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
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.7-9
Lupu-Plesu et al8 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 falls 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.
 2

Evaluating the dosimetric implications over the duration of treatment course is both
necessary and routine in oropharyngeal IMPT.10 This 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 weekly verification CT scans. A weekly verification scan
enables the radiation oncologist to decide whether a replan is necessary.11 Evans et al11
established the importance of optimally timed weekly verification CTs to evaluate variation in
daily setup on planning conformality. 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. This concept is similar to the geometrical uncertainty margin
of a planning target volume (PTV) in photon planning.12 Van Dijk et al13 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.14 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
 3

toxicity of adjacent OAR.15 Institutional plans were calculated using rMFO, which was proven
by Stutzer et al16 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.13 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.13 Currently,
there are limited studies investigating the causes of frequent replanning. Malyapa et al17
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. This research investigates factors that
may induce replanning; the relationship between beam arrangement, field number, CTV number,
initial plan coverage, initial plan robustness and dental fillings will be compared with replan
frequency. 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 factors triggering a replan. Patient data consisting of 15 base of
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
 4

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). Four field
beam arrangements included either 2 lateral or anterior oblique fields with an anterior and a
posterior field or 2 anterior oblique fields with 2 posterior oblique fields.

Secondly, all plans were measured for robustness. Institutional guidelines require that
robustness should not deviate over 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. Note that
robustness curves were evaluated in a singular direction at a time. The curves of least robustness
 5

were recorded for each plan for the percent of prescription dose covering 95% of the volume
(D95%) to align with the initial accepted coverage.

Clinical target volumes delineated by the physician were assessed along with initial
accepted target coverage. Each plan included 1-3 CTV structures that were removed from air.
The lower dose CTVs encompassed upper dose CTVs. Additionally, CTV coverage was defined
according to the D95% 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. Finally, the number of replans
were recorded for each patient, with each patient receiving between 0 and 2 replans.

Results

Fisher’s exact tests were used to determine if number of re-plans (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 re-plan (Yes or No) was related to the initial
approved CTVhigh coverage (95% of volume receives this dose or more) or the initial plan
CTVhigh robustness curve (D95%). A 5% level of significance was used for each test. Statistical
analysis was performed using R software (R Core Team, 2019).

No significant associations were observed between the number of re-plans 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 re-plan was not related to the initial approved high CTV
coverage (P = 0.537) or the initial plan CTVhigh robustness curve (P = 0.712). Data also showed
that over 62% of the sample cases were replanned. Of these total replanned cases, 48.1%
received 1 replan and 14.8% received 2 replans. Seventeen percent of replans occurred for cases
where the initial approved coverage and plan robustness differed by >5%, whereas cases that
were not replanned all fell within the 5% range for robustness agreement.

Discussion
 6

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.
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. Findings are consistent with those by Yeh et al,8
reinforcing the need for adaptive replanning in the treatment H&N cancer.

Conclusion

Ultimately, limiting the number of replans oropharyngeal cancer patients receive can both
improve clinical efficiency and save patients time. 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.

One limitation of this study is that sample populations included bilateral oropharyngeal
volumes treated at a single institution. Further research may be extended to include a larger
sample size, which may identify more definitive factors contributing to oropharyngeal IMPT
replanning. Dose to OAR may also be assessed to gauge relationship with robustness values.
Finally, weekly verification CT data from a single facility revealed that shoulder and inferior
neck positioning is variable in daily setup. Immobilization methods may be explored to
determine the relationship between replan prevalence and shoulder location in IMPT.
 7

References
1. Fakhry C, Cohen E. The rise of HPV-positive oropharyngeal cancers in the United States.
Cancer Prev Res. 2014;8(1):9-11. http://dx.doi.org/10.1158/1940-6207.capr-14-0425
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-
34. http://dx.doi.org/10.3322/caac.21551
3. Sharma S, Zhou O, Thompson R, et al. Quality of life of postoperative photon versus
proton radiation therapy for oropharynx cancer. Int J Part Ther. 2018;5(2):11-17.
http://dx.doi.org/10.14338/ijpt-18-00032.1
4. Wu RY, Liu AY, Sio TT, et al. Intensity-modulated proton therapy adaptive planning for
patients with oropharyngeal cancer. Int J Part Ther. 2017;4(2):26-34.
http://dx.doi.org/10.14338/ijpt-17-00010.1
5. Leeman JE, Romesser PB, Zhou Y, et al. Proton therapy for head and neck cancer:
expanding the therapeutic window. Lancet Oncol.
2017;18(5).http://dx.doi.org/10.1016/s1470-2045(17)30179-1
6. Frank SJ, Blanchard P, Lee JJ, et al. Comparing intensity-modulated proton therapy with
intensity-modulated photon therapy for oropharyngeal cancer: The journey from clinical
trial concept to activation. Semin Radiat Oncol. 2018;28(2):108-113.
http://dx.doi.org/10.1016/j.semradonc.2017.12.002
7. Moreno AC, Frank SJ, Garden AS, et al. Intensity modulated proton therapy (IMPT) –
The future of IMRT for head and neck cancer. Oral Oncol. 2019;88:66-74.
http://dx.doi.org/10.1016/j.oraloncology.2018.11.015
8. Lupu-Plesu M, Claren A, Martial S et al. Effects of proton versus photon irradiation on
(lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head
and neck squamous cell carcinoma. Oncogenesis. 2017;6(7):354.
http://dx.doi.org/10.1038/oncsis.2017.56
9. Zhang J, Nguyen D, Woods K, et al. SU-F-T-186: A treatment planning study of normal
tissue sparing with robustness optimized IMPT, 4Pi IMRT, and VMAT for head and neck
cases. Med Phys. 2016;43(6Part15):3504-3504. http://dx.doi.org/10.1118/1.4956323
10. Yeh B, Georges R, Zhu X, et al. Adaptive replanning is required during intensity
modulated proton therapy for head-and-neck cancers. Int J Radiat Oncol Biol Phys.
2012;84(3):S56-S57. http://dx.doi.org/10.1016/j.ijrobp.2012.07.354
 8

11. Evans J, Mundy D, Anand A, et al. Optimal timing of computed tomography verification
treated in spot scanning intensity-modulated proton therapy for head and neck cancers.
Int J Radiat Oncol Biol Phys. 2017;99(2):E336-E337.
http://dx.doi.org/10.1016/j.ijrobp.2017.06.1404
12. Langen K, Zhu M. Concepts of PTV and robustness in passively scattered and pencil
beam scanning proton therapy. Semin Radiat Oncol. 2018;28(3):248-255.
http://dx.doi.org/10.1016/j.semradonc.2018.02.009
13. Van Dijk L, Steenbakkers R, Ten Haken B, et al. Robust intensity modulated proton
therapy (IMPT) increases estimated clinical benefit in head and neck cancer patients.
PloS One. 2016;11(3): e0152477. http://dx.doi.org/10.1371/journal.pone.0152477.
14. Blakey M, Price S, Robison B, et al. SU-E-J-78: Adaptive planning workflow in a pencil
beam scanning proton therapy center. Med Phys. 2015;42(6Part8):3282-3282.
http://dx.doi.org/10.1118/1.4924165
15. Wei L, Frank S, Xiaoqiang L, et al. Effectiveness of robust optimization in intensity-
modulated proton therapy planning for head and neck cancers. Med Phys. 2013;40(5):
051711. http://dx.doi.org/10.1118/1.4801899
16. Stützer K, Lin A, Kirk M, Lin L. Superiority in robustness of multifield optimization over
single-field optimization for pencil-beam proton therapy for oropharynx carcinoma: an
enhanced robustness analysis. Int J Radiat Oncol Biol Phys. 2017;99(3):738-749.
http://dx.doi.org/10.1016/j.ijrobp.2017.06.017
17. Malyapa R, Lowe M, Bolsi A, Lomax AJ, Weber DC, Albertini F. Evaluation of
robustness to setup and range uncertainties for head and neck patients treated with pencil
beam scanning proton therapy. Int J Radiat Oncol Biol Phys. 2016;95(1):154-162.
http://dx.doi.org/10.1016/j.ijrobp.2016.02.016