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

Medical Dosimetry Program at the University of Wisconsin – La Crosse WI

ABSTRACT

The head and neck (H&N) region is frequently replanned in intensity-modulated proton therapy
(IMPT), but replanning disrupts clinical workflow and presents additional burden on patients.
The purpose of this study was to establish a standard treatment planning 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,
clinical target volume (CTV) coverage, presence of dental fillings, and robustness. The reason
and timing for replan initiation, and patient immobilization was also recorded to identify trends.
Results suggested that beam number, CTV coverage, presence of dental fillings, and the initial
robustness curve on the high dose CTV did not individually contribute to replanning frequency.
Setup variation in the soft tissue of the neck was the most prominent reason for replanning. A
lack of correlation between the number of replans and the studied dosimetric variables highlights
the necessity of verification CT and adaptive replanning in IMPT of H&N cancer. Departments
may therefore benefit from a methodical replan 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.
 2

However, even the most conformal techniques, such as intensity-modulated radiation therapy
(IMRT), still 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 ability to treat targets with
improved normal tissue sparing capabilities.3-4
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 Superior organs at
risk (OAR) sparing is one advantage of IMPT over IMRT. Leeman et al5 observed that
oropharyngeal IMPT yielded increased sparing of unaffected 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
OAR. However, while limiting OAR dose is favorable, proton dose deposition is heavily
dependent on range accuracy and must be accounted for.7
One dosimetric consideration is that 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 clinical
target volumes (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.10
Robustness, defined as the ability to maintain planned dose through setup variations
, is an especially desirable planning characteristic in IMPT.11 A robustness calculation
models daily setup variation, with translational and CT curve shifts that mimic the geometrical
uncertainty margin of a planning target volume (PTV) in photon planning.12-13 Institutional
robustness shifts occurred in one of six directions in either the anterior, posterior, superior,
inferior, right, or left axis. Maximizing robustness is critical in IMPT planning because small
changes in daily setup or weight fluctuation may impose dosimetric challenges throughout a
 3

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.14 Institutional
plans were calculated using rMFO, which was proven by Stützer et al15 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.12 A consensus is lacking about how to maximize plan
robustness, thereby limiting the frequency of replanning.
In addition to robustness considerations, proton range sensitivity necessitates a
continuous verification process. Evaluating the dosimetric implications over the duration of a
treatment course is both essential and routine in oropharyngeal IMPT.11,15,16 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.17 Evans et al17 established the importance of optimally timed verification CTs to
evaluate variation in daily setup on planning conformality. Wu et al4 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, replanning may be initiated at any time between
weeks 2 to 5 of treatment, suggesting a need for a more frequent CT verification
process.18 Therefore, weekly verification CTs may be more appropriate to ensure adequate target
volume coverage.17
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.
Reduction in target coverage is more pronounced for patients with smaller primary tumor sizes
as compared to patients with larger tumor sizes. Continuous evaluation of CTV coverage using
verification CT has sparked periodic replanning in IMPT departments.
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.12 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
 4

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
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.20
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 were 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 hypotheses were that there was no relationship between
number of fields (H1 0 ), initial CTV high coverage (H2 0 ), the presence of dental fillings (H3 0 ) and
least desirable robustness curve (H4 0 ) and replan frequency. Statistically significant associations
between replan frequency and dosimetric variables may indicate whether techniques could be
implemented in the initial 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 or 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
 5

head and shoulder AccuCushion neck rest indexed to an Orfit table H&N 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 2 mm slice 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.
All patients were treated using Hitachi’s PROBEAT-V proton beam spot scanning
system. 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.
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 dataset 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. Robustness calculations in each plan
included 6 directional error tests and 2 calibration curve error tests. Robustness directional
calculations included isocenter shifts of 3 mm in both positive and negative x, y, and z directions
per department standards. The calibration curve calculations assessed 3% positive and negative
 6

uncertainties for range error. Institutional guidelines recommended that robustness on CT

verifications should not deviate > ± 5% from initially approved CTV coverage. For all approved
plans the initial CTV coverage goal was 95% of volume to receive 100% of the dose or more
(D 95% ≥ 100%). The least desirable robustness DVH curve generated during the planning process
demonstrated the lowest acceptable treatment scenario range (Figure 4). Each robustness
calculation curve provided CTV coverage information and displayed changes in volume
coverage with various isocenter shifts (Figure 5). Note that robustness curves were evaluated in a
singular direction at a time. The curves of least desirable robustness were recorded for each plan
to assess the deviation of D 95% 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 higher dose CTVs. Additionally, CTV coverage was defined
according to the D 95% on the original plan. The presence of dental fillings was included in data
collection to examine the relationship with beam number selection and replan outcome. The
number of replans was recorded, with each patient receiving between 0 and 2 replans. Lastly, the
week of treatment (1-6) that a primary or secondary replan was initiated was recorded. 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.
Statistical Analysis
Fisher’s exact tests were used to determine if number of replans (0, 1, or 2) was
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 high dose CTV (CTV high ) coverage 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).
Results
The first null hypothesis (H1 0 ) was that there was no relationship between number of
fields and replan frequency. The percentage of replans in the sample for 3 field beam
 7

arrangements was 52.9% compared to 80% with 4 field beam arrangements. The H1 0 hypothesis
was accepted because of insignificant correlation (P = 0.231) between these measures.
The second null hypothesis (H2 0 ) was that there was no relationship between initial CTV
coverage and replan frequency. In 59.3% of patient plans, CTV D 95% coverage was >100% while
40.7% of patients were planned with D 95% coverage < 100%. No significant statistical
relationship existed at the 5% level of significance (P = 0.369), accepting the H2 0 null
hypothesis.
The third null hypothesis (H3 0 ) was that there was no relationship between presence of
dental fillings and replan frequency. Seventy-five percent of patients with no dental fillings
received replans (1 or 2) whereas 60.8% of patients with dental fillings received replans (1 or 2)
(P = 1.0). Therefore, the null hypothesis was accepted regarding the correlation of dental filling
presence with replan frequency.
Lastly, the fourth null hypothesis (H4 0 ) was that there was no relationship between the
initial plan CTV high least desirable robustness curve value and replan frequency. For patients
receiving replans, the least desirable robustness curve fell within -5% of the initial CTV
coverage for 58.3% of patients. For patients receiving no replans, the least desirable robustness
curve fell within -5% for 41.7% of patients. Patients with least desirable plan robustness value
lower than -5% were replanned 100% of the time (Figure 6). The H4 0 hypothesis was accepted,
demonstrating no significant relationship (P = 0.274) between CTV high robustness 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% of patients received 1 replan and 17.6% of
patients received 2 replans. Reasons for primary replan initiation 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 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 8).
Discussion
 8

No significant associations were observed between the number of replans and the
number of fields (P = 0.231), CTV D 95% coverage (P = 0.369), or the presence of dental fillings
or implants (P = 1.0). Moreover, the need for a replan was not related to the initial plan CTV high
robustness curve (P = 0.274). As P values were > 0.05, beam number and arrangement, CTV
number, and presence of dental fillings did 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 suggested that beam number and arrangement, CTV number, and presence of
dental fillings did not individually contribute to replanning. However, plans with a robustness
value lower than -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. Although
physicians typically adhere to a standard of initial robustness value acceptance, exceptions are
made when prioritizing the sparing of OAR. One possible explanation for the high volumes of
replan initiation, despite meeting robustness criteria, is that exceptions are being made too
frequently.
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
concluded by Yeh et al20 and Stützer et al.15 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 studies demonstrated that changes in
patient anatomy can reduce planned dose to CTVs which were also observed in this study.4,11 As
consistent with Stützer et al,16 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 other than anatomical change. Adaptive
 9

replanning can ensue between weeks 2 through 5 of treatment, as observed by Mundy et al,18 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 al17 and Mundy et al,18 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
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 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 was variable in daily setup.
Immobilization methods across various proton institutions may be explored to determine the
 10

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.
 11

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.
 12

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https://icru.org/home/reports/prescribing-recording-and-reporting-proton-beam-therapy-icru-
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 15

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°).
 16

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

Figure 3. Four field beam arrangements consisted of 2 anterior oblique fields and 2 posterior
oblique fields.
 17

Figure 4. The least desirable robustness curve (CT calibration curve/range error +3.0%)
demonstrates 95% dose coverage to > 96% of the target volume. This curve met acceptable
robustness criteria as it falls within -5% of the planned CTV target volume coverage.
 18

Figure 5. Each robustness calculation curve provides dose information to the CTV and
demonstrates changes in volume coverage in various setup scenarios. This scenario demonstrates
coverage decrease for a +3.0% calibration curve error or range error.

Figure 6. Cases with the least desirable robustness curve lower than the -5% acceptable range
were replanned 100% of the time, whereas cases that were within the -5% range for robustness
agreement, were replanned 58.3% of the time.
 19

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

 20

Tables
Table 1. Initial approved CTV coverage (D 95 ) and least desirable robustness curves (D 95 ) were
compared to assess the percentage of deviation and identify a relationship with replan frequency.
CTV D 95 CTV least desirable Robustness within Robustness Replan
coverage robustness D 95 -5% of D 95 deviation from (Y or N)
(%) (%) coverage (Y or N) D 95 coverage
97.8 96.0 Y (%)
1 Y
96.8 94.0 Y 2 N
99.5 96.5 Y 3 Y
101.3 98.7 Y 2 Y
101.1 99.5 Y 1 N
100.8 97.0 Y 3 N
99.9 97.6 Y 2 Y
100.1 95.0 Y 5 N
100.5 105.0 Y 4 Y
100.1 98.5 Y 1 N
100.8 98.0 Y 2 Y
100.6 99.0 Y 1 N
99.3 97.0 Y 2 Y
87.8 96.0 N 8 Y
100.0 99.0 Y 1 N
101.0 99.6 Y 1 N
100.5 98.7 Y 1 Y
98.5 87.4 N 11 Y
96.7 93.7 Y 3 Y
93.7 90.0 Y 3 Y
105.0 99.0 N 6 Y
100.0 97.5 Y 2 Y
100.6 99.0 Y 1 N
99.0 97.2 Y 1 Y
100.3 97.7 Y 3 Y
100.8 97.6 Y 3 Y
99.2 96.6 Y 2 N