Proton Therapy for Head and Neck Cancers

Pierre Blanchard, MD, PhD,*,† Gary Brandon Gunn, MD,* Alexander Lin, MD,‡
Robert L. Foote, MD,§ Nancy Y. Lee, MD,¶ and Steven J. Frank, MD*

Because of its sharp lateral penumbra and steep distal fall-off, proton therapy offers dosimetric
advantages over photon therapy. In head and neck cancer, proton therapy has been used for
decades in the treatment of skull-base tumors. In recent years the use of proton therapy has
been extended to numerous other disease sites, including nasopharynx, oropharynx, nasal
cavity and paranasal sinuses, periorbital tumors, skin, and salivary gland, or to reirradiation.
The aim of this review is to present the physical properties and dosimetric benefit of proton
therapy over advanced photon therapy; to summarize the clinical benefit described for each
disease site; and to discuss issues of patient selection and cost-effectiveness.
Semin Radiat Oncol 28:53-63 C 2017 Published by Elsevier Inc.

KEYWORDS Intensity-modulated proton therapy, Intensity-modulated radiotherapy, Head and

neck cancer, Radiation therapy

Introduction the improvements in physical delivery of photon therapy have

Radiotherapy for head and neck cancer can be delivered as a
definitive treatment or as an adjuvant treatment after surgery.1
The vast majority of treatments are currently given as external
beam photon therapy. Over the past 20 years, the use of
intensity-modulated photon therapy (IMRT), and more
recently volumetric modulated arc therapy, has allowed
considerable improvement in treatment conformality and
reduction of high doses to neighboring critical structures.
Consequently, this has drastically reduced the incidence of
major forms of toxicity, most notably xerostomia2,3; however,
*
Department of Radiation Oncology, The University of Texas MD Anderson
Cancer Center, Houston, TX.
†
Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France.
‡ clinical experience to date in adult patients, and the best way to
Department of Radiation Oncology, University of Pennsylvania, Philadelphia,
PA.
§
Departments of Radiation Oncology, Mayo Clinic, Rochester, MN.
¶
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center,
New York, NY.
Grant or financial support: Supported in part by the National Institutes of
Health (NIH), United States, by Cancer Center Support (Core) Grant
CA016672 and U19 CA021239 to The University of Texas MD Anderson
Cancer Center.
Conflict of interest: none.
Address reprint requests to Steven J. Frank, MD, Department of Radiation
Oncology, The University of Texas MD Anderson Cancer Center,
1515 Holcombe Boulevard, Unit 853, Houston, TX 77030.
E-mail: sjfrank@mdanderson.org (S.J. Frank)
reached a plateau and come at the cost of alternative toxic
effects such as fatigue, nausea, hair loss, and oral mucositis,2,4
and further improvements in the therapeutic ratio require
alternative methods of radiation delivery.
In this context, proton therapy has emerged as a novel
means to reduce toxicity and potentially further improve
tumor control. The unique physical properties of charged
particles allow a steep dose gradient with a reduced integral
dose delivered to the patient in a proportion that can mean-
ingfully reduce dose-related toxicity. The aims of this review
are to present the current evidence on the use of proton
therapy for the treatment of head and neck cancers. After
discussing the physical properties of protons and the dosi-
metric advantages of proton therapy over IMRT, we will review
the potential clinical implications of this dosimetric benefit, the
further collect evidence while selecting patients for the most
appropriate form of radiation therapy.
References Search
Although this report is not a formal systematic review in that it
does not rely on multiple databases and a broad search
strategy, we conducted a Pubmed search in the process of
writing this review by using the following search equation:
((“proton therapy” OR “protontherapy” OR “proton beam

http://dx.doi.org/10.1016/j.semradonc.2017.08.004 53
1053-4296/& 2017 Published by Elsevier Inc.
54
therapy” OR “particle therapy” OR “hadrontherapy” OR
“hadron therapy” OR “proton radiation” OR “proton beam
radiation”) AND (head and neck cancer)). The final search was
performed on March 22, 2017 by 1 author (P.B.) and
produced 466 references.39 Articles reporting on clinical
results were included in the present review. Fourteen refer-
ences evaluated cost-effectiveness and treatment selection
issues. Select articles from the 373 excluded references, mostly
dosimetric or physics analyses, are used for illustrative
purposes. A diagram of this literature search can be found in
Supplementary Appendix.
Physical Properties and
Dosimetric Results
A focused beam of protons is accelerated by a particle
accelerator that can be used for therapeutic purposes. The
main characteristics of protons that explain their dosimetric
superiority over photons are (1) the absence of exit dose
beyond the target and (2) the sharper lateral dose distribution
secondary to protons' heavier mass relative to photons. The
Bragg peak phenomenon is the sharp increase in dose
deposited at the end of the particle range, and results from
the charged nature of protons (Fig. 1). Proton treatments can
be delivered by using passive scattering or active scanning
techniques. In the passive scattering technique, the proton
beam is spread out by using scattering foils and conformed
laterally by using brass apertures, similar to what would be
done in 3D photon therapy. The depth modulation is done
with range compensators, similar to photon therapy before the
use of multileaf collimators. This technique is less flexible than
active scanning, requires the production of patient-specific
devices that are labor-intensive to create, generates secondary
neutrons, and limits the capacity for adaptive replanning in
case of tumor or anatomical changes during treatment. Active
scanning, also known as intensity-modulated proton therapy
(IMPT), on the other hand, relies on the magnetic properties of
protons. A small proton beam is generated, the energy is varied
entrance target exit
Photon beam (3DCRT, IMRT)
100
Dose / %
Spread-out Proton beam
Single Proton beam
Depth / cm
Figure 1 Dose-depth curve of photons and protons. The dashed red
zone represents the unnecessary dose delivered by photons that can be
“avoided” using protons. 3DCRT: 3-dimensional conformal radiation
therapy; IMRT: intensity-modulated radiation therapy. (Color version
of the figure available online.)
P. Blanchard et al.
to treat the different layers of the tumor, and magnets are used
to deflect and conform the beam to the target volume. IMPT is
currently the most widely used form of proton therapy and all
newly constructed facilities have IMPT capabilities.
Treatment planning for head and neck cancers is done by
using a multifield optimization algorithm that allows optimi-
zation of all spots from all fields simultaneously.5 The draw-
back of protons' dosimetric superiority is their sensitivity to
physical and geometrical uncertainties,6,7 which needs to be
accounted for before and during treatment. At the planning
phase, the robustness of the optimization with regard to
changes in patient setup, changes in anatomy due to tumor
response or changes in weight, and changes in beam range and
patient movement during treatment should be assessed before
the plan is approved.8 Quality checks at the MD Anderson
Proton Therapy Center include complete quality assurance
testing of each plan before delivery, verification of the accuracy
of the dosimetry on a second planning computed tomography
(CT) scan obtained the day before the treatment is started and
on a third scan obtained during the fourth week of treat-
ment.9,10 For tumors at specific locations such as the paranasal
sinuses, doses to organs at risk approaching the tolerance limit,
or for other anatomy changes such as weight loss, additional
verification CTs can be obtained. In addition, at Mayo Clinic,
Monte Carlo dose calculations are performed as a second check
of the treatment planning system dose calculations and for
robust optimization. Verification CT scans are obtained weekly
for at least the first 5 weeks. Daily CT imaging with the patient
on the treatment couch in the treatment position will soon be
implemented. In a prospective analysis of 50 patients with
oropharyngeal cancer (OPC) treated at MD Anderson Cancer
Center, adaptive replanning during IMPT because of weight
loss or tumor volume changes was done for 38% of the
patients, including 1 patient who required adaptive replanning
twice.11 In the first 50 patients treated at Mayo Clinic,
replanning was done for 36% of cases (Dr Foote, personal
communication). The final source of uncertainty is related to
the relative biological effectiveness (RBE) of protons, which is
the factor used to quantify the difference in the effective dose
from protons compared with an equivalent biological dose of
photons. The current practice is to use a uniform RBE value of
1.1, but recent reports suggest that RBE is variable,12 and might
be higher close to the Bragg peak. Although uniform consensus
on the variability of the RBE has not been reached, treatment
planning systems can be developed to maximize the high-RBE
values within tumors, and to avoid organs at risk. At Mayo
Clinic, Monte Carlo dose calculations are used to produce
treatment plans based on physical dose, linear energy transfer,
and variable RBE (used qualitatively, not quantitatively, and to
account for the uncertainties in RBE).
The dosimetric advantage of protons over photons for the
treatment of sinonasal, nasopharyngeal, or oropharyngeal
cancer was suggested as early as 1989.13-15 Scans showing
comparative dosimetry for 2 patients, one with a nasophar-
yngeal carcinoma and the other with a maxillary adenoid cystic
carcinoma, are given in Figure 2. In both cases the use of
protons can spare organs from up to 25 Gy of unnecessary
radiation compared with standard IMRT. Many articles have
Proton therapy for head and neck cancers
A B
Figure 2 Comparative treatment plans using IMRT, IMPT, and subtraction plan (IMRT-IMPT). (A) A 56-year woman with
T1N1 left sided nasopharyngeal carcinoma (4 nodes in left levels IIa, IIb, III, and Va). (B) A 47-year woman with T4N0
adenoid cystic carcinoma of the hard palate (surgery followed by adjuvant radiotherapy).
compared proton dosimetry successively with 3D conformal
radiotherapy, IMRT, and then volumetric modulated arc
therapy dosimetry. Recent publications have confirmed the
reduction in dose to nontarget structures associated with
proton therapy for uni- or bilateral treatment of OPC, in the
postoperative setting, or for reirradiation when compared with
IMRT.16-19 In one dosimetric study, treatment plans for 25
patients with OPC treated with IMPT were compared with
IMRT plans for the same patients or for other patients treated
with IMRT and demonstrated that the doses to the anterior oral
cavity, the posterior oral cavity, the middle and inferior
pharyngeal constrictors, the esophagus, other swallowing
structures such as the genioglossus or mylohioid muscles,20
the brainstem, cerebellum, and central nervous system struc-
tures involved in the nausea and vomiting response were all
significantly lower in the proton therapy plans.17
Clinical Implications of
Dosimetric Advantage—Patient
Selection for Proton Therapy
Radiation therapy to the head and neck has several
potentially serious acute and late adverse effects. In the
acute phase, patients can experience severe mucositis,
pain, fatigue, thickened secretions, altered taste, dehydra-
tion, weight loss, nausea, vomiting, or dermatitis. Numer-
ous acute and late toxic effects have been shown to be dose
and volume related, with the probability and severity of
toxicity or dysfunction directly correlated with higher
55
IMPT plan
IMRT plan
Dose Subtraction (dose avoided using IMPT)
doses and larger volumes. These findings have allowed the
development of models to predict the risk of toxicity in a
given patient based on clinical and dosimetric character-
istics. Such normal tissue complication probability
(NTCP) models have been developed for xerostomia,21-
24
dysphagia or feeding tube dependence,20,25,26 hypo-
thyroidism,27 laryngeal edema,28 nausea,29 and acute
mucositis,30 among others.31 These models all have
limitations, and few have been externally validated, but
they are improving and are likely to be used more often in
clinical practice in the coming years. In theory, these
models could predict the risk and severity of toxicity
based on the planned dosimetry with either proton or
photons. The potential for toxicity reduction using proton
therapy has already been investigated using these
models.32,33
Some have advocated that treatment allocation or patient
selection for proton therapy should be defined based on an
expected reduction of toxicity as predicted by NTCP mod-
els.34,35 This strategy, known as the model-based approach,
can improve the cost-effectiveness of proton therapy by
enriching proton cohorts with patients who stand to gain the
most in terms of avoiding toxicity, and hence the downstream
total cost of managing that toxicity.36,37 The major limitation in
this strategy, however, is to demonstrate that these NTCP
models, which were all developed with cohorts of patients
treated with photons, sometimes using outdated techniques,
are valid in patients treated with protons. To this end, a recent
test of 5 of these models in a proton cohort showed that for
four, the models retained some discriminatory properties and
were potentially clinically useful for toxicity prediction,38
56
although these models still need to be refined and improved.
The model-based approach should also aim to include patient-
reported outcomes and other outcomes to better represent the
experience of patients undergoing treatment. A measure of
total toxicity burden has been proposed for patients with
esophageal cancer that could appropriately summarize patient
burden and adequately measure the benefits of proton over
photon therapy.39
Current Clinical Experience With
Proton Therapy for Head and
Neck Cancers
Skull-Base Chordomas and Chondrosarcomas
These tumors were historically the first ones to be treated with
proton therapy, owing to their proximity to the brainstem and
optic tract and the need for high radiation doses that cannot be
delivered safely with photon therapy, for which 5-year survival
rates were historically about 25%.40,41 Although gross total
resection is a major prognostic factor in chordomas and
chondrosarcomas, it is often not achieved because of the
location and extent of the tumor. The largest series of patients
with chordoma or chondrosarcoma treated with proton
therapy to date involved 519 patients who had received doses
of 66-83 Gy(RBE) through a combination of photons and
protons at Massachusetts General Hospital.42 The 5-year local
relapse-free survival rates after this treatment were 73% for
chordoma and 98% for chondrosarcoma, and the correspond-
ing 5-year overall survival rates were 80% and 91%. Toxicity
was not insignificant in this study, however, as 3 patients died
of brainstem toxicity and another 8 had temporal lobe injury,
hearing loss, cranial neuropathy, or endocrinopathy.42 These
excellent results of proton therapy in terms of local control
have since been confirmed in other series.43-45 In the most
recently reported study, the 5- and 10-year cumulative
incidence rates of grade 3-5 toxicity were 10% and 10%44
and involved severe unilateral hearing loss (n ¼ 8), drug-
resistant epilepsy due to temporal lobe necrosis (n ¼ 1), fatal
radionecrosis after stereotactic hypofractionated raditherapy
for recurrent disease (n ¼ 1), and suspected brainstem glioma
(n ¼ 1). Other reports have confirmed these outcomes.46-48
Sinonasal Tumors
The standard treatment for nasal and paranasal tumors is
surgical resection followed by adjuvant radiation, with or
without chemotherapy. Gross tumor resection is more com-
mon than for skull-base tumors, but advanced tumors often
show involved or close microscopic resection margins. Several
studies have evaluated proton therapy for sinonasal malignan-
cies; the most recent are summarized in Table 1 whereas older
ones are included in a meta-analysis by Patel and colleagues.49
The largest study so far, not included in the Patel meta-
analysis,49 was published in 2008 by the Massachusetts
General Hospital team.50 It included 102 patients with tumors
of various histologic type, treated between 1991 and 2002 with
P. Blanchard et al.
surgery (when operable) followed by an adjuvant combination
of photon and proton therapy. After a median follow-up time
of 5.1 years for surviving patients, univariate analysis showed a
5-year actuarial local control rate of 95% for those who had
complete resection, 82% for partial resection, and 87% and for
biopsy only (P ¼ 0.32). The most common pattern of
treatment failure was distant metastases, occurring in 30% of
patients at 5 years. The extent of surgical resection was
associated with the risk of overall survival (P ¼ 0.02),
disease-free survival (P ¼ 0.009), and distant relapse (P ¼
0.03). The studies reported in Table 1 include a large number
of patients with high survival rates relative to historical photon
series. Only one study included a photon control group, and
that study showed that more feeding tubes and morphine were
used in the IMRT group, although the IMRT group included
many patients with nasopharyngeal cancer, for whom neck
treatment is more extensive neck than for pure sinonasal
malignancies.51 One notable finding in the studies reported in
Table 1 is the high local control and survival rates for patients
with nonoperated mucosal melanoma treated with proton
therapy52-54; however, toxicity remains significant, with rates
of grade 43 toxicity in the 20% range; but these are still within
an acceptable range when compared with photon data.
The Patel meta-analysis summarized this mostly retrospec-
tive, noncomparative evidence and tried to provide compara-
tive effectiveness data between charged-particle and photon
therapy.49 Several histologic types of tumors were included.
The median follow-up interval was about 40 months for both
groups. Pooled overall survival was higher at 5 years for those
given charged-particle versus photon therapy (relative risk ¼
1·51, 95% CI: 1.14-1·99; P ¼ 0·0038) and at longest follow-up
(1·27, 1·01-1·59; P ¼ 0·037), as well as disease-free survival at
5 years (1·93, 1·36-2·75, P ¼ 0·0003). Locoregional control
rates did not differ at 5 years (relative risk ¼ 1.06, P ¼ 0.79)
but were higher for the charged-particle therapy group at the
longest follow-up (relative risk ¼ 1.18, P ¼ 0.031). The studies
included in this meta-analysis are limited, as their results may
have been confounded by selection and publication bias, as
well as the retrospective and noncomparative nature of the
included studies; however, given the number of patients
included in these analyses and the consistent outcomes
reported, it seems reasonable to state that charged-particle
therapy should be considered a valid option for patients with
malignancies of the nasal cavity and paranasal sinuses.
Pharyngeal Tumors
The first study reporting the use of proton therapy for
pharyngeal cancers was published in 2005 by Slater and
colleagues. It included 29 patients with stage II-IV OPC with a
combination of 3D conformal photon (to 50.4 Gy) and
passively scattered proton therapy (an additional 25.5 Gy)
using a concomitant boost technique from 1991-2002.55 At a
median follow-up time of 28 months, the authors described
encouraging rates of locoregional control and disease-free
survival of 88.0% and 65% at 5 years. The 2-year actuarial
incidence of grade 3 or higher toxicity was 16%. More recent
reports of patients with oropharyngeal, nasopharyngeal and
 Proton therapy for head and neck cancers
Table 1 Studies Evaluating Proton Therapy for Sinonasal Malignancies
References Type Accrual Pts (n) Technique Comp CCT, S, Histology Follow- Outcomes Late toxicity
photon, % % up
(median)
Resto et al50 Retro 1991-2002 102 PSPT No 4 100 Various 61 mo 5-y; LC 95%, 82%, and 87%, Not reported.
OS 90%, 53%, and 49% for
complete resection, partial
resection, and biopsy only

Nakamura Retro 1999-2012 42 PSPT No 26 0 ENB 69 mo 5-y; OS/PFS: 100/80% for 6 pts with G3-4 (ipsilateral visual
et al75 Kadish A, 86/65% for impairment, 3; bilateral visual
Kadish B, 76/39% for impairment, 1; liquorrhea, 1; cataract, 1).
Kadish C

Russo et al76 Retro 1991-2008 54 PSPT No 39 69 SCC 82 mo 5-y; LRC 73%, OS, 47%, 9 pts with G3 and 6 with G4. Mostly wound
site issues (eg, fistulas). No G5.

Dagan et al77 Retro 2007-2013 84 PSPT No 75 74 Various 32 mo 3-y; LC 83%, NC 94%, G3-5: overall 24%. CNS necrosis: G2 in
freedom from DM 73.2%, 11%, G3 in 4% and G5 in 1 pt. G3-4 bone
OS 68% or soft tissue necrosis in 7 pts. 3 pts died
of Tx-related complications (G5).

Nakamura Pro 2009-2011 26 PSPT No 100 0 Various ND 3-y; OS 58% G4: 2 pts (osteonecrosis, retinopathy); G3:
et al78 4 pts (cataract: 2, mucositis/dermatitis: 2).

McDonald Retro 2010-2014 14 þ 26 PSPT Yes 75 ND Various ND ND More feeding tubes and more morphine
et al51 used in IMRT group (but more NPC in
IMRT group and more paranasal in proton
group).

Zenda et al54 Pro 2008-2012 32 PSPT No 0 0 Mel 36 mo 1-y; LC 76%3-year; OS 46%, No late G3þ toxicity reported.
PFS 36%

Zenda et al79 Retro 1999-2008 90 PSPT No 12 18 Various 57 mo 5-y; OS 64%, PFS 44% Late toxicity G3 in 17 pts (19%), G4 in 6 pts
(7%; encephalomyelitis infection 2, optic
nerve disorder 4).

Linton et al80 Retro 2004-2012 26 PSPT No 0 77 ACC 25 mo 2-y; LC 95%, OS 93% (not Late toxicity G3 in 2 pts, G4 in 1, and G5 in
previously irradiated) 1 (after reirradation).

Takagi et al81 Retro 2002-2012 40 PSPT No 0 0 ACC 38 mo 5-y; OS 63%, PFS 30%, LC 36 G3þ events in 21 pts (26%). Gþ in
76% 24 pts, mostly osteonecrosis, G4 in 9 pts
(mostly vision loss) and G5 in 3 (NP
ulcers). Not separated according to

57
proton or carbon ion therapy.
58 P. Blanchard et al.

(relative risk 1.51, 95% CI: 1.14-1.99; P ¼ 0·0038) and at longest follow-

ACC, adenoid cystic carcinoma; CCT, concomitant chemotherapy; Comp, comparison; DFS, disease-free survival; DM, distant metastases; ENB, esthesioneuroblastoma; G, grade; LC, local control; LRC,
locoregional control; Mel, melanoma; NPC, nasopharyngeal carcinoma; OC, oral cancer; PFS, progression-free survival; Pro, prospective study; PSPT, passive scattered proton therapy; pts, patients;
G3-4 in 3 pts: 2 G3 (cataract, oral mucositis

up (1.27, 1.01-1.59; P ¼ 0.037), as well as DFS at 5 y (1·93, 1.36-2.75, P ¼

No G3. G4 in 1 pt (optic neuropathy). No
oral cavity cancer are shown in Table 2. Most of these reports

and pain); 2 G4 (optic neuropathy and

are of prospective studies. A recent case-matched analysis of 50

Pooled OS higher at 5 y for charged particle than for photon therapy

patients with OPC treated with IMPT and matched with 100
contemporary controls treated with IMRT was reported with a
median follow-up of 32 months.56 Overall survival and
progression-free survival were not different between the
2 groups, but IMRT patients had more grade 3 weight loss
(20% or more compared with baseline) or gastrostomy tubes at
3 months (age-adjusted odds ratios [aOR] for the IMPT group:
Late toxicity

retinopathy). 0.44, P ¼ 0.05) and 1 year after treatment (aOR ¼ 0.23, P ¼

0.01).56 An analysis of the pattern of failures in the IMPT group
did not show any marginal failures that would have suggested
G5.

geographic target misses.11 An analysis of patient-reported

outcomes by Sio et al57 suggested that IMPT could reduce the
symptom burden during the subacute recovery phase after
treatment. Two smaller series of patients with nasopharyngeal
3-y; OS 68%, PFS 60%

cancer reported excellent locoregional control and survival

2-y; LC 71%, OS 44%

rates at 2 years after treatment, and perhaps lower rates of

gastrostomy tube use. Another prospective study from Japan
evaluated the combination of photon or proton therapy with
Histology Follow- Outcomes

intra-arterial chemotherapy for locally advanced tongue cancer

0.0003)

as a definitive treatment for patients who had refused surgical

intervention. Median follow-up was 43 months. Three-year
local control, regional control, progression-free survival, and
(median)

overall survival rates were 86.6%, 83.9%, 74.1%, and 87.0%,

respectively. No grade 3 osteoradionecrosis was observed, but
35 mo

18 mo

38 mo

Retro, retrospective study; RC, regional control; S, surgery; SCC, squamous cell carcinoma; Tx, treatment.

the authors reported dental caries of grade 2 in 10 patients

up

(33%) and of grade 3 in 4 patients (13%).

Various

Reirradiation
Mel

Mel

Reirradiation is an important area of investigation for proton

therapy, given the need to minimize overlap of current and
Pts (n) Technique Comp CCT, S,
%

previous doses to minimize the risk of severe toxicity. Four

series have been published to date, including 2 prospective
photon, %

studies, and are summarized in Table 3. The largest series is a

0

multi-institutional retrospective study that evaluated 92

patients reirradiated passive scatter proton therapy between
286 PSPT þ CIT Yes

2011 and 2014.58 At 1 year after treatment, locoregional failure

No

No

had occurred in 25.1% of the patients, and overall survival rate

was 65.2%. At MD Anderson Cancer Center, among 60
patients, including 45 treated with IMPT, the rates of locore-
20 PSPT

33 PSPT

gional failure-free and overall survival at 1 year were 68.4% and

83.8%.59 Differences between series are likely influenced by
patient selection, rates of salvage surgery, use of concomitant
chemotherapy and case mix between squamous and non-
squamous cancers. From a toxicity standpoint, these reports all
Retro 1975-2013
Retro 2006-2012

Retro 2003-2011

confirm that reirradiation is quite toxic, with a significant risk

References Type Accrual

of treatment-related severe side effects and death. One study

reported lower rates of toxicity, but patients in this report were
a mix of previously irradiated patients and patients with
recurrence after single-modality surgery, and hence probably
Table 1 (continued )

underestimated the side effects of reirradiation.60

Patel et al49
Fuji et al53

analysis

Periorbital Tumors
et al52
Demizu

Meta-

Orbital preservation is a challenge for patients with these rare

tumors. A multidisciplinary orbit-sparing approach has been
 Proton therapy for head and neck cancers
Table 2 Studies Evaluating Proton Therapy for Oral and Pharyngeal Cancers
References Subsite Accrual Type Technique (dose) Comp CCT Patients Follow- Outcomes Toxicity
IMRT (n) up
(median)
Slater et al55 OPC 1991-2002 Retro Cobalt (50.4), boost No No 29 28 mo 5 y; LRC 2-y actuarial incidence of G3þ toxicity 16%
PSPT (25.5 Gy) 88.0%, DFS
65%

Gunn et al,11 OPC 2011-2014 Pro IMPT (70 Gy) Yes Yes 50 30 mo 3 y; LRC Reduced use of gastrostomy tube or severe
Blanchard et al,56 91.0%, OS weight loss at 3 mo and 1 y; less subacute
and Sio et al57 94.3% impairment of quality of life

Chan et al82 NPC 2006-2011 Pro PSPT (70 Gy, upper No Yes 23 28 mo 2 y; LRC 100%, As expected
neck only) OS 100%

Lewis et al83 and NPC 2011–2013 Pro IMPT (70 Gy) Yes Yes 10 24 mo 2 y; LRC 100%, Less gastrostomy tube in IMPT patients
Holliday et al84 OS 88.9% compared to IMRT (P ¼ 0.02)

Takayama et al85 OC 2009-2012 Pro Photon (36 Gy) and No Yes* 33 43 mo 3-y; LC 86.6%, No grade 3þ osteonecrosis
boost PSPT (28.6- RC 83.9 %,
39.6 Gy), no surgery OS 87.0 %
CCT, concomitant chemotherapy; Comp, comparison; IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated (photon) radiation therapy; LC, local control; LRC, locoregional control; NPC,
nasopharyngeal carcinoma; OC, oral cancer; OPC, oropharyngeal carcinoma; OS, overall survival; Pro, prospective study; PSPT, passive scattered proton therapy; Retro, retrospective study; RC, regional
control. Proton doses are Gy(RBE) *Intra-arterial chemotherapy.

59
 60 P. Blanchard et al.

dysphagia. 1 death during treatment (progression) and 2 G5

CCT, concomitant chemotherapy; Comp, comparison; G, grade; IMPT, intensity-modulated proton therapy; LF, local failure; LRF, locoregional failure; LRFFS, locoregional failure-free survival; OS, overall
blindness, 1 soft tissue necrosis); 3 treatment-related deaths
described with the aim of achieving the goals of function

irradiated pts and pts with recurrence after single-modality

1 y; LRF 25.1%, G3þ late toxicity: 6 pts (8.7%) for skin and 4 pts (7.1%) for

2 y; LF 30%, OS, 1 pt with late G4. No G5. Patients were a mix of previously
Acute G3þ toxicity 30%, including 22% feeding tubes; 1-y
(vision), cure, and cosmesis.61,62 Twenty patients were treated
8 G3 (bone and soft tissue necrosis); 3 G4 (2 unilateral according to this protocol with orbit-sparing surgery followed

G3þ toxicity 16.7%; 3 treatment-related deaths (G5)

by proton therapy for newly diagnosed malignant epithelial
tumors of the lacrimal gland (n ¼ 7), lacrimal sac or

surgery, for whom side effects may have been

nasolacrimal duct (n ¼ 10), or eyelid (n ¼ 3). The 2 most
frequent histologic types were adenoid cystic and squamous
cell carcinomas. At a median follow-up time of 27.1 months,
no patient had experienced local recurrence; 1 had regional
recurrence and 1 had developed distant metastases. Major
forms of toxicity were chronic grade 3 epiphora (3 patients)
and grade 3 exposure keratopathy (3 patients). Four patients
(G5) (1 acute and 2 late)

experienced a decrease in visual acuity from baseline. Chronic

grade 3 toxicity was associated with high maximum dose to the

underestimated.
cornea.63 Proton therapy is now added as an option in the

survival; Pro, prospective study; pts, patients; PSPT, passive scattered proton therapy; Retro, retrospective study; SCC, squamous cell carcinoma.
late bleeding

updated 2017 National Comprehensive Cancer Network

guidelines for periorbital tumors.1
Toxicity

Skin and Salivary Gland Tumors

Three reports have addressed proton therapy for salivary
2 y; LF 19.7%,

gland tumors. One study of 9 patients with adenoid cystic

OS, 32.7%,

68.4%, OS,

OS, 65.2%
CCT, Histology Follow-up Outcomes

1 y; LRFFS

carcinoma showed that at 27 months of follow-up the

83.8%

combination of concurrent cisplatin and IMPT could result

46%,

in high rates of locoregional control.64 The second study

assessed the benefit of proton therapy for unilateral radiation
for skin and salivary gland cancers and compared 2 consecutive
(median)

cohorts, one treated initially with IMRT and the other more
13.6 mo

13.3 mo

24 mo
29 mo

recent cohort with PSPT. That study demonstrated a reduction

of grade 2 or greater acute dysgeusia (5.6% vs 65.2%, P o
0.001), mucositis (16.7% vs 52.2%, P ¼ 0.019), and nausea
(11.1% vs 56.5%, P ¼ 0.003) in favor of proton therapy.65 The
SCC (40)

SCC (25)
SCC (32)

SCC (52)
Other

Other

Other

third study was a dosimetric comparison of IMRT and proton

(29)

(20)

(40)

beam therapy for parotid cancers.66 These studies are impor-

Table 3 Studies Evaluating Proton Therapy for Head and Neck Reirradiation

tant to consider, given that the approach of unilateral neck

radiation is now being applied more often for other tumors,
73
47.5 29

39

such as for treatment of well-lateralized oropharynx cancers.

IA
%

58

46
39
Type Pts S,
(n) %

Demonstrating the Value of

60

25
Retro 61

Retro 92

Proton Therapy—Gathering
2011–2015 PSPT (n ¼ 15), Pro

Pro

Prospective Comparative
Evidence
IMPT (n ¼ 45)
Technique

The value of a treatment is defined as the outcomes obtained

divided by the cost, measured over the entire cycle of care.67
2004-2014 PSPT

2011-2014 PSPT

2009-2013 PSPT

The cost of particle therapy has been evaluated in several

studies37,68-73 and was recently summarized in a systematic
review.74 Most of these studies currently convey that the cost of
References Accrual

delivering proton therapy is approximately 2-3 times higher

than for delivering IMRT. However, the cost difference is
reduced when costs are considered over the entire cycle of care.
Indeed, initial cost increments can be partially offset by later
Phan et al59

reductions in use of other resources because of reduced

McDonald

Romesser

Hayashi

toxicity, at least in a subset of patients. If NTCP models are

et al86

et al58

et al60

used to predict treatment-related toxicity, a cost-effective

strategy could be defined in which proton therapy would be
Proton therapy for head and neck cancers
used only for a subpopulation of patients for whom proton
therapy is likely to reduce side effects and subsequent use of
health care resources.37 This hypothesis, along with the
demonstration of toxicity reduction with IMPT versus IMRT,
can be tested in clinical trials. This is actually being done in a
multicenter randomized trial conducted by MD Anderson
Cancer Center for patients with locally advanced OPC
(NCT01893307). The collection of prospective evidence is
essential, either through classic randomized trials or by using
prospective studies or model-based approaches. All of these
approaches should involve the collection of metrics on efficacy,
toxicity, patient-reported outcomes, and cost-effectiveness.
Conclusion—Technical
Evolution—Cooperation
Proton therapy represents the latest technical improvement of
radiation therapy, and has demonstrated clinical efficacy and
the potential for toxicity reduction compared with photon
therapy. Per National Comprehensive Cancer Network guide-
lines, proton therapy is a standard of care for base of skull
tumors and is an option for periorbital tumors. The use of
proton therapy is expanding for other head and neck tumor
sites as well. Novel forms of proton therapy such as IMPT, and
technical improvements in dose modeling, patient setup,
image guidance and radiobiology, will help further enhance
the benefits of proton therapy. Prospective studies are under-
way to quantify the benefits of proton therapy and to better
predict patient response and toxicity with in the framework of
personalized medicine.
Appendix A. Supporting
information
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.semradonc.
2017.08.004.
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