Purpose

To investigate the potential impact of anatomic change in the treatment of locally advanced oropharyngeal cancer with proton pencil beam scanning.

Materials and Methods

Ten patients with locally advanced oropharyngeal cancer who previously received intensity-modulated radiation therapy (IMRT) and synchronous chemotherapy underwent replanning by using RapidArc IMRT and proton pencil beam scanning. Deformable image registration deformed the planning computed tomography (CT), target volumes, and organs at risk (OARs) contours onto each weekly cone-beam CT scan. Target and OARs volumes were reviewed and modified. Treatment plans were forward calculated onto each corrected cone-beam CT scan and dose-volume histograms produced for targets and OARs volumes.

Results

Proton pencil beam scanning compared with RapidArc IMRT achieved lower mean doses to the contralateral parotid gland (14.8 Gy versus 20.6 Gy, P < .05) and oral cavity (31.5 Gy versus 43.0 Gy, P < .001). For proton pencil beam scanning, mean delivered doses to several OARs significantly increased from week 3 or 4 of treatment; this was not observed in RapidArc plans. The respective overall increases in mean delivered doses (average weeks 1 to 7, compared with week 1) to the pharyngeal constrictor muscles, larynx, and oral cavity were 1.0 Gy (SD, ± 1.3), 3.3 Gy (SD, ± 3.3), and 1.7 Gy (SD, ± 1.9).

Conclusions

Although proton therapy provided dosimetric advantages on initial planning, it was more sensitive to interfraction anatomic changes, resulting in clinically significant increases in delivered doses to several OARs. We would therefore advocate for clinical implementation of methods to measure, account for, and adapt to these changes during the course of treatment in order to fully realize the potential benefits of proton therapy in this setting.

Locally advanced oropharyngeal cancer may be treated by an organ- and function-preservation approach with intensity-modulated radiation therapy (IMRT) and synchronous chemotherapy [1]. Improvements in local regional control and survival outcomes have focused attention on reducing late treatment effects [2, 3]. The increased incidence of human papilloma virus–associated disease [4, 5], which is associated with younger age at diagnosis and excellent cure rates [6, 7], has made this a pressing objective. The use of advanced technologies and function-sparing IMRT reduces late treatment–related toxicities, but these remain of concern and adversely impact quality of life [8, 9]. An alternative strategy is to use proton therapy, whereby dosimetric data for head and neck cancer demonstrate improved treatment conformity and normal tissue sparing [10, 11]. Preliminary clinical data suggest it is also well tolerated with encouraging outcomes [12].

Proton pencil beam scanning (PBS) uses single-field uniform dose (SFUD) and/or multifield optimization (MFO), also termed intensity-modulated proton therapy [13]. Compared to photons, the nature of the rapid dose falloff with proton therapy causes it to be more sensitive to setup errors or changes in anatomy. The effect of per-treatment changes in aeration of the nasal cavity/sinuses on proton dose distribution was reported in a retrospective study of 20 patients treated for sinonasal disease, using a passive scatter technique [14]. The effect of the proton beam passing through air rather than tumor or fluid resulted in more distal dose deposition and clinically relevant increases in delivered doses to critical structures.

The effect of per-treatment anatomic changes is also of concern for the primary treatment of locally advanced oropharyngeal cancer, where tumor shrinkage is commonly observed [15, 16]. In a planning study of intensity-modulated proton therapy for oropharyngeal cancer, the combined effects of simulated anatomic, range, and setup uncertainties resulted in compromise to target volume coverage, which was improved by adaptive replanning [17]. The implementation of on-line adaptive treatment with correction for setup variations and anatomic changes remains challenging, and for proton therapy there is currently very limited access to cone-beam computed tomography (CBCT) verification imaging.

This study compares proton PBS and rotational arc IMRT (RapidArc) for definitive treatment of locally advanced oropharyngeal cancer.

Patient Selection

This study comprised 10 patients with locally advanced oropharyngeal cancer who previously received definitive IMRT and concurrent cisplatin or cetuximab, with at least weekly kilovoltage CBCT verification imaging and an adequate field of view (extending superiorly from the pterygoid plates and inferiorly through the cricoid cartilage).

Treatment Volumes, Organs at Risk, and Dose Prescription

Planning CT scans were acquired at 2-mm-slice intervals from the vertex of skull to the carina. Target volume contours for the initial CT scans were adjusted to the craniocaudal field of view for the CBCT scans and included gross tumor volume (GTV); clinical target volume 1 (CTV1), GTV without additional margin; CTV2, CTV1 with a 5-mm isotropic margin (edited for natural barriers to disease spread such as bone, air, fascia), involved and ipsilateral nodal levels II-III, VIIb (retrostyloid nodal level); and CTV3, ipsilateral nodal levels Ib, Va, VIIa (retropharyngeal nodal level) and contralateral nodal levels II-III. Nodal level IV was not included, as the CBCT images did not adequately encompass this region. The planning target volumes (PTVs) for RapidArc IMRT and proton PBS were defined by respective isotropic expansions of 3 mm and 5 mm (for proton PBS, the additional margin represents standard departmental policy and accounts for range uncertainty, approximated to 3.5% nominal beam range plus 1 mm), both edited for skin. Defined organs at risk (OARs) dose constraints were as follows: spinal cord, maximum dose (1 cm3) < 45 Gy; contralateral parotid gland, mean dose < 26 Gy; ipsilateral parotid gland, mean dose as low as reasonably achievable; contralateral submandibular gland, mean dose < 39 Gy; oral cavity [18], mean dose < 40 Gy; pharyngeal constrictor muscles [19], mean dose < 50 Gy; and supraglottic and glottic larynx [20], mean dose < 40 Gy. For quality assurance, the target and OARs volumes were reviewed by a second radiation oncologist.

Prescribed doses to PTV1, PTV2, and PTV3 were 70, 63, and 59.5 Gy (cobalt Gray equivalent using a relative biological effectiveness of 1.1 for proton therapy), over 35 respective daily fractions of 2.0, 1.8, and 1.7 Gy, using a simultaneous integrated boost technique.

Treatment Planning, Optimization, and Cone-Beam Computed Tomography Scan Dose Recalculation

The planning objectives (in order of priority) were as follows: (1) dose constraint to spinal cord; (2) PTV coverage; and (3) dose constraints for remaining OARs. Goal PTV coverage was 95% and 99% of each PTV to receive 100% and 93% of the prescription dose, respectively. A proton PBS plan was generated for each patient for purposes of comparison to the treated IMRT plan. For proton plans, SFUD and MFO were used to maximize dose homogeneity and treatment conformity (SFUD/MFO, relative contributions for 6 patients was 80%/20% and for 4 patients, 50%/50%). The ratio of SFUD to MFO used was implemented with priority on using SFUD as much as possible (given less uncertainty with SFUD versus MFO), but incorporating MFO to the extent needed to be able to meet planning constraints, consistent with current clinical practice at our center. The Eclipse treatment planning system v.11.0 (Varian Medical Systems, Palo Alto, California) was used for both modalities.

A 2-field, posterior oblique arrangement was used, so that beam could be delivered through a 7.3-cm water-equivalent high-density table that serves as a range shifter, as required given the spot sizes needed to treat shallow targets associated with the head and neck region, and consistent with the current clinical practice unique to our center. The minimum and maximum energies were 100 MeV and 230 MeV (approximate range, 7.5-32 cm in water), controlled by an upstream energy selection system. The spot size varied with energy and depth; the full-width half maximum for the maximal energy spot measured at the isocenter in air was 8 mm.

To facilitate dose recalculation and target volume delineation on the 7 weekly CBCT scans, SmartAdapt v.11.0 deformable image registration software (Varian Medical Systems), based on the validated “demons” algorithm, was used to deform the planning CT onto each of the CBCTs [21] for CBCT image intensity correction. In this way, the deformed planning CTs contained the geometric features (head positioning, body, soft tissue, and bony anatomy outlines) of CBCTs but with Hounsfield units similar to the planning CT that were calibrated for photon or proton dose calculation, and with image quality equal to planning CT for purposes of target volume delineation on the CBCT. Deformable registration was also used to transfer the target volumes and OARs contours to each of the corrected CBCTs. The target and OARs volumes were then reviewed and where required, modified by a radiation oncologist. CTV1/PTV1 was not adjusted (keeping with standard practice not to reduce the gross tumor volume owing to tumor response); CTV2/PTV2, CTV3/PTV3, and OAR contours were amended to account for anatomic and positional alterations (ie, redefined to conform to anatomic definitions/boundaries) [22]. The GTV was redefined on each corrected CBCT only to allow later correlation of change in volume with variations in dosimetric parameters. To reduce the potential for introduction of bias, the redefined GTVs were independently assessed by a second radiation oncologist. The initial RapidArc IMRT and PBS plans were forward calculated onto each corrected CBCT.

Evaluation Criteria and Statistics

For each treatment plan, dose-volume histograms were produced for targets and OARs. On the initial planning CT, dosimetric comparisons were made between RapidArc IMRT and PBS for mean doses to OARs and PTV coverage: V95%, V99%, V107% (volume receiving 95%, 99%, and 107% of the prescribed dose, respectively); mean dose to PTV; PTV coverage conformity index: PTV covered by 95% isodose divided by PTV volume; and, for normal tissues sparing, the healthy tissues conformity index: PTV covered by 95% isodose divided by volume of 95% isodose [23]; homogeneity index: dose received by 2% of PTV minus dose received by 98% of PTV divided by mean dose to PTV. Mean doses to OARs were compared by using 2-tailed paired Student t test.

PTV1 and PTV2 coverage (mean V95%, conformity and homogeneity indices) and mean doses to OARs were evaluated on the forward calculated RapidArc IMRT and PBS plans on the corrected CBCTs. For 2 patients, data from 1 CBCT were not evaluable and for purposes of data analysis values imputed from the previous scan. Comparisons from weeks 1 to 7 were made by repeated-measures one-way analysis of variance. Where significant differences were observed, the Dunnett post hoc test was used to compare the means at week 1 with each subsequent time point (weeks 2 to 7). Significant per-treatment weekly changes in dose were investigated by multivariate regression analyses: patient, week of treatment (time), change in GTV volume, and change in weight were independent variables. Analyses were performed by using GraphPad Prism 6 (GraphPad Software, La Jolla, CA) and R version 3.1.0. Differences were considered statistically significant at P < .05.

Baseline patient, tumor, and treatment factors are shown in Table 1.

Table 1.

Patient, tumor, and treatment factors.

Patient, tumor, and treatment factors.
Patient, tumor, and treatment factors.

Dosimetric Comparison of Intensity-Modulated Radiation Therapy versus Pencil Beam Scanning on Baseline Plans

All baseline plans (IMRT and PBS) met planning objectives with respect to OAR sparing and PTV coverage (Tables 2 and 3). The PBS plan (when compared to IMRT) significantly reduced mean doses to the oral cavity and contralateral parotid gland (Table 2), but with higher doses to centrally located structures such as the spinal cord, larynx, and pharyngeal constrictors (without violation of planning goals/constraints; Table 2).

Table 2.

Mean doses to organs at risk for RapidArc IMRT and proton pencil beam scanning on the planning CT scan.

Mean doses to organs at risk for RapidArc IMRT and proton pencil beam scanning on the planning CT scan.
Mean doses to organs at risk for RapidArc IMRT and proton pencil beam scanning on the planning CT scan.

Per-Treatment Changes in Doses to Organs at Risk and Coverage of Planned Target Volumes for RapidArc Intensity-Modulated Radiation Therapy and Proton Pencil Beam Scanning

There were no statistically significant changes in mean doses to OARs from weeks 1 to 7 with IMRT (Table 4). However, for PBS, statistically significant increases in mean doses to the pharyngeal constrictors, larynx, and oral cavity occurred over time (Table 4), with the greatest increase in doses observed between weeks 3 and 5 (Figure 1). For both modalities, the coverage of PTVs was maintained during treatment (Table 5). There were decreases in the healthy tissues conformity index for normal tissue sparing from weeks 1 to 7 for both IMRT and PBS, suggesting increased volume of normal tissue encompassed by the respective 95% treatment isodose lines.

Table 4.

Mean radiation doses to organs at risk recalculated on cone-beam computed tomography scans from weeks 1 to 7 for (A) RapidArc IMRT and (B) proton pencil beam scanning plans.

Mean radiation doses to organs at risk recalculated on cone-beam computed tomography scans from weeks 1 to 7 for (A) RapidArc IMRT and (B) proton pencil beam scanning plans.
Mean radiation doses to organs at risk recalculated on cone-beam computed tomography scans from weeks 1 to 7 for (A) RapidArc IMRT and (B) proton pencil beam scanning plans.
Figure 1.

Increase in mean radiation dose to organs at risk recalculated on cone-beam computed tomography scans from weeks 1 to 7 for proton pencil beam planning plans. Significance was assessed by the Dunnett test for post hoc analysis of repeated-measures one-way analysis of variance, which compared mean values at week 1 with each subsequent week (2 to 7): *P < .05, **P < .01.

Figure 1.

Increase in mean radiation dose to organs at risk recalculated on cone-beam computed tomography scans from weeks 1 to 7 for proton pencil beam planning plans. Significance was assessed by the Dunnett test for post hoc analysis of repeated-measures one-way analysis of variance, which compared mean values at week 1 with each subsequent week (2 to 7): *P < .05, **P < .01.

Close modal
Table 5.

Dosimetric coverage of PTVs (PTV1, PTV2) on cone-beam computed tomography scans from weeks 1 to 7 for (A) RapidArc IMRT and (B) proton pencil beam scanning plans.

Dosimetric coverage of PTVs (PTV1, PTV2) on cone-beam computed tomography scans from weeks 1 to 7 for (A) RapidArc IMRT and (B) proton pencil beam scanning plans.
Dosimetric coverage of PTVs (PTV1, PTV2) on cone-beam computed tomography scans from weeks 1 to 7 for (A) RapidArc IMRT and (B) proton pencil beam scanning plans.

Correlation of Proton Pencil Beam Scanning Changes in Doses to Organs at Risk with Gross Tumor Volume and Patient Weight

From the initiation to the completion of treatment, GTV volume decreased an average of 75% (34.6 cm3 to 8.8 cm3), and patient body weight decreased by an average of 5.8% (77.7 kg to 73.2 kg).

Multivariate regression analysis confirmed a significant relationship between increase in delivered dose to OARs and week of treatment (time), with neither change in GTV volume nor weight loss providing additional predictive information, despite GTV volume decrease showing significant correlation with increase in dose to OARs on univariate analysis.

With the evolving demographics of head and neck cancer to a larger proportion of patients being diagnosed with HPV-associated cancers, and fewer with tobacco-induced, HPV-negative cancers [4], many patients now will have the expectation of excellent, long-term disease outcomes [6]. However, even with the most advanced techniques of radiation delivery, many patients will need to live and cope with the long-term effects of their treatment on their daily quality of life [8, 9]. Promising methods to diminish treatment toxicity, such as with proton therapy, are therefore critical in the evolution of the multimodality approach to treating head and neck cancer. Current technologies, such as on-board soft tissue imaging and adaptive replanning, shown to be helpful in maximizing the therapeutic benefit in patients receiving IMRT [16], are not yet commonly available for patients receiving PBS. To our knowledge, this is the first article to report per-treatment weekly changes in proton PBS target coverage and doses to OARs for oropharyngeal cancer, and to highlight the importance and potential clinical implications of integrating adaptive replanning in the treatment of locally advanced oropharynx cancer with pencil beam scanning proton therapy.

Our study shows that PBS is superior to IMRT in sparing several critical structures, such as the parotid gland and oral cavity. Sparing of such structures has the potential to reduce late effects such as xerostomia [19, 24], dysphagia [25], and dysgeusia. The physical characteristics of a proton beam that make such improvements possible, however, also make PBS more susceptible to changes in anatomy, such as that seen from a bulky head and neck cancer that responds briskly during the course of therapy. We found that not performing PBS adaptation for a responding tumor, while not compromising target coverage, does lead to significant increases in doses delivered to several critical OARs. While we found that increases in mean doses over the course of treatment were on average only several units of Gray, there were individual patients for whom non-adaptation of the RT plan in response to anatomic changes from disease response and/or weight loss led to very large increases in OAR dose to structures such as the oral cavity (Figure 2) and larynx (Figure 3). For patients such as these, failure to perform adaptive planning could possibly subject them to a significantly higher risk of treatment-related morbidity, both short and long term.

Figure 2.

Oropharyngeal base of tongue squamous cell carcinoma T4aN2c. Top row: pencil beam scanning plan, with mean oral cavity dose increasing from 28 to 35 Gy from baseline to week 4. Bottom row: IMRT plan, with mean oral cavity dose remaining at 43 Gy from baseline to week 4. Abbreviations: CBCT, cone-beam computed tomography; CT, computed tomography; IMRT, intensity-modulated radiation therapy.

Figure 2.

Oropharyngeal base of tongue squamous cell carcinoma T4aN2c. Top row: pencil beam scanning plan, with mean oral cavity dose increasing from 28 to 35 Gy from baseline to week 4. Bottom row: IMRT plan, with mean oral cavity dose remaining at 43 Gy from baseline to week 4. Abbreviations: CBCT, cone-beam computed tomography; CT, computed tomography; IMRT, intensity-modulated radiation therapy.

Close modal
Figure 3.

Oropharyngeal base of tongue squamous cell carcinoma T4aN2c. Top row: pencil beam scanning plan, with mean larynx (yellow) dose increasing from 35 to 47 Gy from baseline to week 4. Bottom row: IMRT plan, with mean larynx dose increasing from 27 to 31 Gy from baseline to week 4. Abbreviations: CBCT, cone-beam computed tomography; CT, computed tomography; IMRT, intensity-modulated radiation therapy.

Figure 3.

Oropharyngeal base of tongue squamous cell carcinoma T4aN2c. Top row: pencil beam scanning plan, with mean larynx (yellow) dose increasing from 35 to 47 Gy from baseline to week 4. Bottom row: IMRT plan, with mean larynx dose increasing from 27 to 31 Gy from baseline to week 4. Abbreviations: CBCT, cone-beam computed tomography; CT, computed tomography; IMRT, intensity-modulated radiation therapy.

Close modal

There are several limitations to our study that warrant mention. First, ours was a dosimetric-based study of 10 patients and does not report clinical patient outcomes. Although all patients had similar tumors (large, bulky, unresectable squamous cell carcinoma of the oropharynx), and were treated in a similar fashion (concurrent chemoradiation), it is possible that our findings may not be applicable to other types of head and neck cancers (of different histology or location). We chose the 2-field, posterior oblique approach (used clinically for PBS treatment of patients with head and neck cancer at our institution) based on its ability to cover targets unique to oropharynx cancer and sparing structures such as the salivary glands and especially anterior structures such as the oral cavity; however, we acknowledge that other approaches that are in clinical use [12], which use a greater number of total beams with some entering anteriorly, may be less susceptible to changes in anatomy and may yield results different from ours. Finally, the question of optimal timing for treatment adaptation and plan robustness is outside the scope of our 10-patient study. These issues are addressed through clinical implementation of adaptive techniques (such as proton-based cone-beam CT, real-time plan reevaluation, and adaptive replanning) and are the subject of current work at our institutions.

In summary, we find that for PBS-based treatment of bulky, oropharyngeal squamous cell carcinoma, treatment adaptation in response to anatomic changes from disease response is required to fully realize the potential benefits of PBS proton therapy for head and neck cancers. We believe that this is most relevant for patients with large, baseline tumors, located close to or abutting critical OARs, for which clinical response during the course of treatment is brisk and early, and without adaptation, would lead to unintended increase in doses to OARs, with an expected resultant increase in risk of toxicity. We therefore advocate for the continued development and clinical implementation of methods to reliably and efficiently image for anatomic changes (such as with on-board CBCT) and assess the potential consequences of such changes (real-time dose calculation), and of methods to perform adaptive replanning in response to these changes. This is the subject of current and future work at our institutions, and we expect that through these efforts, the questions regarding the important issues of plan robustness and optimal timing will be answered. It is only through this, and reporting on patient outcomes, that the full potential of PBS for treatment of head and neck cancer will be realized.

Table 3.

Dosimetric data and coverage of planning target volumes (A) PTV1, (B) PTV2, and (C) PTV3, for RapidArc IMRT and proton pencil beam scanning on the planning computed tomography scan.

Dosimetric data and coverage of planning target volumes (A) PTV1, (B) PTV2, and (C) PTV3, for RapidArc IMRT and proton pencil beam scanning on the planning computed tomography scan.
Dosimetric data and coverage of planning target volumes (A) PTV1, (B) PTV2, and (C) PTV3, for RapidArc IMRT and proton pencil beam scanning on the planning computed tomography scan.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflicts of interest: The authors have no conflicts to disclose.

Acknowledgments: David Thomson was supported by The Bernstein Family Bursary in Research. This work was presented at PTCOG-NA 2014, Houston, Texas, October 2014; and NCRI Cancer Conference, Liverpool, United Kingdom, November 2014.

1
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 1
.
2014
.
www.nccn.org. Accessed June 20, 2014
.
2
Beadle
BM
,
Liao
KP
,
Elting
LS
,
Buchholz
TA
,
Ang
KK
,
Garden
AS
,
Guadagnolo
BA.
Improved survival using intensity-modulated radiation therapy in head and neck cancers: a SEER-Medicare analysis
.
Cancer
.
2014
;
120
:
702
10
.
3
Garden
AS
,
Kies
MS
,
Morrison
WH
,
Weber
RS
,
Frank
SJ
,
Glisson
BS
,
Gunn
GB
,
Beadle
BM
,
Ang
KK
,
Rosenthal
DI
,
Sturgis
EM.
Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century
.
Radiat Oncol
.
2013
;
8
:
21
.
4
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
.
5
Habbous
S
,
Chu
KP
,
Qiu
X
,
La Delfa
A
,
Harland
LT
,
Fadhel
E
,
Hui
A
,
Perez-Ordonez
B
,
Weinreb
I
,
Liu
FF
,
Waldron
J
,
O'Sullivan
B
,
Goldstein
D
,
Xu
W
,
Huang
SH
,
Liu
G.
The changing incidence of human papillomavirus-associated oropharyngeal cancer using multiple imputation from 2000 to 2010 at a Comprehensive Cancer Centre
.
Cancer Epidemiol
.
2013
;
37
:
820
9
.
6
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
.
7
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
.
8
Hunter
KU
,
Schipper
M
,
Feng
FY
,
Lyden
T
,
Haxer
M
,
Murdoch-Kinch
CA
,
Cornwall
B
,
Lee
CS
,
Chepeha
DB
,
Eisbruch
A.
Toxicities affecting quality of life after chemo-IMRT of oropharyngeal cancer: prospective study of patient-reported, observer-rated, and objective outcomes
.
Int J Radiat Oncol Biol Phys
.
2013
;
85
:
935
40
.
9
Langendijk
JA
,
Doornaert
P
,
Verdonck-de Leeuw
IM
,
Leemans
CR
,
Aaronson
NK
,
Slotman
BJ.
Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy
.
J Clin Oncol
.
2008
;
26
:
3770
6
.
10
Chan
AW
,
Liebsch
NJ.
Proton radiation therapy for head and neck cancer
.
J Surg Oncol
.
2008
;
97
:
697
700
.
11
Lin
A MS
,
Millar
L
,
Kirk
M
,
Yeager
C
,
Kassaee
A
,
Teo
K
,
Hahn
S.
Proton therapy for head and neck cancer: current applications and future directions
.
Transl Cancer Res
.
2012
;
1
:
255
63
.
12
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
.
13
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
.
14
Fukumitsu
N
,
Ishikawa
H
,
Ohnishi
K
,
Terunuma
T
,
Mizumoto
M
,
Numajiri
H
,
Aihara
T
,
Okumura
T
,
Tsuboi
K
,
Sakae
T
,
Sakurai
H.
Dose distribution resulting from changes in aeration of nasal cavity or paranasal sinus cancer in the proton therapy
.
Radiother Oncol
.
2014
;
113
:
72
6
.
15
Chen
AM
,
Li
J
,
Beckett
LA
,
Zhara
T
,
Farwell
G
,
Lau
DH
,
Gandour-Edwards
R
,
Vaughan
AT
,
Purdy
JA.
Differential response rates to irradiation among patients with human papillomavirus positive and negative oropharyngeal cancer
.
Laryngoscope
.
2013
;
123
:
152
7
.
16
Lee
H
,
Ahn
YC
,
Oh
D
,
Nam
H
,
Kim
YI
,
Park
SY.
Tumor volume reduction rate measured during adaptive definitive radiation therapy as a potential prognosticator of locoregional control in patients with oropharyngeal cancer
.
Head Neck
.
2014
;
36
:
499
504
.
17
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
.
18
Hoebers
F
,
Yu
E
,
Eisbruch
A
,
Thorstad
W
,
O'Sullivan
B
,
Dawson
LA
,
Hope
A.
A pragmatic contouring guideline for salivary gland structures in head and neck radiation oncology: the MOIST target
.
Am J Clin Oncol
.
2013
;
36
:
70
6
.
19
Deasy
JO
,
Moiseenko
V
,
Marks
L
,
Chao
KS
,
Nam
J
,
Eisbruch
A.
Radiotherapy dose-volume effects on salivary gland function
.
Int J Radiat Oncol Biol Phys
.
2010
;
76
:
S58
63
.
20
Christianen
ME
,
Langendijk
JA
,
Westerlaan
HE
,
van de Water
TA
,
Bijl
HP.
Delineation of organs at risk involved in swallowing for radiotherapy treatment planning
.
Radiother Oncol
.
2011
;
101
:
394
402
.
21
Wang
H
,
Dong
L
,
O'Daniel
J
,
Mohan
R
,
Garden
AS
,
Ang
KK
,
Kuban
DA
,
Bonnen
M
,
Chang
JY
,
Cheung
R.
Validation of an accelerated ‘demons' algorithm for deformable image registration in radiation therapy
.
Phys Med Biol
.
2005
;
50
:
2887
905
.
22
Gregoire
V
,
Jeraj
R
,
Lee
JA
,
O'Sullivan
B.
Radiotherapy for head and neck tumours in 2012 and beyond: conformal, tailored, and adaptive?
Lancet Oncol
.
2012
;
13
:
e292
300
.
23
Feuvret
L
,
Noel
G
,
Mazeron
JJ
,
Bey
P.
Conformity index: a review
.
Int J Radiat Oncol Biol Phys
.
2006
;
64
:
333
42
.
24
Little
M
,
Schipper
M
,
Feng
FY
,
Vineberg
K
,
Cornwall
C
,
Murdoch-Kinch
CA
,
Eisbruch
A.
Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond sparing the parotid glands
.
Int J Radiat Oncol Biol Phys
.
2012
;
83
:
1007
14
.
25
Kumar
R
,
Madanikia
S
,
Starmer
H
,
Yang
W
,
Murano
E
,
Alcorn
S
,
McNutt
T
,
Le
Y
,
Quon
H.
Radiation dose to the floor of mouth muscles predicts swallowing complications following chemoradiation in oropharyngeal squamous cell carcinoma
.
Oral Oncol
.
2014
;
50
:
65
70
.