1

Evaluation of Replanning in Intensity Modulated Proton Therapy for Oropharyngeal

Cancer: Factors Influencing Plan Robustness
Noelle Deiter, BS, R.T.(R)(T); Felicia Chu, BS, R.T.(T); Nishele Lenards, PhD, CMD,
R.T.(R)(T), FAAMD; Ashley Hunzeker, MS, CMD; Karen Lang, MS, CMD, R.T.(T); Daniel
Mundy, PhD

ABSTRACT

The head and neck (H&N) region is often replanned in intensity modulated proton therapy
(IMPT), but replanning disrupts clinical workflow and presents additional burden on patients.
The purpose of this study is to establish a standard approach to minimize H&N replanning by
identifying a correlation between dosimetric variables and replan frequency. In a retrospective
study of 27 bilateral oropharyngeal cancer patients treated with IMPT at a single institution,
cases were evaluated using Fisher’s exact tests and logistic regression for a significant
relationship between replan frequency and the following variables: beam number, beam
arrangement, CTV coverage, robustness, and presence of dental artifact. The reason and timing
for replan initiation, and patient immobilization was also recorded to identify trends.
Results suggested that beam number and arrangement, CTV number, and presence of dental
fillings did not individually contribute to replanningreplanned most frequently. Setup variation in
the soft tissue of the neck was the most prominent reason for replan. A lack of correlation
between the number of replans and the studied dosimetric variables highlights the necessity of
verification CT and adaptive replanning in the treatment of H&N cancer. Departments may
therefore benefit from a methodical replan workflow. workflow.

Keywords: Oropharyngeal cancer, adaptive replanning, IMPT, robustness, verification CT

Introduction
The incidence of oropharyngeal cancer has been steadily increasing in recent decades. 1
The American Cancer Society estimates that there will be 53,000 new cases of oral cavity and
pharyngeal cancers and 10,860 deaths in 2019. 2 Conventional radiation therapy, with or without
chemotherapy, is the standard of care for medically inoperable oropharyngeal cancer. However,
even the most conformal techniques, such as intensity modulated radiation therapy (IMRT), still
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produce debilitating acute and late radiation toxicities. 3 With growing efforts to reduce toxicity
and improve quality of life for patients with oropharyngeal cancer, intensity modulated proton
therapy (IMPT) has been gaining attention for its normal tissue sparing capabilities. 3-4
Intensity modulated proton therapy holds several distinct advantages over IMRT. Leeman
et al5 observed that oropharyngeal IMPT yielded increased sparing of oral cavity and major
salivary glands compared to IMRT. Reducing toxicity to normal tissue with IMPT improves
quality of life as less patients suffer from malnutrition and feeding tube dependence. 6-7 In
addition to superior sparing of normal tissue, IMPT is biologically advantageous over IMRT. 7-8
Lupu-Plesu et al9 noted that IMPT enables dose escalation for tumor control without increasing
side effects. Overall, proton dose distribution conforms more closely to target volumes and
effectively spares organs at risk (OAR).
The conformality of protons can be attributed to their physical properties; protons deposit
the majority of the dose at a specific depth, termed a “Bragg peak”, then sharply fall off or
decreases dose, minimizing exit dose to normal structures beyond that range. 5 While OAR
sparing is favorable, proton dose deposition is heavily dependent on range accuracy. 7 The
sensitive nature of protons necessitates both unique uncertainty considerations in the planning
process and a continuous verification process throughout treatment.

Evaluating the dosimetric implications over the duration of a treatment course is both
necessary and routine in oropharyngeal IMPT.10-12 Plan verification convention introduced
adaptive replanning, the process of evaluating conformity to initial planning constraints through
the progression of treatment. Wu et al4 found that the target coverage can be diminished by as
much as 70% for oropharyngeal cancer patients experiencing tumor shrinkage, weight loss, or
positioning-related anatomical differences. Dosimetric variation in head and neck (H&N) cancer
patients can be measured throughout treatment with verification CT scans. A verification scan
enables the radiation oncologist to decide whether a replan is necessary. 13
Evans et al13 established the importance of optimally timed verification CTs to evaluate
variation in daily setup on planning conformality. Wu et al 4 noted that the ideal timing of a
verification scan was during week 4 of a patient’s treatment course, as most anatomical changes
occur between weeks 3 to 4. However, adaptive replanning may be initiated at any time between
weeks 2 to 5 of treatment, suggesting a need for a more frequent CT verification process.14
Therefore, weekly verification CTs may be more appropriate to ensure adequate target volume
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coverage.13 Continuous evaluation of clinical target volume (CTV) coverage in daily setup is one
consideration when accounting for the physical uncertainty of a Bragg peak range.
Another consideration lies in the IMPT planning process. The relationship between CT
value and relative stopping power presents calculation uncertainty in the proximal and distal
range of each beam.5 Variation in patient setup and anatomical difference may alter where dose
is deposited, changing both target volume coverage and dose to OAR. To ensure adequate
coverage of CTVs, the International Commission on Radiation Units and Measurements (ICRU)
recommends implementation of robustness calculations to test target coverage for multiple setup
scenarios and range uncertainties. A robustness calculation is similar to the geometrical
uncertainty margin of a planning target volume (PTV) in photon planning. 15 Van Dijk et al16
describe how robustness calculations simulate daily setup variation by shifting isocenter in one
of six directions, with a 3.5 mm displacement mimicking a PTV margin. Directional values for
institutional robustness shifts occurred in either the anterior, posterior, superior, inferior, right, or
left axis.
Robustness, defined as the ability to conform to initial constraints through variation in
setup, is an especially desirable planning characteristic. 11 Maximizing robustness is critical in
IMPT planning because small changes in daily setup or weight fluctuation may impose
dosimetric challenges throughout a course of treatment. 4 A notable feature in IMPT planning
software that enables creation of such plans is robust multi-field optimization (rMFO). Robust
optimization achieves a higher level of homogeneity within target volumes, thereby minimizing
toxicity of adjacent OAR.17 Institutional plans were calculated using rMFO, which was proven
by Stutzer et al18 to yield superior CTV coverage and OAR sparing compared to single-field
optimization (SFO). Because robust plans incorporate daily setup variation into dose
calculations, increasing robustness decreases likelihood of a setup related replan. 16 A consensus
is lacking about how to maximize plan robustness, thereby limiting the frequency of replanning.
The H&N region is the most frequently replanned anatomic site in proton therapy due to
setup variation, but replans are time consuming and unsettling for patients. 16 Presently, there is
insufficient literature identifying the causes of frequent replanning. Malyapa et al19 recognized
that plan robustness and field number are interlinked for oropharynx treatments. The number of
beams is a major determinant in whether a setup-related replan will be necessary at some point
throughout the course of treatment. Additionally, previous studies have established the
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dosimetric advantage of a multi-field approach over single-field, but there has been no further
investigation comparing robustness between 3 and 4-field arrangements.10
Patients receiving oropharyngeal IMPT may require periodic replanning because of
dosimetric similarities that diminish plan robustness. By identifying a relationship between plan
variables and replan frequency, future replanning can be limited. The purpose of this study was
to establish a standard approach to minimize H&N replanning. First, the cause and timing of
replan, and method of patient immobilization was recorded to establish common trends in replan
initiation. Secondly, variables in plan dosimetry including number of fields, presence of dental
fillings, initial CTV coverage, and initial robustness was compared with replan frequency using
Fisher’s exact test to determine if there were nonrandom associations. Logistic regression
modeling was used to verify if the occurrence of a replan was related to the initial CTV coverage
or initial robustness value. The null hypothesis (H 0 ) was that there was no relationship between
plan variables and replan frequency. Statistically significant associations between replan
frequency and dosimetric variables may indicate whether techniques could be implemented in
the planning process to reduce or eliminate the need for replanning altogether.
Methods and Materials
Patient Selection & Setup
A retrospective study of 27 bilateral oropharyngeal cancer patients who received IMPT
was performed to evaluate the variables triggering a replan. Patient data comprised of 15 base of
tongue cancers, 10 tonsil cancers, and 2 unspecified oropharynx cancers was collected from a
single proton institution. Exclusion criteria consisted of unilateral volumes, nasopharynx cancers,
and cases with beam arrangements > or < 3 and 4 fields.
The simulation process for patients receiving oropharyngeal IMPT consisted of 2
separate components. The initial appointment was dedicated to immobilization construction,
whereas the second appointment involved CT data acquisition in treatment position. A time
delay between appointments allowed for proper solidifying of custom immobilization.
Immobilization included: Orfit 5-points head, neck and shoulders thermoplastic mask, Klarity
head and shoulder AccuCushion neck rest indexed to an Orfit table head and neck extension. The
Bionix true-guard or Civco Precise Bite was used to immobilize the jaw. Grip rings or handles
were used to stabilize arm position. Patients were scanned headfirst supine using 1 mm slice
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thickness. Scans extended from the top of the Orfit extension through the lungs. Iterative metal
artifact reduction (iMAR) was applied to minimize metal artifact induced by dental hardware.
Of the 27 patients, 24 had dental fillings. Eleven patients received 60 Gy, 4 patients
received 63 Gy, 2 patients received 66 Gy, 4 patients received 69.96 Gy, and 6 received 70 Gy.
Eclipse treatment planning system (TPS) with Proton Convolution Superposition (PCS) and
Nonlinear Universal Proton Optimizer (NUPO) algorithms were used for dosimetric calculations.
All patients were treated using Hitachi’s PROBEAT-V proton beam spot scanning system.
Additionally, all patients received weekly CT verifications throughout the course of
treatment. Immediately following treatment, patients were imaged with a Siemens CT scanner in
the same treatment position. The newly acquired verification CT was fused with the original
treatment planning CT and the isocenter coordinates were verified to match. The original plan
was then calculated using the verification data set to evaluate differences in dose distribution
induced by deviations from initial simulation setup. The radiation oncologist was responsible for
reviewing the dose variation with setup differences for each weekly verification plan. Adaptive
replanning was then initiated if target coverage or OAR sparing significantly deviated from the
original plan. Seventeen patients received at least 1 replan during the course of IMPT treatment.
Planning Evaluations
Initially, all cases were evaluated for beam number and beam arrangement. Standard
planning techniques for the institution include 3 and 4 field rMFO beam arrangements. Optimal
gantry angles were selected to minimize entrance through chin, shoulders, and skin fold areas,
and maximize plan robustness. Three field beam arrangements consisted of 2 anterior oblique
fields (+/- 45 to 55°) and a posterior or posterosuperior field (15 to 30°) (Figure 1). Four field
beam arrangements included either 2 lateral or anterior oblique fields with an anterior and a
posterior field (Figure 2) or 2 anterior oblique fields with 2 posterior oblique fields (Figure 3).
Secondly, all plans were measured for robustness. Institutional guidelines recommend
that robustness should not deviate > 5% from initially approved CTV coverage. Robustness
directional calculations included shifts of 3 mm in both positive and negative x, y, and z
directions. The calibration curve calculations assessed 3% positive and negative uncertainties for
range error. Robustness calculations in each plan included 6 directional error tests and 2
calibration curve error tests. Each robustness calculation curve provides dose information to the
CTV and demonstrates changes in volume coverage in various setup scenarios (Figure 4). Note
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that robustness curves were evaluated in a singular direction at a time. The curves of least
robustness were recorded for each plan for the percent of prescription dose covering 95% of the
volume (D 95%) to align with the initial accepted coverage (Table 1).
Clinical target volumes delineated by the physician were assessed along with initial
accepted target coverage. Each plan included 1 to 3 CTV structures that were removed from air.
The lower dose CTVs encompassed upper dose CTVs. Additionally, CTV coverage was defined
according to the D 95% on the original plan. Furthermore, dental artifacts contoured by the medical
dosimetrist or medical physicist were assessed for all plans. The presence of dental artifact s were
included in data collection to examine the relationship with beam number selection in the
planning process. The number of replans were recorded for each patient, with each patient
receiving between 0 and 2 replans. Lastly, data lists the week of treatment (1-6) that a primary or
secondary replan was initiated. Reasons for replan initiation included: weight change determined
by the radiation oncologist, tumor change determined by the radiation oncologist, or setup
variation with neck soft tissue location, shoulder and clavicle position, bony alignment, oral
cavity or tongue placement, or trachea location.

Results
Fisher’s exact tests were used to determine if number of replans (0, 1, or 2) is associated
with beam number, CTV coverage, or the presence of dental fillings or implants for patients
under treatment with proton radiation therapy for H&N cancer. Additionally, logistic regression
modeling was used to verify if the occurrence of a replan (yes or no) was related to the initial
approved CTV high coverage (95% of volume receives this dose or more) or the initial plan
CTV high robustness curve (D 95%). A 5% level of significance was used for each test. Statistical
analysis was performed using R software (R Core Team, 2019).
The P value for association between the number of replans and following variables was P
= 0.472 for the number of fields, P = 0.486 for CTV coverage, and P = 0.800 for the presence of
dental fillings or implants. Moreover, P = 0.537 for the initial approved CTV high coverage and P
= 0.712 for the initial plan CTV high robustness curve. All P values for the listed plan variables
were > 0.050, supporting the null hypothesis; there is no correlation between each singular
variable and replan frequency.
With regard to replanning, results showed that 63% of the total sample cases were
replanned. Of these total replanned cases, 82.4% received 1 replan and 17.6% received 2 replans.
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Seventeen percent of total replans occurred for cases where the initial approved coverage and
plan robustness differed by > 5%, whereas cases that were not replanned fell within the 5% range
for robustness agreement (Figure 5). Reasons for primary replan initation differed by anatomical
discrepancies in various locations: neck soft tissue for 75% of total replanned cases, shoulder and
clavicle setup for 35%, bony alignment for 20%, weight fluctuation for 15%, oral cavity, tongue,
or trachea for 10%, and tumor change for 5%. Additionally, reasons for secondary replan
initiation included variation in weight for 50% of patients receiving 2 replans, variation in neck
soft tissue for 33%, and variation in shoulder and clavicle setup for 16% (Figure 6). Finally,
replans occurred most often during week 2 (25.9%), followed by week 1 and 4 (11.1%), week 3
and 5 (7.4%), and week 6 (3.7%). Finally, replans occurred most often during week 2 (25.9%),
followed by week 1 and 4 (11.1%), week 3 and 5 (7.4%), and week 6 (3.7%) (Figure 7).
Discussion
No significant associations were observed between the number of replans and the
number of fields (P = 0.472), CTV (P = 0.486), or the presence of dental fillings or implants (P =
0.800). Moreover, the need for a replan was not related to the initial approved high CTV
coverage (P = 0.537) or the initial plan CTV high robustness curve (P = 0.712). As P values were >
0.05, beam number and arrangement, CTV number, and presence of dental fillings do not
individually contribute to replanning. It is possible that the observed dosimetric variables
collectively influence plan robustness, which was not measured in this study.
Results support the null hypothesis, suggesting that beam number and arrangement, CTV
number, and presence of dental fillings did not individually contribute to replanning. However,
plans with robustness deviation > 5% from initial approved coverage were noted to be replanned
most frequently. The most frequent documented reason for replan was setup variation in the soft
tissue of the neck followed by setup variation in shoulder and clavicle position. The high
percentage of patients with neck soft tissue variability (75% of total replanned cases) suggested a
need to explore more precise immobilization methods for H&N patients. Trends also revealed
that physicians were choosing to replan regardless of CTV coverage falling within robustness
parameters, as measured on plan comparisons from weekly CT verifications. One possible reason
for this trend is a lack of standardization in initial robustness acceptance.
A lack of correlation between the number of replans and the studied dosimetric variables
reinforces the necessity of adaptive replanning in the treatment of H&N cancer, as initially
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concluded by Yeh et al10 and Stutzer et al.12 The requirement of a planning verification process is
further supported by Blakey et al,11 where proton H&N plans were found to be particularly
sensitive to changes in patient setup. Results from previous studies4,11 demonstrated that changes
in patient anatomy can reduce planned dose to CTVs; effects were similarly observed in this
study. As consistent with Stutzer et al,12 IMPT adaptive replanning was initiated with
degradations in target dose observed through verification CT scans.
Although Wu et al4 proposed that the ideal timing for a verification scan is between
weeks 3 and 4, when most anatomical changes occur, results of this study reveal that replans can
occur during almost all weeks of treatment for reasons besides anatomical change. Adaptive
replanning can ensue between weeks 2-5 of treatment, as observed by Mundy et al,14 but also
occasionally on week 6 (3.7%). The occurrence of replans throughout any week of a patient’s
treatment reinforces the significance of weekly verification CTs. Results are consistent with
those of Evans et al13 and Mundy et al,14 confirming the importance of weekly CT verification
imaging throughout treatment.
Overall, evaluating the dosimetric implications of patient anatomical variation throughout
a course of treatment is essential in H&N IMPT. Proton departments may therefore benefit from
a strategic adaptive replanning process. As observed by Blakey et al,11 with proper planning tools
and procedures, a replan can be generated in a timely manner without delaying the patient or
obstructing clinical workflow.

Conclusion
Ultimately, limiting the number of replans oropharyngeal cancer patients receive can both
improve clinical efficiency and save patients time. However, adaptive replanning remains an
integral component of oropharyngeal IMPT planning and departments may therefore benefit
more from a methodical replan workflow. Researchers in this study identified potential factors
contributing to replanning for oropharyngeal patients receiving IMPT, which were not previously
addressed in earlier studies. Although there were no singular factors contributing to replans
identified, physicians should be cognizant of acceptable initial CTV coverage and reasonable
lowest robustness curve values that minimize the necessity of replanning throughout the course
of patient treatment.
Furthermore, a change in practice to either tighten robustness acceptance or consistently
evaluate percentage of coverage in comparison to robustness may be sensible. High tendency to
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replan implies that physicians may be either accepting inadequate CTV coverage and robustness
in initial planning or are deviating from their initial accepted goals. Both actions may obstruct
clinical workflow and fatigue patients. More definitive verdicts of acceptable initial fluctuation
in CTV coverage may be required.
One limitation of this study was that sample populations were immobilized with
equipment from a single institution. Further research may be extended to include multi-
institutional immobilization practices which may identify a definitive relationship between
replan prevalence and immobilization selection. Weekly verification CT data from a single
facility revealed that shoulder and inferior neck positioning is variable in daily setup.
Immobilization methods across various proton institutions may be explored to determine the
relationship between replan prevalence and shoulder location in IMPT. Finally, patient weight
loss and dose to OAR may be assessed to gauge the relationship with robustness values and
replan frequency.

Acknowledgements
The authors would like to thank Dr. David Reineke of the UW-La Crosse Statistical Consulting
Center for his assistance in statistical analysis and interpretation of statistical results of the study;
however, any errors of fact or interpretation remain the sole responsibility of the authors.
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11. Blakey M, Price S, Robison B, et al. SU-E-J-78: Adaptive planning workflow in a pencil
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Figures

Figure 1. Three field beam arrangements consisted of 2 anterior oblique fields (+/- 45 to 55°)
and a posterior or posterosuperior field (15 to 30°).

Figure 2. Four field beam arrangements consisted of 2 lateral or anterior oblique fields with an
anterior and a posterior field.
 13

Figure 3. Four field beam arrangements consisted of 2 anterior oblique fields with 2 posterior
oblique fields.

Figure 4. Each robustness calculation curve provides dose information to the CTV and
demonstrates changes in volume coverage in various setup scenarios. This scenario demonstrates
coverage change for a negative 0.3 cm shift in the x axis direction.
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Figure 5. Cases with plan robustness >5% were replanned 100% of the time, whereas cases that
were within the 5% range for robustness agreement, were replanned 58.3% of the time.

Figure 6. Reasons for 1st replan were variation in neck soft tissue for 75% of total replanned
cases (3), variation in shoulder and clavicle setup for 35% (4), variation in bony alignment for
20% (5), variation in weight for 15% (1), setup variation in oral cavity (6), tongue (6), or trachea
(7) for 10%, and tumor change for 5% (2). Reasons for a 2nd replan were variation in weight for
 15

50% of patients receiving 2 replans (1), variation in neck soft tissue for 33% (3), and variation in
shoulder and clavicle setup for 16% (4).

Figure 7. Replans were initiated during weeks 1-6 of treatment.

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Tables
Table 1. CTV coverage and lowest robustness curve relationships with replan frequency
CTV D 95 CTV lowest Robustness Robustness Replan
coverage robustness within 5% of deviation from (Y or N)
D95 plan coverage D95 coverage
(Y or N) (%)
0.978 0.960 Y 1 Y
0.968 0.940 Y 2 N
0.995 0.965 Y 3 Y
1.013 0.987 Y 2 Y
1.011 0.995 Y 1 N
1.008 0.970 Y 3 N
0.999 0.976 Y 2 Y
1.001 0.950 Y 5 N
1.005 1.050 Y 4 Y
1.001 0.985 Y 1 N
1.008 0.980 Y 2 Y
1.006 0.990 Y 1 N
0.993 0.970 Y 2 Y
0.878 0.960 N 8 Y
1.000 0.990 Y 1 N
1.010 0.996 Y 1 N
1.005 0.987 Y 1 Y
0.985 0.874 N 11 Y
0.967 0.937 Y 3 Y
0.937 0.900 Y 3 Y
1.050 0.990 N 6 Y
1.000 0.975 Y 2 Y
1.006 0.990 Y 1 N
0.990 0.972 Y 1 Y
1.003 0.977 Y 3 Y
1.008 0.976 Y 3 Y
0.992 0.966 Y 2 N