice, with considerations based on clinical scenarios and motion
characteristics. The study's limitations include a small sample size, site-specific results, and
sensitivity to clinic-specific procedures. Future research can explore broader patient populations,
motion characteristics, and automated processes to enhance clinical efficiency.
Keywords: Proton therapy; 4DCT; verifications; interplay; adaptive radiation therapy; phase-
gated
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 organs at risk (OAR) sparing.1,3 To
manage these uncertainties and ensure the ongoing safety and effectiveness of the proton therapy
 2

treatments, acquiring routine CT verification scans is essential.1 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.2,6,7 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.1,4,6,8
Another significant challenge of proton pencil beam therapy is the impact of respiratory
motion, which can introduce interplay effects that produce suboptimal dose distributions. 2,3,5,9
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.2 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.2,10
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.2,8,10 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.2,8 If this motion amplitude
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.2,8,9 The corresponding treatment is only delivered during these breathing
phases by actively gating the beam using the breathing surrogate signal.2,8
In modern radiation therapy, the demand for streamlined and efficient workflows is
paramount, particularly when dealing with 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
 3

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.1,4,7,11 Adaptive radiation therapy is especially beneficial during hypofractionated
treatments because of the increased relative importance of each fraction. 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.2,7 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.7,11 Decreased efficiency can lead to targeting
inaccuracies due to changes between initial imaging and beam delivery.2
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 target coverage reported on phase-gated average verification plans to target coverage on
single-phase verification plans using the same scan to determine whether a single-phase
verification is an acceptable surrogate. If a single-phase scan is suitable, it will improve current
online, pre-treatment dose verification efforts for phase-gated proton treatments by providing a
timely, automated result which can be evaluated prior to treatment by care teams while the
patient is still in treatment position. Researchers tested the hypothesis (H1A) that the target
coverage (specified as V95%) on a single, full, exhale phase verification plan will be within 5% of
the target coverage (V95%) on a phase-gated average verification plan. Researchers hypothesized
that the target coverage comparison of the for all sites based on evaluation of rigid, , deformable,
and newly created target contoursphysician-modified CTVs will be within 5% of the target
coverage V95% for the studied lung (H1A), liver (H2A) and esophageal (H3A) patients. Also, this
will be true within each treatment site individually, as well as within groups based on replan
requirement. This 5% threshold was established by the physicians on the research team as an
attempt to put a general, clinically meaningful tolerance on the comparison.
Methods and Materials
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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 and 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 for our research 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, the verification process was completed to create both a phase-
gated average verification along with a single-phase verification. Each of the patients in this
study received a weekly 4DCT verification scan, with one of these weekly scans designated for
this analysis. 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 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.
Each of these data sets was individually sent to MIM Maestro (MIM) for auto-
contouring. A MIM workflow was performed on each data set, systematically covering each
of the steps needed in MIM, including the manual registration process and the creation of
rigid and deformable contours. A rigid and deformable CTV contour was created for each
high and low dose CTV. Registration was based on daily image guidanceed radiation therapy
(IGRT) matching instructions which were patient dependent and instructed the radiation
therapists how to match the patient on a daily basis. For this reason, the verification scan had to
mimic how the patient was matched on the treatment machine. The original contours were both
rigidly and deformably transferred from the original simulation scan to the verification scan. The
 5

verification scan and contours were transferred with MIM and imported into treatment planning
software Eclipse 15.6. A verification plan was completed by calculating the original treatment
plan onto the new verification data set. Each plan was then checked by a physicist for its
accuracy and then reviewed by the physician.
Physician Review
A new CTV contour was created by the physician to accurately delineate the target on
both the original phase-gated average data set as well as the 50-phase. This resulted in a new
target contour on both data sets that was more accurate than the rigid and deformable CTV
obtained through the verification process. The CTV contour from the phase-gated average data
set was also copied to the 50-phase for target coverage comparison. This process was completed
for lung and esophagus patients. Liver patients did not have a new CTV contour created due to
the lack of magnetic resonance imaging (MRI) necessary to delineate target volumes.
The physician performed a side-by-side evaluation of the phase-gated and 50-phase
verification for each patient. Any significant differences between the two verification plans were
noted. The physician determined if the clinical decision regarding the plan acceptability and the
need for replanning would vary between the two verifications.
Data Collection and Statistical Analysis
Data collection involved recording the V95% for the rigidly transferred contours, the
deformably transferred contours, and the modified physician contours for both the high and low
dose CTV on both the single-phase and phase-gated verification plan for each patient. To
compare the target coverage between the single-phase and phase-gated verification, a dependent
t-test was performed. Data was examined within various cohorts including a comprehensive
cohort as well as groupings by disease site and replan requirement.
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 and single-phase verification
was assessed for the rigid, deformable, new phase-gated, and new 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). The mean difference in target coverage for the deformable CTV contour between the
 6

phase-gated average verification and the single-phase verification (n=30) was – 0.13% ± 1.7%
(P=0.683). The mean difference in target coverage for the new 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). The mean difference in target coverage between the new phase-gated
CTV contour on the phase-gated verification and the new single-phase CTV contour on the
single-phase verification (n=20) was -– 0.45% ± 1.3% (P=0.139). (Figure 1) 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 considering the comprehensive
cohort of treatment sites.
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, new phase-
gated, and new 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). 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). The mean difference in target coverage for the new 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). The mean difference in target coverage
between the new phase-gated CTV contour on the phase-gated verification and the new single-
phase CTV contour on the single-phase verification (n=7) was – 1.08% ± 2.2%. (P=0.234).
(Figure 2). 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.
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). 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). (Figure 3). This patient population did not have the CTV
 7

recontoured on the verification data sets due to inability to delineate target volumes in absence of
more advanced imaging. 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 liver patient cohort.
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). 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). The mean difference in target coverage for
the new 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). The mean difference in target
coverage between the new phase-gated CTV contour on the phase-gated verification and the new
single-phase CTV contour on the single-phase verification (n=13) was –0.12% ± 0.3 (P=0.124).
(Figure 4) 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.
Replan Status Comparison
Verification plans were divided into two2 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 did require 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=7) of – 0.75% ± 1.1% (P=0.120). 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 - 1.02%± 2.4% (P=0.313). The mean difference in target coverage
for the new 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). The mean difference in target
coverage between the new phase-gated CTV contour on the phase-gated verification and the new
single-phase CTV contour on the single-phase verification (n=8) was – 0.65% ± 2.0%.
 8

(P=0.379). (Figure 5) 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.
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). 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). The mean difference in target
coverage for the new 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). The mean difference in
target coverage between the new phase-gated CTV contour on the phase-gated verification and
the new single-phase CTV contour on the single-phase verification (n=12) was – 0.32% ± 0.7%.
(P=0.137). (Figure 6) The mean difference in target coverage was within 5% for each contour
evaluated for the sample of verifications not resulting in re-planning.
The hypothesis (H1) was that the target coverage (specified as V95%) on a single full
exhale phase verification plan will be within 5% of the target coverage (V95%) on a phase-gated
average verification plan for all sites based on evaluation of rigid, deformable, and newly created
target contours. Also, this will be true within each treatment site individually, as well as within
groups based on replan requirement. Target coverage was within 5% for all contours evaluated
within each cohort; therefore,. Therefore, the null hypothesis (H10) was rejected.
Qualitative Analysis
A site group physician reviewed both the original phase-gated verification along with the
newly generated single-phase verification. They elaborated on whether encountering either
version would lead to a different clinical decision. For instance, reconsidering the need for a
replan, introducing an extra verification, or conveying specific instructions to therapists
regarding the setup process. Any significant differences between the verifications were noted.
The lung patient population consisted of 6 patients, of these 4 were replanned. For two of
these patients, the physician noted similar target coverage with an identical clinical decision
regarding replanning between the phase-gated average verification and the single-phase
verification. Three patients had a decrease in target coverage on the single-phase verification.
However, in two of these cases the clinical decision would not have been changed. One case
 9

would require a replan that was not indicated on the original verification. The final case the
physician felt unable to assess using the single-verification due to diaphragm motion
considerations. The liver patient population consisted of 5 patients, of these 1 was replanned. The
case requiring replanning showed similar insufficient coverage and hot spots on both verification
plans. An equivalent decision to replan would have resulted in either scenario. One case showed
a decrease in coverage near the dome of the liver that was not present on the original phase-gated
verification. This would have triggered an additional verification that was not originally
requested. For all other patients, the original phase-gated verification and new single-phase
verification were similar and showed plans held up. The esophagus patient population consisted
of 7 patients, of these 2 were replanned. All esophagus evaluations resulted in equivalent clinical
decisions from the physician.
Discussion
The aim of this study was to investigate whether the target coverage in phase-gated
proton pencil beam radiotherapy verification plans could be adequately represented by single-
phase verification plans, which would be more efficient for online adaptive radiation therapy.
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, irrespective of treatment site or replanning status. This
finding is crucial as it supports the hypothesis that single-phase verification plans are acceptable
surrogates for phase-gated plans. This result has significant clinical implications for proton
therapy practice. By using single-phase verification, proton therapy clinics can reduce the time
and resource requirements associated with phase-gated scans and streamline their treatment
process. This is particularly pertinent in the context of online adaptive radiation therapy, where
real-time adjustments to treatment plans are essential.
The specific values of mean differences were also generally small, further underscoring
the clinical viability of single-phase verification plans. The data indicate that the difference in
target coverage is not clinically significant and should not necessitate different clinical decisions,
such as replanning. These findings are particularly relevant for lung, liver, and esophagus
patients who often require phase-gated treatment due to respiratory motion. The results show that
single-phase verification plans provide accurate representations of the target coverage in phase-
 10

gated plans for these patients, potentially streamlining the treatment process and reducing the
need for resource-intensive phase-gated scans.
The qualitative analysis revealed that, for the most part, the clinical decisions made by
physicians based on the single-phase verification plans were consistent with those made using
the phase-gated plans. In many cases, the single-phase verification plans supported the same
clinical decisions as the phase-gated plans, even in scenarios where there was a minor decrease
in target coverage. However, there were a few instances where the single-phase verification plans
led to different clinical decisions. These discrepancies were primarily observed in lung patients
and, in one1 case, for a liver patient.
For the lung patients, in most instances, the differences in coverage were clinically
acceptable and would not necessitate a change in the treatment plan. However, the study
identified one1 case where the diaphragm motion influenced the assessment, suggesting that the
choice between single-phase and phase-gated verification might depend on the specific clinical
scenario and motion characteristics. The liver patient, with a decrease in coverage in the dome of
the liver, highlights a situation where the single-phase verification could have led to a different
clinical decision, such as an additional verification or replanning. While this was a single case, it
underscores the need for a case-by-case assessment to ensure the appropriateness of using single-
phase verification for liver patients. For esophagus patients, the clinical decisions remained
consistent between single-phase and phase-gated verification plans, indicating that for certain
anatomical sites, single-phase verification may be a suitable option.
It is important to acknowledge the limitations of this study. The sample size was
relatively small, which could impact the extent to which the results can be generalized to a
broader patient population. The study only included lung, liver, and esophagus patients, and the
results may not be directly applicable to other treatment sites. Additionally, the results may be
sensitive to the specific motion characteristics and setup procedures at the clinic where the study
was conducted.
Future research in this area could focus on expanding the patient population to include a
wider range of treatment sites. Additionally, investigating the impact of varying degrees of
motion amplitude on the suitability of single-phase verification could provide valuable insights.
Furthermore, research could explore the implementation of automated processes for generating
single-phase verification plans to enhance clinical efficiency.
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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 requires the creation of a new phase-gated average scan which is time-
consuming and incompatible with current workflows utilizing automated software. The study's
The primary objective of the study was to assess whether single-phase verification plans could
effectively substitute phase-gated plans by comparing target coverage. The study included 18
patients with lung, liver, and esophagus treatment sites who underwent phase-gated IMPT.
Weekly 4DCT verification scans were performed for each patient, allowing for the creation of
phase-gated and single-phase verification plans. Data collected included V95% for target coverage,
evaluated for rigid, deformable, and newly created contours. Both qualitative and quantitative
analyses were conducted to evaluate the suitability of single-phase verification plans.
The quantitative analysis revealed that the mean difference in target coverage (V 95%)
between phase-gated average and single-phase verification plans was within 5% for all contours
assessed, irrespective of treatment site or replanning status. The qualitative assessment generally
supported these findings, with clinical decisions remaining consistent for the majority of cases,
even when minor decreases in target coverage were observed. The results suggest that single-
phase verification plans offer a clinically viable and efficient alternative to phase-gated plans in
proton therapy. While some scenarios showed differences between plan types, they were
generally clinically acceptable. A case-by-case assessment may be necessary for certain patient
groups, and the choice between single-phase and phase-gated verification may depend on
specific clinical scenarios and motion characteristics.
The study's limitationslimitations 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 shcould 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.
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Acknowledgements
The authors would like to thank Douglas Baumann and the UW-La Crosse Statistical Consulting
Center for their guidance with data analysis and display of statistical results for the study. Any
errors in statistics or interpretation of data are the sole responsibility of the authors.
 13

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Figures

Figure 1. Difference in target coverage (V95%) for comprehensive treatment site cohort.
 16

Figure 2. Difference in target coverage (V95%) for lung cohort.

Figure 3. Difference in target coverage (V95%) for liver cohort.

 17

Figure 4. Difference in target coverage (V95%) for esophagus cohort.

Figure 5. Difference in target coverage (V95%) for cohort initially requiring a replan.
 18

Figure 6. Difference in target coverage (V95%) for cohort not initially requiring a replan.

Tables

Table 1. Mean Difference in Target Coverage (V95%).

Mean Standard p-value
Difference Deviatio
(%) n
All Sites
Rigid Contour -0.46 1.1 0.030
Deformable Contour –0.13 1.7 0.683
New Phase-gated contour -0.63 1.3 0.471
New Phase-gated vs. New Single-phase contour -0.45 1.3 0.139

Lung
Rigid Contour -1.72 1.8 0.043
Deformable Contour -1.13 2.2 0.220
New Phase-gated contour -1.67 1.9 0.057
New Phase-gated vs. New Single-phase Contour -1.08 2.2 0.234

Liver
 19

Rigid Contour 0.03 0.2 0.593

Deformable Contour 0.94 1.3 0.052

Esophagus
Rigid Contour -0.16 0.3 0.053
Deformable Contour -0.41 1.3 0.288
New Phase-gated contour -0.07 0.3 0.328
New Phase-gated vs. New Single-phase Contour -0.12 0.3 0.124

Re-Plan
Rigid Contour -0.75 1.1 0.120
Deformable Contour -1.02 2.4 0.313
New Phase-gated contour -1.34 1.9 0.079
New Phase-gated vs. New Single-phase Contour -0.65 2.0 0.379

No Re-Plan
Rigid Contour -0.15 0.4 0.088
Deformable Contour 0.38 1.1 0.138
New Phase-gated contour -0.16 0.5 0.313
New Phase-gated vs. New Single-phase Contour -0.32 0.7 0.137