Abstract

A 79-year-old woman underwent transoral robotic resection and selective dissection of the right side of the neck for a right tonsil squamous cell carcinoma, positive for human papillomavirus, final pathologic stage IVa, T2N2bM0. Given the finding of extracapsular extension, postoperative chemoradiation was recommended for the patient, and radiation was given via pencil-beam scanning proton therapy. During the course of radiation, regular evaluation computed tomography scans consistently revealed random variation in the position of large skinfolds in the posterior portion of the neck, which resulted in undercoverage of clinical targets. As a result, the decision was made to change the remainder of the patient's radiation therapy course to intensity-modulated photon radiation, which was less sensitive to the random variation of setup in the soft tissues of her neck. She remained disease free at the 20-month follow-up. This case illustrates the importance of routine evaluation of soft tissue anatomy with proton therapy and has implications on developing methods of immobilization and evaluation to minimize variation in setup.

Introduction

The epidemiology of head and neck cancer is evolving, and a growing number of younger patients diagnosed with human papillomavirus–positive oropharyngeal squamous cell carcinoma [1, 2] have been treated and have achieved excellent long-term disease outcomes [3, 4]. Given that standard radiation techniques can cause severe late effects [511] and affect quality of life [7], it is increasingly important to consider novel approaches to minimizing long-term treatment-related complications.

In this context use of proton therapy holds significant promise in the treatment of head and neck malignancies. The unique physical characteristics of a proton beam allow for potential therapeutic gains, particularly by decreasing exposure and toxicity for healthy tissue. However, issues such as daily variation in patient positioning [12], anatomic changes that occur during the course of treatment [13], and the inherent uncertainties associated with pencil-beam scanning (PBS) [1416] warrant particular attention when implementing proton therapy. Here we present a case report of the dosimetric impact of random variation of soft tissue positioning when treating a patient with PBS for locally advanced head and neck cancer.

Case Report

A 79-year-old woman presented with a mass on the right side of the neck. Initial workup with computed tomography (CT) scan of the neck revealed a 2-cm node on the right side of the upper neck, and positron emission tomography–CT revealed increased fludeoxyglucose uptake in the right node and tonsil, with no evidence of systemic metastases. Biopsy of the neck node and right tonsil revealed squamous cell carcinoma, positive for p16 on immunohistochemistry.

She underwent initial treatment with a staged selective (levels I though IV) dissection of the right side of the neck, followed by a transoral robotic resection of the primary tumor. Pathologic examination revealed that 3 of 41 were nodes involved with cancer (2 nodes in level II, 1 node in level IV), with focal microscopic extracapsular extension in a level II node and a tonsillar tumor, 2.5 cm in greatest dimension, resected with negative margins, without evidence of lymphovascular involvement or perineural invasion.

The treating physician recommended that the patient then receive adjuvant radiotherapy with concurrent weekly cetuximab. Based on the dosimetric advantages of a pencil-beam proton plan compared with a volumetric modulated arc therapy intensity-modulated radiation therapy (IMRT) photon plan (Figure 1), the decision was made to deliver her radiotherapy with protons. Immobilization was achieved with thermoplastic mask, neck rest, and a foot box attached to ropes of indexed length held by the patient for shoulder retraction. The planning technique used a single-field uniform dosing approach with 2 posterior oblique beams and a right lateral beam. Targets were defined as follows: the highest-risk target (planning target volume [PTV] 1) comprised the region of extracapsular extension, PTV2 comprised the primary tumor bed and the ipsilateral portion of the neck (levels II through IV), and PTV3 comprised second echelon nodal levels (ipsilateral levels Ib and V, ipsilateral retropharyngeal and contralateral levels II through IV). Prescribed doses were 63 Gy (relative biological effectiveness) to PTV1, 60 Gy to PTV2, and 54 Gy to PTV3, all over 30 fractions. Treatment instructions were given for online daily kilovolt alignment (to bony anatomy) with offline weekly verification CT imaging surveillance.

During the first week of treatment, daily kilovolt imaging was obtained and demonstrated consistent setup to bony anatomy, with daily physician approval. However, the first weekly verification CT imaging scan demonstrated variation in the skinfolds and soft tissues of the posterior portion of the neck (Figure 2), which was not visualized on online kilovolt imaging. The dose distribution from the original proton plan calculated on the verification CT showed a change in coverage in the targets of the anterior portion of the neck (Figure 2) and reflected a significant compromise in coverage of the clinical targets as observed on dose-volume histogram (Figure 3). Given concern over these findings, a repeat CT verification scan was performed a few days after, which again demonstrated an unpredictable variation in the skinfolds and soft tissues of the posterior portion of the neck compared with the original CT simulation as well as the first CT verification scan, with corresponding loss of clinical targets.

As a result, the decision was made to switch the remainder of the radiation therapy course to IMRT because the IMRT plan was much less sensitive to the random variation of setup in the soft tissues of the patient's neck (Figure 4), and there was no appreciable compromise in target coverage. She tolerated the remainder of treatment well, with mild mucositis and minimal other toxicity. She remained disease free 20 months after completion of radiation therapy.

Discussion

Several studies have suggested potential dosimetric advantages associated with the use of proton therapy for head and neck cancers [1727], and recent clinical implementation of PBS has demonstrated encouraging early outcomes [28]. Efforts such as these can and should be continued and extended for other patients, as the unique dosimetric advantages available with PBS may lead to significant improvements in the therapeutic ratio for these patients; however, these unique qualities and uncertainties [1416] subsequently require attention to such issues as patient positioning [12] and anatomic changes [13], for which proton therapy may be more sensitive than IMRT.

Our case reveals how random variation in the setup and positioning of soft tissues can affect the robustness of a PBS-based plan. In the process, it brings up several areas that warrant further study and development. Current daily imaging for patients undergoing proton therapy is largely limited to kilovolt imaging, which is optimally suited for matching to bony anatomic structures but inadequate to assess soft tissue anatomy. In our study, we performed offline CT verification, and because of the issues identified, we advocate for the continued development and implementation of online cone-beam CT imaging for proton therapy. CT-based imaging is critical for evaluating daily setup and response of soft tissue, and we believe it has a greater importance for proton-based therapy than for photon-based radiation. Another topic to consider is patient and planning technique selection. Our patient was an elderly woman with significant soft tissue and skinfolds in the posterior portion neck, treated with most of the dose delivered via posterior oblique fields. Considerations such as the detailed evaluation of patient-specific anatomy at the time of consultation and simulation, as well as selection of beam directions to avoid areas of potential greatest variability in setup of the soft tissues, is critical in a proton-based treatment setting. Additionally, the continued development of customized immobilization devices will help reduce setup variability. In our patient, the thermoplastic mask and neck rest reliably immobilized the head and upper neck but did not adequately address the tissues of the mid and lower neck. As a result, we have developed and implemented a new immobilization device where patients have customized molds that cover and immobilize posterolaterally the extent of the anatomic region being treated with an overlying 5-point thermoplastic mask extending from the vertex of the scalp to below the shoulders and clavicles and to the upper thorax. The patient documented in this report was treated early in our institutional experience with PBS for head and neck cancer, when our currently used immobilization device was not available. Therefore, we believed the safest clinical decision at the time was to switch her to IMRT. However, since we have incorporated our new immobilization device as our standard approach, there has been far less setup variability in soft tissues, largely reducing the need for routine CT verification and eliminating the need to switch to IMRT.

Random setup variability of soft tissues is an important issue to consider for patients undergoing proton therapy for head and neck cancer. We advocate for the continued development of online CT-based imaging for routine setup verification and for the continued use of the most appropriate customized immobilization devices to minimize soft tissue setup variation. Doing so will help maximize the opportunities that proton therapy can have to improve the outcomes for our patients.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflict of Interest: The authors have no conflicts of interest to disclose.

References

References
1
Chaturvedi
AK
,
Engels
EA
,
Pfeiffer
RM
,
Hernandez
BY
,
Xiao
W
,
Kim
E
,
Jiang
B
,
Goodman
MT
,
Sibug-Saber
M
,
Cozen
W
,
Liu
L
,
Lynch
CF
,
Wentzensen
N
,
Jordan
RC
,
Altekruse
S
,
Anderson
WF
,
Rosenberg
PS
,
Gillison
ML.
Human papillomavirus and rising oropharyngeal cancer incidence in the United States
.
J Clin Oncol
.
2011
;
29
:
4294
301
.
2
Marur
S
,
D'Souza
G
,
Westra
WH
,
Forastiere
AA.
HPV-associated head and neck cancer: a virus-related cancer epidemic
.
Lancet Oncol
.
2010
;
11
:
781
9
.
3
Ang
KK
,
Harris
J
,
Wheeler
R
,
Weber
R
,
Rosenthal
DI
,
Nguyen-Tan
PF
,
Westra
WH
,
Chung
CH
,
Jordan
RC
,
Lu
C
,
Kim
H
,
Axelrod
R
,
Silverman
CC
,
Redmond
KP
,
Gillison
ML.
Human papillomavirus and survival of patients with oropharyngeal cancer
.
N Engl J Med
.
2010
;
363
:
24
35
.
4
O'Sullivan
B
,
Huang
SH
,
Siu
LL
,
Waldron
J
,
Zhao
H
,
Perez-Ordonez
B
,
Weinreb
I
,
Kim
J
,
Ringash
J
,
Bayley
A
,
Dawson
LA
,
Hope
A
,
Cho
J
,
Irish
J
,
Gilbert
R
,
Gullane
P
,
Hui
A
,
Liu
FF
,
Chen
E
,
Xu
W.
Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis
.
J Clin Oncol
.
2013
;
31
:
543
50
.
5
Dorresteijn
LD
,
Kappelle
AC
,
Boogerd
W
,
Klokman
WJ
,
Balm
AJ
,
Keus
RB
,
van Leeuwen
FE
,
Bartelink
H.
Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years
.
J Clin Oncol
.
2002
;
20
:
282
8
.
6
Eisbruch
A
,
Lyden
T
,
Bradford
CR
,
Dawson
LA
,
Haxer
MJ
,
Miller
AE
,
Teknos
TN
,
Chepeha
DB
,
Hogikyan
ND
,
Terrell
JE
,
Wolf
GT.
Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head-and-neck cancer
.
Int J Radiat Oncol Biol Phys
.
2002
;
53
:
23
8
.
7
Lin
A
,
Kim
HM
,
Terrell
JE
,
Dawson
LA
,
Ship
JA
,
Eisbruch
A.
Quality of life after parotid-sparing IMRT for head-and-neck cancer: a prospective longitudinal study
.
Int J Radiat Oncol Biol Phys
.
2003
;
57
:
61
70
.
8
Smith
GL
,
Smith
BD
,
Buchholz
TA
,
Giordano
SH
,
Garden
AS
,
Woodward
WA
,
Krumholz
HM
,
Weber
RS
,
Ang
KK
,
Rosenthal
DI.
Cerebrovascular disease risk in older head and neck cancer patients after radiotherapy
.
J Clin Oncol
.
2008
;
26
:
5119
25
.
9
Smith
GL
,
Smith
BD
,
Garden
AS
,
Rosenthal
DI
,
Sherman
SI
,
Morrison
WH
,
Schwartz
DL
,
Weber
RS
,
Buchholz
TA.
Hypothyroidism in older patients with head and neck cancer after treatment with radiation: a population-based study
.
Head Neck
.
2009
;
31
:
1031
8
.
10
Swisher-McClure
S
,
Mitra
N
,
Lin
A
,
Ahn
P
,
Wan
F
,
O'Malley
B
,
Weinstein
GS
,
Bekelman
JE.
Risk of fatal cerebrovascular accidents after external beam radiation therapy for early-stage glottic laryngeal cancer
.
Head Neck
.
2014
;
36
:
611
6
.
11
Tsai
CJ
,
Hofstede
TM
,
Sturgis
EM
,
Garden
AS
,
Lindberg
ME
,
Wei
Q
,
Tucker
SL
,
Dong
L.
Osteoradionecrosis and radiation dose to the mandible in patients with oropharyngeal cancer
.
Int J Radiat Oncol Biol Phys
.
2013
;
85
:
415
20
.
12
Ahn
PH
,
Ahn
AI
,
Lee
CJ
,
Shen
J
,
Miller
E
,
Lukaj
A
,
Milan
E
,
Yaparpalvi
R
,
Kalnicki
S
,
Garg
MK.
Random positional variation among the skull, mandible, and cervical spine with treatment progression during head-and-neck radiotherapy
.
Int J Radiat Oncol Biol Phys
.
2009
;
73
:
626
33
.
13
Ahn
PH
,
Chen
CC
,
Ahn
AI
,
Hong
L
,
Scripes
PG
,
Shen
J
,
Lee
CC
,
Miller
E
,
Kalnicki
S
,
Garg
MK.
Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications
.
Int J Radiat Oncol Biol Phys
.
2011
;
80
:
677
85
.
14
Kraan
AC
,
van de Water
S
,
Teguh
DN
,
Al-Mamgani
A
,
Madden
T
,
Kooy
HM
,
Heijmen
BJ
,
Hoogeman
MS.
Dose uncertainties in IMPT for oropharyngeal cancer in the presence of anatomical, range, and setup errors
.
Int J Radiat Oncol Biol Phys
.
2013
;
87
:
888
96
.
15
Lomax
AJ.
Intensity modulated proton therapy and its sensitivity to treatment uncertainties 2: the potential effects of inter-fraction and inter-field motions
.
Phys Med Biol
.
2008
;
53
:
1043
56
.
16
Lomax
AJ.
Intensity modulated proton therapy and its sensitivity to treatment uncertainties 1: the potential effects of calculational uncertainties
.
Phys Med Biol
.
2008
;
53
:
1027
42
.
17
Chera
BS
,
Malyapa
R
,
Louis
D
,
Mendenhall
WM
,
Li
Z
,
Lanza
DC
,
Yeung
D
,
Mendenhall
NP.
Proton therapy for maxillary sinus carcinoma
.
Am J Clin Oncol
.
2009
;
32
:
296
303
.
18
Cozzi
L
,
Fogliata
A
,
Lomax
A
,
Bolsi
A.
A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours
.
Radiother Oncol
.
2001
;
61
:
287
97
.
19
Kandula
S
,
Zhu
X
,
Garden
AS
,
Gillin
M
,
Rosenthal
DI
,
Ang
KK
,
Mohan
R
,
Amin
MV
,
Garcia
JA
,
Wu
R
,
Sahoo
N
,
Frank
SJ.
Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison
.
Med Dosim
.
2013
;
38
:
390
4
.
20
Liu
SW
,
Li
JM
,
Chang
JY
,
Yu
JM
,
Chen
Q
,
Jiang
QA
,
Mu
XK
,
Zhao
MH
,
Tian
Y
,
Wei
QL.
A treatment planning comparison between proton beam therapy and intensity-modulated x-ray therapy for recurrent nasopharyngeal carcinoma
.
J Xray Sci Technol
.
2010
;
18
:
443
50
.
21
Quan
EM
,
Liu
W
,
Wu
R
,
Li
Y
,
Frank
SJ
,
Zhang
X
,
Zhu
XR
,
Mohan
R.
Preliminary evaluation of multifield and single-field optimization for the treatment planning of spot-scanning proton therapy of head and neck cancer
.
Med Phys
.
2013
;
40
:
081709
.
22
Ramaekers
BL
,
Grutters
JP
,
Pijls-Johannesma
M
,
Lambin
P
,
Joore
MA
,
Langendijk
JA.
Protons in head-and-neck cancer: bridging the gap of evidence
.
Int J Radiat Oncol Biol Phys
.
2013
;
85
:
1282
8
.
23
Simone
CB
II,
Ly
D
,
Dan
TD
,
Ondos
J
,
Ning
H
,
Belard
A
,
O'Connell
J
,
Miller
RW
,
Simone
NL.
Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer
.
Radiother Oncol
.
2011
;
101
:
376
82
.
24
Steneker
M
,
Lomax
A
,
Schneider
U.
Intensity modulated photon and proton therapy for the treatment of head and neck tumors
.
Radiother Oncol
.
2006
;
80
:
263
7
.
25
van de Water
TA
,
Lomax
AJ
,
Bijl
HP
,
de Jong
ME
,
Schilstra
C
,
Hug
EB
,
Langendijk
JA.
Potential benefits of scanned intensity-modulated proton therapy versus advanced photon therapy with regard to sparing of the salivary glands in oropharyngeal cancer
.
Int J Radiat Oncol Biol Phys
.
2011
;
79
:
1216
24
.
26
van der Laan
HP
,
van de Water
TA
,
van Herpt
HE
,
Christianen
ME
,
Bijl
HP
,
Korevaar
EW
,
Rasch
CR
,
van 't Veld AA, van der Schaaf A, Schilstra C, Langendijk JA. The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: a planning comparative study
.
Acta Oncol
.
2013
;
52
:
561
9
.
27
Widesott
L
,
Pierelli
A
,
Fiorino
C
,
Dell'oca
I
,
Broggi
S
,
Cattaneo
GM
,
Di Muzio
N
,
Fazio
F
,
Calandrino
R
,
Schwarz
M.
Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation
.
Int J Radiat Oncol Biol Phys
.
2008
;
72
:
589
96
.
28
Frank
SJ
,
Cox
JD
,
Gillin
M
,
Mohan
R
,
Garden
AS
,
Rosenthal
DI
,
Gunn
GB
,
Weber
RS
,
Kies
MS
,
Lewin
JS
,
Munsell
MF
,
Palmer
MB
,
Sahoo
N
,
Zhang
X
,
Liu
W
,
Zhu
XR.
Multifield optimization intensity modulated proton therapy for head and neck tumors: a translation to practice
.
Int J Radiat Oncol Biol Phys
.
2014
;
89
:
846
53
.