1

Evaluation of Replanning in Intensity Modulated Proton Therapy for Oropharyngeal

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

ABSTRACT

Keywords:

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 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
5
et al 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
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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 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 Weekly verification CTs may therefore be more appropriate to ensure adequate target
volume 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.
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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.

Head and neck 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 Currently,
there is limited data supporting 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
dosimetric advantage of a multi-field approach over single-field, but there has not been further
investigation comparing robustness between 3 and 4-field arrangements.10

Overall, the purpose of this study is to limit the frequency of IMPT oropharyngeal
replanning by identifying similarities in plan dosimetry. The relationship between beam
arrangement, field number, CTV number, initial plan coverage, initial plan robustness and dental
fillings will be compared with replan frequency. The cause and timing of replan initiation were
also assessed. Data may be used to formulate a standard approach to minimize proton H&N
replanning, if optimal techniques are distinguished.

Methods and Materials

Patient Selection

A retrospective study of 27 bilateral oropharyngeal cancer patients who received IMPT

was selected to evaluate the variables triggering a replan. Patient data consisting of 15 base of
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tongue cancers, 10 tonsil cancers, and 2 unspecified oropharynx cancers was collected from a
single proton institution. Exclusion criteria included unilateral volumes, nasopharynx cancers,
and cases with beam arrangements > or < 3 and 4 fields.

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 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 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 degrees) and a posterior or posterosuperior field (15-30 degrees) (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 require that
robustness should not deviate over 5% from initially approved CTV coverage. Robustness
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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
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.

Dental artifacts contoured by the medical dosimetrist or medical physicist were assessed
for all plans. The presence of dental artifact was included in data collection to examine
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
includes the week of treatment a primary or secondary replan was initiated and reasons for
initiation: 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, 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).
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No significant associations were observed between the number of replans and the number
of fields (P = 0.472), CTV (P = 0.486), 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). Data also 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. 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 replan 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% (Figure 6). Finally, replans
occurred most often during week 2 (25.9%), followed by and week 1 and 4 (11.1%), week 3 and
5 (7.4%), and week 6 (3.7%) (Figure 7).

Discussion

Results suggest that beam number and arrangement, CTV number, and presence of dental
fillings do not individually contribute to replanning. However, plans with robustness deviation
greater than 5% from initial approved coverage were noted to be replanned most frequently. The
most frequent documented reason for replan was setup variation in neck soft tissue followed by
setup variation in shoulder and clavicle position. Findings suggest a need to explore more precise
immobilization methods for H&N patients. Trends also reveal that physicians are choosing to
replan regardless of CTV coverage falling within robustness parameters, as measured on plan
comparisons from weekly CT verifications.

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. A change in practice may be
prudent towards either tighter robustness acceptance, or a more continuous evaluation process of
verification coverage in relation to robustness. More definitive verdicts of acceptable initial
fluctuation in CTV coverage may be required.
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Findings are consistent with those by Yeh et al10 and Stutzer et al,12 reinforcing the
necessity of adaptive replanning in the treatment H&N cancer. 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. 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 methodical adaptive replanning process. As observed by Blakey et al11, 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 systematic replan workflow. Findings of this study identified potential factors
contributing to replanning for oropharyngeal patients receiving IMPT, which were not previously
addressed in current 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 minimizes 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. A
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lack of statistically significant variables contributing to replanning emphasizes the complexity

and multifaceted nature of IMPT H&N planning.

One limitation of this study is 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.
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References
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Figures

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

Figure 2. Four field beam arrangement with 2 lateral or anterior oblique fields with an anterior
and a posterior field.
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Figure 3. Four field beam arrangement with 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 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).
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Figure 7. Week of treatment in which replan was initiated by verification CT scan.

Figure 8. All cases planned with a 4 field arrangement had dental fillings, whereas 76.5% of 3
field arrangements had dental fillings.
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Tables
Table 1
CTV coverage and lowest robustness curve relationships with replan frequency (Y or N)
CTV D 95 CTV lowest Robustness within 5% Robustness deviation Replan
coverage robustness D 95 of plan coverage (Y or from D 95 coverage (Y or N)
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

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