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
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.1,2,3 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.2,4,5 Daily variations in patient setup and anatomical changes can alter
the dose distribution, affecting both target coverage and organs at risk (OAR) sparing.1,2 In an
attempt to manage these uncertainties and ensure the ongoing safety and effectiveness of the
proton therapy treatments, it is important to perform routine CT verification scans. 1 In this
process, the treatment plan is recalculated on the CT verification image set, which allows for a
quantitative assessment of the dose on the 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.3,6,7 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.3 Furthermore, respiratory motion can also
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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.3,10
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.3,8,10 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.3,8 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.3,8,9 The corresponding treatment is only delivered during these breathing
phases by actively gating the beam using the breathing surrogate signal.3,8
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 in our clinic
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 push toward automation in online
adaptive radiation therapy (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.3,7 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.3
Our current 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
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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 can be used in place of a phase-gated scan, 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. In this work, researchers tested the hypothesis (H 1)
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. 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
This study utilized 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. The final study
population included 18 patients with a site breakdown of 7 esophagus, 6 lung, and 5 liver
patients.
Each of the patients in this study received a weekly 4DCT verification scan, with one of
these weekly scans being selected for this analysis. The 4D image set was sub-divided into 10
respiratory phases, and a phase-gated average scan was created utilizing the same phase selection
from initial treatment planning. The image data set was sent to MIM Maestro (MIM) for auto-
contouring. A MIM workflow was performed on the phase-gated average scan. The workflow
systematically covered each of the steps needed in MIM and includes the manual registration
process and the creation of rigid and deformable contours. A manual registration was performed
between the phase-gated average verification scan and the original phase-gated average
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treatment planning scan. Registration was based on daily image guidance radiation therapy
(IGRT) matching instructions which are patient dependent and instruct the radiation therapists
how to match the patient on a daily basis. For this reason, the verification scan must 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
verification scan and contours were transferred and imported into treatment planning software
using Eclipse 15.6. A verification plan was completed that involved calculating the original
treatment plan onto the new verification data set which was then reviewed by the physician.
For this study, the identical workflow mentioned above was completed utilizing the 50-
phase scan from the 4D data set in place of the phase-gated average scan. The MIM workflow
was completed to register the 50-phase scan with the original phase-gated average planning scan
and transferred contours to the new data set. This was imported into the treatment planning
software and a verification plan was completed. All verification plans received a physics quality
assurance check prior to physician review and data collection.
A physician reviewed both the phase-gated and 50-phase verification plans. 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 indicated whether the clinical decision that would be made concerning plan
acceptability and replan necessity would have differed between the two verifications.
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 MRI imaging necessary to delineate target volumes.
Data collection involved recording the V95% for both the high and low dose CTV on each
verification plan. This was reported for the rigidly transferred contours, the deformably
transferred contours, and the modified physician contours. To compare the target coverage
between the single-phase and phase-gated verification, a dependent t-test was performed. Data
was examined for the rigid, deformable, and newly created physician contours for the entire
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research group, as well as within disease site groups individually. Analysis was also made with
groupings of patients who both did and did not initially require a replan based on the verification
process.
Results
Quantitative Analysis
When analyzing all treatment sites together, the mean difference in target coverage (V 95%)
between the phase-gated average and single-phase verification was assessed (Table 1, Table 2).
The mean difference for the rigid CTV contour (n=30) was -0.46% ± 1.1% (p=0.030). The mean
difference for the deformable CTV contour (n=30) was –0.13% ± 1.7% (p=0.683). The physician
recontoured the CTV on the phase-gated average scan, this was copied to single-phase scan and
the CTV coverage for this contour was recorded for both the single-phase and phase-gated
verification plan (n=20). The mean difference between the phase-gated average and single-phase
verification was –0.63% ± 1.3% (p=0.471). The CTV was also recontoured on the single-phase
scan (n=20). The target coverage for this contour was compared to coverage to the recontoured
CTV contour on the phase-gated average scan. The mean difference in CTV coverage was –
0.45% ± 1.3% (p=0.139). This data is represented in Figure 1. The mean difference in target
coverage was within 5% for each contour evaluated when considering all treatment sites
together.
The mean difference in target coverage (V95%) was also assessed for each treatment site
individually. The lung patient population had a mean difference between the phase-gated average
and single-phase verification rigid CTV contour (n=7) of –1.72% ± 1.8% (p= 0.043). The mean
difference for the deformable contour (n=7) was -1.13%± 2.2% (p=0.220). The comparison
between the new phase-gated contour on the phase-gated verification and the 50-phase
verification (n=7) resulted in a mean difference of –1.67% ± 1.9% (p=0.057). The comparison
between the new phase-gated contour and the new 50-phase contour (n=7) resulted in a mean
difference of –1.08% ± 2.2%. (p=0.234). This data is represented in Figure 2. The mean
difference in target coverage was within 5% for each contour evaluated for the lung patient
sample.
Liver patients had a mean difference in target coverage (V95%) between the phase-gated
average and single-phase verification rigid CTV contour (n=10) of 0.03% ± 0.2% (p= 0.593).
The mean difference for the deformable contour (n=10) was 0.94% ± 1.3% (p= 0.052). This
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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. This data is represented in
Figure 3. The mean difference in target coverage was within 5% for the liver patient sample.
Esophagus patients had a mean difference in target coverage (V95%) between the phase-
gated average and single-phase verification rigid CTV contour (n=13) of –0.16% ± 0.3%
(p=0.053). The mean difference for the deformable CTV contour (n=13) was –0.41% ± 1.3%
(p=0.288). The comparison between the new phase-gated contour on the phase-gated verification
and the 50-phase verification (n=13) resulted in a mean difference of –0.07% ± 0.3% (p=0.328).
The comparison between the new phase-gated contour and the new 50-phase contour (n=13)
resulted in a mean difference of –0.12% ± 0.3%. (p=0.124). This data is represented in Figure 4.
The mean difference in target coverage was within 5% for each contour evaluated for the
esophagus patient sample.
The mean difference in target coverage (V95%) was also assessed for verification plans
that resulted in a need for replanning as well as for those that did not. The verification plans that
did require a replan had a mean difference between the phase-gated average and single-phase
verification rigid CTV contour (n=7) of –0.75% ± 1.1% (p= 0.120). The mean difference for the
deformable contour (n=7) was -1.02%± 2.4% (p=0.313). The comparison between the new
phase-gated contour on the phase-gated verification and the 50-phase verification (n=8) resulted
in a mean difference of –1.34% ± 1.9% (p=0.079). The comparison between the new phase-gated
contour and the new 50-phase contour (n=8) resulted in a mean difference of –0.65% ± 2.0%.
(p=0.379). This data is represented in Figure 5. The mean difference in target coverage was
within 5% for each contour evaluated for the sample of verifications resulting in re-planning.
The verification plans that did not require a re-plan had a mean difference between the
phase-gated average and single-phase verification rigid CTV contour (n=20) of –0.15% ± 0.4%
(p= 0.088). The mean difference for the deformable contour (n=20) was 0.38% ± 1.1%
(p=0.138). The comparison between the new phase-gated contour on the phase-gated verification
and the 50-phase verification (n=12) resulted in a mean difference of –0.16% ± 0.5% (p=0.313).
The comparison between the new phase-gated contour and the new 50-phase contour (n=12)
resulted in a mean difference of –0.32% ± 0.7%. (p=0.137). This data is represented in 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.
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The null hypothesis (H10) was that the target coverage (specified as V95%) on a single full
exhale phase verification plan will not be within 5% of the target coverage (V 95%) on a phase-
gated average verification plan for all sites based on evaluation of rigid, deformable, and newly
created target contours. Also, this will not be true within each treatment site individually, as well
as within groups based on replan requirement. However, target coverage was within 5% for all
contours evaluated across treatment sites and replanning status. Therefore, the null hypothesis
was rejected.
Qualitative Analysis
A site group physician reviewed both the original phase-gated verification along with the
newly generated 50-phase verification. They elaborated on whether encountering either version
would lead to a distinct 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. 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 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
Conclusion
Acknowledgements
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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.
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References
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proton therapy. Int J of Part Ther. 2022;9(2):49-58. https://doi.org/10.14338/IJPT-21-
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2023;182:109488. https://doi:10.1016/j.radonc.2023.109488
6. 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
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10. Taasti VT, Hattu D, Vaassen F, et al. Treatment planning and 4D robust evaluation
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Figures

Figure 1. Difference in target coverage (V95%) for all treatment sites.

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

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

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

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Figure 5. Difference in target coverage (V95%) for replanned verifications.

Figure 6. Difference in target coverage (V95%) for not replanned verifications.

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Tables

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

CTV CTV CTV CTV CTV CTV CTV CTV
Low Low Low Low High High High High
Patient Deform New New PG- Deforma New PG-
Number Site Replan Rigid able PG New50 Rigid ble New PG New50
1 Lung no -0.76 -0.51 -0.13 -1.21
2 Lung yes -0.20 -0.44 -0.20 -0.99
3 Lung no -1.54 2.01 -1.64 -2.14
4 Lung yes -0.06 0.00 -0.06 -0.06
5 Lung yes -5.17 -3.98 -5.02 -4.69
6 Lung yes -1.55 -0.95 -1.32 -0.98 -2.75 -4.04 -3.35 2.50
7 Esophagus no 0.00 -0.39 0.01 -0.51 0.00 -0.34 0.00 0.00
8 Esophagus no 0.06 0.70 0.54 0.40 0.00 0.01 0.00 0.00
9 Esophagus no -0.13 -0.15 -0.11 -0.11 -0.02 -0.50 -0.02 -0.02
10 Esophagus yes -0.16 1.30 -0.07 -0.06 -0.63 -1.95 -0.41 -0.41
11 Esophagus no -0.37 -0.16 -0.50 -0.23 -0.03 1.01 -0.03 -0.03
12 Esophagus no -0.01 -1.02 -0.01 -0.01 0.00 -0.02 0.00 0.00
13 Esophagus yes -0.77 -3.82 -0.31 -0.56
14 Liver yes 0.03 -0.05 0.55 2.38
15 Liver no 0.00 0.00 0.00 0.00
16 Liver no 0.00 0.21 -0.01 0.55
17 Liver no 0.00 -0.11 -0.23 0.32
18 Liver no 0.00 2.86 0.01 3.19
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Table 2. Mean Difference in Target Coverage (V95%).

Mean Standard p-value
Difference Deviation
(%)
All Sites
Rigid Contour -0.46 1.1 0.030
Deformable Contour –0.13 1.7 0.683
New PG contour -0.63 1.3 0.471
New PG contour vs. 50-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 PG contour -1.67 1.9 0.057
New PG contour vs. New 50-Phase Contour -1.08 2.2 0.234

Liver
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 PG contour -0.07 0.3 0.328
New PG contour vs. New 50-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 PG contour -1.34 1.9 0.079
New PG contour vs. New 50-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 PG contour -0.16 0.5 0.313
New PG contour vs. New 50-Phase Contour -0.32 0.7 0.137