Review History Definitions or - Home | Aetna Medicaid · Number: 0270 Policy ... Retroperitoneal/pelvic sarcoma Rhabdomyoma ... ablation therapy; no ascites; age of 20 years or older;

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Number: 0270

Policy

*Please see amendment for Pennsylvania Medicaid at the

end of this CPB.

I. Aetna considers proton beam radiotherapy (PBRT) medically

necessary in any of the following radiosensitive tumors:

A. Chordomas or chondrosarcomas arising at the base of the

skull or cervical spine without distant metastases; or

B. Malignancies in children (21 years of age and younger); or

C. Uveal melanomas confined to the globe (i.e., not distant

metastases) (the uvea is comprised of the iris, ciliary body,

and choroid [the vascular middle coat of the eye]).

Last Review 03/09/2017

Effective: 07/16/1998

Next Review: 03/08/2018

Review History

Definitions

II. Aetna considers proton beam radiotherapy for treatment of

prostate cancer not medically necessary for individuals with

localized prostate cancer because it has not been proven to be

more effective than other radiotherapy modalities for this

indication. Proton beam therapy for metastatic prostate

cancer is considered experimental and investigational.

Clinical Policy Bulletin Notes

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III. Aetna considers proton beam radiotherapy experimental and

investigational for all other indications, including the following

indications in adults (over age 21) (not an all‐inclusive list)

because its effectiveness for these indications has not been

established:

Adenoid cystic carcinoma Age‐

related macular degeneration

Angiosarcoma

Bladder cancer

Brain tumors

Breast cancer

Cardiac intimal sarcoma

Carotid body tumor

Cavernous hemangioma

Cervical cancer

Cholangiocarcinoma

Choroidal hemangioma

Dermatofibrosarcoma protuberans

Desmoid fibromatosis

Desmoid fibrosarcoma

Desmoid tumor (aggressive fibromatosis)

Ependymoma

Esophageal cancer

Ewing's sarcoma

Fibrosarcoma of the extremities

Gangliomas

Glioma

Head and neck cancer (including nasopharyngeal

carcinoma)

Hemangioendothelioma

Hepatocellular carcinoma

Hodgkin's lymphoma

Intracranial arterio‐venous malformations

Large cell lymphoma

Leiomyosarcoma of the extremities

Liver metastases

Lung cancer (including non‐small‐cell lung carcinoma)

Maxillary sinus tumor

Mesothelioma

Multiple myeloma

Nasopharyngeal tumor

Non‐Hodgkin lymphoma

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Non‐uveal melanoma

Oligodendroglioma Optic

nerve schwannoma

Optic nerve sheath meningioma

Pancreatic cancer

Parotid gland tumor

Pineal tumor

Pituitary neoplasms

Rectal cancer

Retroperitoneal/pelvic sarcoma

Rhabdomyoma

Salivary gland tumors (e.g., sublingual gland tumor,

submandibular gland tumor)

Seminoma Sino‐nasal

carcinoma

Small bowel adenocarcinoma

Soft tissue sarcoma

Squamous cell carcinoma of the eyelid, tongue/glottis

Thymic tumor

Thymoma

Tonsillar cancer

Uterine cancer

Vestibular schwannoma

Yo lk cell tumor

IV. Aetna considers neutron beam therapy medically necessary

for the treatment of any of the following salivary gland

tumors:

Inoperable tumor; or

Locally advanced tumor especially in persons with gross

residual disease; or

Unresectable tumor.

V. Aetna considers neutron beam therapy experimental and

investigational for all other indications including malignancies

listed below (not an all inclusive list) because its effectiveness

for these indications has not been established:

Colon cancer

Dermatofibrosarcoma protuberans

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Proton Beam and Neutron Beam Radiotherapy http://qawww.aetna.com/cpb/medical/data/200_299/0270_draft.html

Ghost cell odontogenic carcinoma

Glioma

Kidney cancer

Laryngeal cancer

Lung cancer

Pancreatic cancer

Prostate cancer

Rectal cancer

Soft tissue sarcoma.

Background

Proton Beam Therapy

Proton beam radiation therapy (PBRT) is a type of external beam

radiation therapy (EBRT) that utilizes protons (positively charged

subatomic particles) that are precisely targeted to a specific tissue

mass. Proton beams have the ability to penetrate deep into

tissues to reach tumors, while delivering less radiation to

superficial tissues such as the skin. This may make PBRT more

effective for inoperable tumors or for those individuals in which

damage to healthy tissue would pose an unacceptable risk.

Proton beams have less scatter than other sources of energy such

as gamma rays, x‐rays, or electrons. Because of this feature,

proton beam radiotherapy (PBRT) has been used to escalate

radiation dose to diseased tissues while minimizing damage to

adjacent normal tissues. Proton beams have been used in

stereotactic radiosurgery of intracranial lesions; the gamma knife

and linear accelerator have also been used in stereotactic

radiosurgery. Proton beam radiotherapy has been shown to be

particularly useful in treating radiosensitive tumors that are

located next to vital structures, where complete surgical excision

or administration of adequate doses of conventional radiation is

difficult or impossible. Examples include uveal melanomas,

chordomas and chondrosarcomas at the base of the skull, and

inoperable arterio‐venous malformations. There is inadequate

data on the application of PBRT for the treatment of non‐uveal

melanoma.

The American Society of Radiation Oncology (ASTRO, 2013) has

http://qawww.aetna.com/cpb/medical/data/200_299/0270_draft.html

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stated: "At the present time, ASTRO believes the comparative

efficacy evidence of proton beam therapy with other prostate

cancer treatments is still being developed, and thus the role of

proton beam therapy for localized prostate cancer within the

current availability of treatment options remains unclear."

The emerging technology committee of the American Society of

Radiation Oncology (ASTRO) concluded that current evidence

provides a limited indication for proton beam therapy (Allen, et

al., 2012). The ASTRO report concluded that current data do not

provide sufficient evidence to recommend proton beam therapy

in lung cancer, head and neck cancer, gastrointestinal

malignancies, and pediatric non‐CNS malignancies. The ASTRO

report stated that, in hepatocellular carcinoma and prostate

cancer, there is evidence for the efficacy of proton beam

therapy but no suggestion that it is superior to photon based

approaches. In pediatric central nervous system (CNS)

malignancies, proton beam therapy appears superior to photon

approaches but more data is needed. The report found that, in

large ocular melanomas and chordomas, there is evidence for a

benefit of proton beam therapy over photon approaches. The

ASTRO report stated that more robust prospective clinical trials

are needed to determine the appropriate clinical setting for

proton beam therapy.

A systematic evidence review (Lodge et al, 2007) compared the

efficacy and cost‐effectiveness of PBRT and other types of hadron

therapy (neutron and heavy and light ion therapy) with photon

therapy. The authors concluded that, overall, the introduction or

extension of PBRT and other types of hadron therapy as a major

treatment modality into standard clinical care is not supported by

the current evidence base. The authors stated, however, that the

efficacy of PBRT appears superior to that of photon therapy for

some ocular and skull base tumours. The authors found that, for

prostate cancer, the efficacy of PBRT seems comparable to

photon therapy. The authors stated that no definitive conclusions

can be drawn for the other cancer types. The authors also noted

that they found little evidence on the relative cost‐effectiveness

of PBRT and other types of hadron therapy compared to photon

therapy or with other cancer treatments. Other systematic


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evidence reviews of PBRT have reached similar conclusions

(Lance, 2010; Brada et al, 2009; Efstathiou et al, 2009; ICER, 2008;

Wilt et al, 2008; Brada et al, 2007; Olsen et al, 2007).

The only randomized controlled clinical trial comparing PBRT to

conventional radiotherapy published to date found no advantage

of PBRT in overall survival (OS), disease‐specific survival, or total

recurrence‐free survival (Shipley, 1995). A total of 202 patients

with stage T3‐T4 prostate cancer were randomly assigned to a

standard dose of conventional radiotherapy plus a 25.2 Gy

equivalent PBRT boost or to a standard dose of conventional

radiotherapy with a 16.8 Gy boost of conventional radiotherapy.

After a median follow‐up of 61 months, there were no significant

differences between the 2 groups in OS, disease‐specific survival,

total recurrence‐free survival, or local control. Local control was

better with the proton beam boost only among the subgroup of

patients with poorly differentiated carcinoma. Patients receiving

the proton beam boost had increased rates of late radiation

sequelae.

Loma Linda University’s experience with PBRT of prostate cancer

was reported in an article published in 1999 by Rossi et al. These

investigators reported the results of an uncontrolled study of

PBRT treatment of 319 patients with biopsy‐proven early‐stage

prostate cancer, with no patient having an initial PSA of greater

than 15. Because the study was uncontrolled, one is unable to

determine whether the results of PBRT are superior to

conventional forms of radiation therapy. In addition, the

definitions of success and failure used in this study are not

comparable to those used in other recent studies of prostate

cancer treatments. In the study by Rossi et al, patients were

considered to have an adequate response if their PSA level fell

below 1.0; most other recent studies define an adequate

response as PSA level below 0.5. In the study by Rossi et al,

patients were considered treatment failures if they had 3

consecutive rises of PSA of 10 % or more, measured at 6‐month

intervals. In other words, for a patient to be considered a

treatment failure, it would take at least 18 months, and patients

would have to have 3 consecutive rises in PSA, each greater than

10 %. By contrast, other reported studies of prostate cancer


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radiotherapy have defined failure as any PSA elevation over a

target PSA nadir. Finally, Rossi et al defined clinical disease free

survival as having "no symptoms and no evidence of disease upon

physical examination or radionuclide scans". These are very gross

tests to determine success, and one would expect these tests to

be negative in a high number of patients who harbored occult

disease.

Of the 319 patients included in the study by Rossi et al, only 288

patients (91 %) who had achieved a nadir (any nadir) or who had

been followed for at least 24 months were included in the

analysis. This would indicate that 31 (9 %) of the patients

originally included in the study either had persistently rising PSA

levels without a nadir despite treatment, had dropped out of the

study, or had not been followed for a sufficient length of time for

some unspecified reason. Only 187 patients (59 % of the original

319 patients) achieved a PSA nadir of 0.5 or less, 66 (21 %)

achieved a PSA nadir of 0.51 to 1.0, and 35 (11 %) achieved a PSA

nadir of 1.0 and above. Thus, only 59 % of patients would be

considered to have had an adequate response by the measure

most commonly used in other recent prostate cancer treatment

studies. In addition, because of the peculiar way the results are

reported, there is no way of knowing how many patients' PSA

nadirs were maintained.

In a randomized, prospective, sham‐controlled, double‐masked

study (n = 37), Ciulla et al (2002) examined the effect of PBRT on

subfoveal choroidal neovascular membranes associated with age‐

related macular degeneration. These investigators concluded

that with the acceptance of photodynamic therapy, future studies

will require more complex design and larger sample size to

determine whether radiation can play either a primary or

adjunctive role in treating these lesions.

In a phase II clinical study (n = 30), Kawashima and colleagues

(2005) assessed the safety and effectiveness PBRT for patients

with hepatocellular carcinoma (HCC). Eligibility criteria for this

study were: solitary HCC; no indication for surgery or local

ablation therapy; no ascites; age of 20 years or older; Zubrod

performance status of 0 to 2; no serious co‐morbidities other


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than liver cirrhosis; written informed consent. Proton beam

radiotherapy was administered in doses of 76 cobalt gray

equivalent in 20 fractions for 5 weeks. No patients received

transarterial chemoembolization or local ablation in combination

with PBRT. All patients had liver cirrhosis, the degree of which

was Child‐Pugh class A in 20, and class B in 10 patients. Acute

reactions of PBRT were well‐tolerated, and PBRT was completed

as planned in all patients. Four patients died of hepatic

insufficiency without tumor recurrence at 6 to 9 months; 3 of

these 4 patients had pre‐treatment indocyanine green retention

rate at 15 minutes of more than 50 %. After a median follow‐up

period of 31 months (range of 16 to 54 months), only 1 patient

experienced recurrence of the primary tumor, and 2‐year

actuarial local progression‐free rate was 96 %. Actuarial overall

survival rate at 2 years was 66 %. These investigators concluded

that PBRT showed excellent control of the primary tumor, with

minimal acute toxicity. They stated that further study is

warranted to scrutinize adequate patient selection in order to

maximize survival benefit of this promising modality.

In a phase II prospective trial, Bush et al (2011) evaluated the

safety and effectiveness of PBRT for HCC. Patients with cirrhosis

who had radiological features or biopsy‐proven HCC were

included in the study. Patients without cirrhosis and patients

with extra‐hepatic metastasis were excluded. The mean age was

62.7 years. The mean tumor size was 5.5 cm. Eleven patients

had multiple tumors, and 46 % were within the Milan criteria.

Patients received 63 Gy delivered over a 3‐week period with

PBRT. A total of 76 patients were treated and followed

prospectively. Acute toxicity was minimal; all patients completed

the full course of treatment. Radiation‐induced liver disease was

evaluated using liver enzyme, bilirubin, and albumin levels; no

significant change supervened 6 months post‐treatment. Median

progression‐free survival for the entire group was 36 months,

with a 60 % 3‐year progression‐free survival rate for patients

within the Milan criteria. Eighteen patients subsequently

underwent liver transplantation; 6 (33 %) explants showed

pathological complete response and 7 (39 %) showed only

microscopic residual. The authors concluded that PBRT was

found to be a safe and effective local‐regional therapy for


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inoperable HCC. They noted that a randomized controlled trial to

compare its efficacy to a standard therapy has been initiated.

Olfactory neuroblastoma (ONB) is a rare disease, and a standard

treatment strategy has not been established. Radiation therapy

for ONB is challenging because of the proximity of ONB to critical

organs. Nishimura et al (2007) analyzed the feasibility and

effectiveness of PBRT for ONB. A retrospective review was

performed on 14 patients who underwent PBRT for ONB as

definitive treatment. The total dose of PBRT was 65 cobalt Gray

equivalents (Gy(E)), with 2.5‐Gy(E) once‐daily fractionations. The

median follow‐up period for surviving patients was 40 months.

One patient died from disseminated disease. There were 2

persistent diseases, 1 of which was successfully salvaged with

surgery. The 5‐year overall survival rate was 93 %, the 5‐year local

progression‐free survival rate was 84 %, and the 5‐year relapse‐

free survival rate was 71 %. Liquorrhea was observed in 1 patient

with Kadish's stage C disease (widely destroying the skull base).

Most patients experienced grade 1 to 2 dermatitis in the acute

phase. No other adverse events of grade 3 or greater were

observed according to the RTOG/EORTC acute and late morbidity

scoring system. The authors concluded that these preliminary

findings of PBRT for ONB achieved excellent local control and

survival outcomes without serious adverse effects. They stated

that PBRT is considered a safe and effective modality that

warrants further study.

Proton beam radiotherapy represents a special case for children

for several reasons (Wilson et al, 2005; Hall, 2006;

Merchant, 2009). It has been shown in dosimetric planning

studies to have a potential advantage over conventional photon

therapy because of the ability to confine the high‐dose treatment

area to the tumor volume and minimize the radiation dose to the

surrounding tissue. This especially important in children, as

children are more sensitive to radiation‐induced cancer than

adults. An increased risk of second cancers in long‐term survivors

is more important in children than older adults. In addition to

second malignant neoplasms, late effects of radiation to normal

tissue can include developmental delay. Also, radiation scattered

from the treatment volume is more important in the small body


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of the child. Finally, the question of genetic susceptibility arises

because many childhood cancers involve a germline mutation.

An assessment of proton beam radiotherapy by the Veterans

Health Administration Technology Assessment Program (VATAP)

(Flynn, 2010) found that available English‐language reviews for

proton therapy generally concur on the state of the literature as

consisting primarily of observational studies from which

conclusions about the relative effectiveness of proton therapy

versus alternatives cannot validly be made. The assessment

reported that available reviews reflect the state of the literature

in that they attempt to cover so much territory (multiple poor‐

prognosis inoperable tumors in both children and adults) that

the reviews themselves are cumbersome to read, not well

organized, and provide only diffuse or equivocal conclusions by

individual diagnoses. "In other words, the literature reflects the

early clinical investigation status of proton therapy, where

observational studies are framed in terms of potential benefits,

reasoning from pathophysiology, dose‐finding, refinement of

treatment protocols, and baseline safety of the entire approach"

(Flynn, 2010). The assessment noted that only prostate cancer is

represented by randomized controlled clinical trials, and in that

case two small ones primarily concerned with refinement of

protocol/dose escalation.

Regarding cost‐effectiveness analyses of PBRT, the VATAP

assessment found that the availability of studies titled by their

authors as “economic evaluations” is misleading (Flynn, 2010).

The assessment stated that such studies require cost and efficacy

data about both the intervention and its alternatives (costs and

consequences of alternative interventions), hence should be

conducted only after efficacy data from randomized controlled

trials are available. The assessment noted that, in the case of

proton therapy, the economic studies are premature, really

should be labeled simple cost rather than cost‐effectiveness

analyses, and their conclusions based on unwarranted efficacy

assumptions. Cost data have been carefully collected and

reported, but these are only one element of decision making

about investment in proton therapy. The VATAP assessment

concluded that there are no indications for which proton therapy


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has been shown unequivocally to be effective, or more effective

than its alternatives. The VATAP assessment also concluded that

no research published subsequent to the searches conducted for

available systematic reviews has changed the conclusions of

those reviews.

Regarding research implications, the VATAP assessment

concluded that, in order to obtain the next generation of data,

explicit decisions need to be made about which malignancies are

amenable to/should require randomized trials (e.g., prostate

cancer is sufficiently common) and which malignancies are

sufficiently rare or difficult to treat with surgery or conventional

radiotherapy (e.g., ocular tumors, tumors of the optical nerve,

spinal cord, or central nervous system) that observational studies

with larger cohorts than studies to date are the best approach

(Flynn, 2010). The VATAP assessment also concluded that future

studies should strongly consider valid and reliable embedded

collection of cost data in order to inform better quality economic

evaluation than currently available.

An assessment prepared for the Agency for Healthcare Research

and Quality (Trikalinos, et al., 2009) found that a large number of

scientific papers on charged particle radiotherapy for the

treatment of cancer currently exist. However, these studies do

not document the circumstances in contemporary treatment

strategies in which radiotherapy with charged particles is superior

to other modalities. Comparative studies in general, and

randomized trials in particular (when feasible), are needed to

document the theoretical advantages of charged particle

radiotherapy to specific clinical situations. The assessment noted

that most eligible studies were noncomparative in nature and had

small sample sizes. The report stated that it is likely that focused

systematic reviews will not be able to provide a definitive answer

on the effectiveness and safety of charged particle beam

radiotherapies compared with alternative interventions. This is

simply because of the relative lack of comparative studies in

general, and randomized trials in particular. The report stated that

comparative studies (preferably randomized) are likely necessary

to provide meaningful answers on the relative safety and

effectiveness of particle beam therapy versus other treatment


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options in the context of current clinical practice. This is especially

true for the treatment of common cancers. The report stated that,

especially for many common cancers, such as breast,

prostate, lung, and pancreatic cancers, it is essential that the

theorized advantages of particle beam therapy versus

contemporary alternative interventions are proven in controlled

clinical trials, along with concomitant economic evaluations.

An assessment of the comparative effectiveness and value of

management options in low‐risk prostate cancer by the Institute

for Clinical and Economic Review (ICER) (Ollendorf et al, 2008)

found that the evidence on the comparative effectiveness and

harms of proton beam therapy is limited to relatively small, highly

selective case series of short duration, making any judgments

about its relative benefit or inferiority to other

options premature. The uncertainty regarding PBRT is

accentuated because this technology involves delivery of a novel

form of radiation, and there remain important questions about

the full spectrum of possible effects. ICER rated PBRT's

comparative clinical effectiveness as "insufficient", indicating that

there is not enough evidence to allow a reasonable judgment of

the likely balance of harms and benefits of PBRT in comparison

to radical prostatectomy or other management options. ICER

judged the comparative value of PBRT to be low compared to

other options. The ICER reported explained, that, while ICER does

not always provide a comparative value rating for

technologies with insufficient evidence on comparative clinical

effectiveness, the decision was made to rate the comparative

value of PBRT as “low” relative to radical prostatectomy, based on

current levels of reimbursement that are more than 3‐fold higher

for PBRT.

The Blue Cross and Blue Shield Association Medical Advisory

Panel (BCBSA, 2010) concluded that proton beam radiation

therapy for treatment of non‐small‐cell lung cancer at any stage

or for recurrent non‐small‐cell lung cancer does not meet the

Technology Evaluation Center criteria. The TEC assessment stated

that, overall, evidence is insufficient to permit conclusions about

the results of proton beam therapy for any stage of non‐small‐cell

lung cancer. The report found that all proton beam


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therapy studies are case series; there are no studies directly

comparing proton beam therapy and stereotactic body

radiotherapy. Among study quality concerns, no study mentioned

using an independent assessor of patient reported adverse

events, adverse events were generally poorly reported, and

details were lacking on several aspects of proton beam

therapy treatment regimens. The proton beam therapy studies

had similar patient ages, but there was great variability in percent

within stage Ia, sex ratio, and percent medically inoperable. There

is a high degree of treatment heterogeneity among the proton

beam therapy studies, particularly with respect to planning

volume, total dose, number of fractions, and number of beams.

Survival results are highly variable. It is unclear if the

heterogeneity of results can be explained by differences in

patient and treatment characteristics. Indirect comparisons

between proton beam therapy and stereotactic body

radiotherapy, comparing separate sets of single‐arm studies

on proton beam therapy and stereotactic body radiotherapy, may

be distorted by confounding. In the absence of randomized,

controlled trials, the comparative effectiveness of proton beam

therapy and stereotactic body radiotherapy is uncertain.

Mizumoto et al (2010) evaluated the efficacy and safety of PBRT

for locoregionally advanced esophageal cancer. The subjects

were 51 patients with esophageal cancer who were treated

between 1985 and 2005 using proton beams with or without X‐

rays. All but 1 had squamous cell carcinoma. Of the 51 patients,

33 received combinations of X‐rays (median of 46 Gy) and protons

(median of 36 GyE) as a boost. The median total dose of

combined X‐rays and proton radiation for these 33 patients was

80 GyE (range of 70 to 90 GyE). The other 18 patients received

PBRT alone (median of 79 GyE, range of 62 to 98 GyE). Treatment

interruption due to radiation‐induced esophagitis or hematologic

toxicity was not required for any patient. The overall 5‐year

actuarial survival rate for the 51 patients was 21.1 % and the

median survival time was 20.5 months (95 % confidence interval

[CI]: 10.9 to 30.2). Of the 51 patients, 40 (78 %) showed a

complete response within 4 months after completing treatment

and 7 (14 %) showed a partial response, giving a response rate of

92 % (47/51). The 5‐year local


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control rate for all 51 patients was 38.0 % and the median local

control time was 25.5 months (95 % CI: 14.6 to 36.3). The

authors concluded that these findings suggested that PBRT is an

effective treatment for patients with locally advanced esophageal

cancer. Moreover, they stated that further studies are needed to

determine the optimal total dose, fractionation schedules, and

best combination of PBRT with chemotherapy. Furthermore,

the National Comprehensive Cancer Network (NCCN) guideline

on esophageal cancer (2011) does not mention the use of PBRT

as a therapeutic option for this condition.

Bassim et al (2010) reviewed the literature on radiation therapy

for the treatment of vestibular schwannoma (VS). PubMed

searches for English language articles on radiation treatment of

VS published from January 2002 to July 2007 were conducted.

Studies presenting outcomes were selected, yielding 56 articles

(58 studies) in journals of neurosurgery (30), oncology (18),

otolaryngology (6), and other (2). Data included type of study,

number of subjects, demographics, follow‐up times, type of

radiation, tumor size, tumor control definition, control rates,

facial nerve function measure and outcome, type of hearing and

vestibular testing and outcomes, and complications. Descriptive

statistics were performed. Studies (72.9 %) were retrospective

reviews with stated sample sizes ranging from 5 to 829.

Gamma‐knife (49.2 %), linear accelerator (35.6 %), and proton

beam (6.8 %) were used with various doses. Average follow‐up

was less than 5 years in 79.6 % of studies, and 67.4 % included

patients at less than or equal to 1 year. Tumor size was reported

as diameter (23.7 %), volume (49.2 %), both (11.9 %), other (3.4

%), or not reported (11.9 %). Definition of tumor control varied:

less than or equal to 2 mm growth (22.0 %), no

visible/measurable change (16.9 %), required surgery (10.2 %),

other (17.0 %), and not clearly specified (33.9 %). Facial nerve

outcome was reported as House‐Brackmann (64.4 %),

normal/abnormal (11.9 %), other (1.7 %), or was not reported (22

%). The authors concluded that the lack of uniform reporting

criteria for tumor control, facial function and hearing

preservation, and variability in follow‐up times make it difficult to

compare studies of radiation treatment for VS. They

recommended consideration of reporting guidelines such as


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those used in otology for reporting VS resection results.

Mizumoto et al (2011) evaluated the safety and effectiveness of

hyper‐fractionated concomitant boost proton beam therapy (PBT)

for patients with esophageal cancer. The study participants were

19 patients with esophageal cancer who were treated with

hyperfractionated photon therapy and PBT between 1990 and

2007. The median total dose was 78 GyE (range of 70 to 83 GyE)

over a median treatment period of 48 days (range of 38 to 53

days). Ten of the 19 patients were at clinical T Stage 3 or 4. There

were no cases in which treatment interruption was required

because of radiation‐induced esophagitis or hematologic toxicity.

The overall 1‐ and 5‐year actuarial survival rates for all 19 patients

were 79.0 % and 42.8 %, respectively, and the median survival

time was 31.5 months (95 % limits: 16.7 to 46.3 months). Of the

19 patients, 17 (89 %) showed a complete response within 4

months after completing treatment and 2 (11 %) showed a partial

response, giving a response rate of 100 % (19/19). The 1‐ and 5‐

year local control rates for all 19 patients were 93.8 % and 84.4

%, respectively. Only 1 patient had late esophageal toxicity of

Grade 3 at 6 months after hyperfractionated PBT. There were no

other non‐hematologic toxicities, including no cases of radiation

pneumonia or cardiac failure of Grade 3 or higher. The authors

concluded that these findings suggested that hyperfractionated

PBT is safe and effective for patients with esophageal cancer.

They stated that further studies are needed to establish the

appropriate role and treatment schedule for use of PBT for

esophageal cancer.

In a phase I clinical study, Hong et al (2011) evaluated the safety

of 1 week of chemo‐radiation with proton beam therapy and

capecitabine followed by early surgery on 15 patients with

localized resectable, pancreatic ductal adenocarcinoma of the

head. Patients received radiation with proton beam. In dose

level 1, patients received 3 GyE × 10 (week 1, Monday to Friday;

week 2, Monday to Friday). Patients in dose levels 2 to 4 received

5 GyE × 5 in progressively shortened schedules: level 2 (week 1,

Monday, Wednesday, and Friday; week 2, Tuesday and Thursday),

level 3 (week 1, Monday, Tuesday, Thursday, and Friday; week 2,

Monday), level 4 (week 1, Monday through Friday). Capecitabine


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was given as 825 mg/m(2) b.i.d. Weeks 1 and 2 Monday through

Friday for a total of 10 days in all dose levels. Surgery was

performed 4 to 6 weeks after completion of chemotherapy for

dose levels 1 to 3 and then after 1 to 3 weeks for dose Level 4.

Three patients were treated at dose levels 1 to 3 and 6 patients at

dose level 4, which was selected as the MTD. No dose limiting

toxicities were observed. Grade 3 toxicity was noted in 4 patients

(pain in 1; stent obstruction or infection in 3). Eleven patients

underwent resection. Reasons for no resection were metastatic

disease (3 patients) and unresectable tumor (1 patient). Mean

post‐surgical length of stay was 6 days (range of 5 to 10 days). No

unexpected 30‐day post‐operative complications, including leak

or obstruction, were found. The authors concluded that pre‐

operative chemo‐radiation with 1 week of PBRT and capecitabine

followed by early surgery is feasible. A phase II study is

underway.

UpToDate reviews on "Management of locally advanced and

borderline resectable exocrine pancreatic cancer" (Ryan and

Mamon, 2012) and "Surgery in the treatment of exocrine

pancreatic cancer and prognosis" (Fernandez‐del Castillo et al,

2012) do not mention the use of proton beam therapy.

Furthermore, the NCCN's clinical practice guideline on "Pancreatic

adenocarcinoma" (2011) does not mention the use of proton

beam.

Available peer‐reviewed published evidence does not support the

use of PBRT for squamous cell carcinomas of the head and neck.

There is a lack of clinical outcome studies comparing PBRT to

stereotactic radiosurgery or other photon‐based methods. What

few comparative studies exist are limited to dosimetric planning

studies and not studies of clinical outcomes. Current guidelines

from the NCCN and the National Cancer Institute (PDQ) include

no recommendation for use of PBRT for squamous cell carcinoma

of the head and neck. A report from the American Society for

Therapeutic and Radiation Oncology (ASTRO) (2012) concludes

that there is insufficient evidence to support the use of proton

beam therapy for head and neck cancers, and conclude that

“current data do not provide sufficient evidence to recommend

PBT in ... head and neck cancer… “. An AHRQ comparative


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effectiveness review (2010) on radiotherapy for head and neck

cancer reached the following conclusions regarding proton beam

therapy versus other radiotherapy treatments for head and neck

cancer: “The strength of evidence is insufficient as there were no

studies comparing proton beam therapy to any other

radiotherapy modality. Therefore, no conclusions can be reached

regarding the comparative effectiveness of proton beam therapy

for any of the four key questions.”

An UpToDate review on "Clinical presentation and management

of thymoma and thymic carcinoma" (Salgia, 2012) does not

mention the use of proton beam therapy. Also, the NCCN's

clinical practice guideline on "Thymoma and thymic carcinomas"

(2011) does not mention the use of proton beam therapy.

Guidelines on soft tissue sarcoma from the National

Comprehensive Cancer Network (2012) indicate a potential role

for proton therapy in retroperitoneal soft tissue sarcomas in

persons who did not receive preoperative radiotherapy. The

guidelines state: "Postoperative RT using newer techniques such

as intensity‐modulated radiation therapy (IMRT), 3D conformal

proton therapy, and intensity modulated proton therapy (IMPT)

may allow tumor target coverage and acceptable clinical

outcomes within normal tissue dose constraints to adjacent

organs at risk in some patients with retroperitoneal STS who did

not receive pre‐operative radiotherapy. Multicenter randomized

controlled trials are needed to address the toxicities and

therapeutic benefits of adjuvant RT techniques in patients with

retroperitoneal STS."

A BCBS TEC assessment found insufficient evidence for PBRT in

the treatment of non‐small‐cell lung cancer. In addition, the

American Society for Radiation Oncology (ASTRO) guidelines

(Allen et al, 2012) found insufficient evidence for PBRT in lung

cancer.

An UpToDate review on "Malignant salivary gland tumors:

Treatment of recurrent and metastatic disease" (Laurie, 2012)

stated that "The most common malignant salivary gland tumors

include mucoepidermoid carcinoma, adenoid cystic carcinoma,


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polymorphous low grade adenocarcinoma, carcinoma ex

pleomorphic adenoma, acinic cell carcinoma, and

adenocarcinoma not otherwise specified". However, it does not

mention the use of PBRT as a therapeutic option.

UpToDate reviews on “Treatment of early (stage I and II) head and

neck cancer: The larynx” (Koch and Machtay, 2012) and

“Treatment of locoregionally advanced (stage III and IV) head and

neck cancer: The larynx and hypopharynx” (Brockstein et al,

2012) do not mention the use of NBT.

Given concerns of excess malignancies following adjuvant

radiation for seminoma, Efstathiou et al (2012) evaluated photon

beam therapy and PBRT treatment plans to assess dose

distributions to organs at risk and model rates of second cancers.

A total of 10 stage I seminoma patients who were treated with

conventional para‐aortic AP‐PA photon radiation to 25.5 Gy at

Massachusetts General Hospital had PBRT plans generated (AP‐

PA, PA alone). Dose differences to critical organs were

examined. Risks of second primary malignancies were

calculated. Proton beam radiotherapy plans were superior to

photons in limiting dose to organs at risk; PBRT decreased dose

by 46 % (8.2 Gy) and 64 % (10.2 Gy) to the stomach and large

bowel, respectively (p < 0.01). Notably, PBRT was found to avert

300 excess second cancers among 10,000 men treated at a

median age of 39 and surviving to 75 (p < 0.01). The authors

concluded that in this study, the use of protons provided a

favorable dose distribution with an ability to limit unnecessary

exposure to critical normal structures in the treatment of early‐

stage seminoma. It is expected that this will translate into

decreased acute toxicity and reduced risk of second cancers, for

which prospective studies are warranted. Furthermore,

UpToDate reviews on “Treatment of stage I seminoma” (Beard,

2012) and “Treatment of stage II seminoma” (Beard and Oh,

2012) do not mention the use of PBRT.

Proton beam radiotherapy has been used as therapeutic option

for choroidal hemangiomas. However, available evidence on its

effectiveness for this indication is mainly in the form of

retrospective reviews with small sample size and a lack of


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comparison to standard therapies. Furthermore, a review on

“Choroidal hemangioma” (Finger, 2013) from the Eye Cancer

Network’s website does not mention PBRT as a therapeutic

option. Thus, PBRT is not an established treatment for patients

with choroidal hemangiomas.

In a retrospective study, Hocht et al (2006) compared the results

of therapy in patients with uveal hemangioma treated with

photon or proton irradiation at a single center. From 1993 to

2002, a total of 44 patients were treated. Until 1998 radiotherapy

was given with 6 MV photons in standard fractionation of 2.0 Gy

5 times per week. In 1998 PBRT became available and was used

since then. A dose of 20 to 22.5 Cobalt Gray Equivalent (CGE; CGE

= proton Gy x relative biological effectiveness 1.1) 68 MeV

protons was given on 4 consecutive days. Progressive symptoms

or deterioration of vision were the indications for therapy. Of the

44 patients treated, 36 had circumscribed choroidal

hemangiomas (CCH) and 8 had diffuse choroidal hemangiomas

(DCH) and Sturge‐Weber syndrome. Of the patients, 19 were

treated with photons with a total dose in the range of 16 to 30

Gy. A total of 25 patients were treated with PBRT. All patients

with DCH but 1 were treated with photons. Stabilization of visual

acuity was achieved in 93.2 % of all patients. Tumor thickness

decreased in 95.4 % and retinal detachment resolved in 92.9 %.

Late effects, although generally mild or moderate, were

frequently detected. In all, 40.9 % showed radiation‐induced

optic neuropathy, maximum Grade I. Retinopathy was found in

29.5 % of cases, but only 1 patient experienced more than Grade

II severity. Retinopathy and radiation‐induced optic neuropathy

were reversible in some of the patients and in some resolved

completely. No differences could be detected between patients

with CCH treated with protons and photons; treatment was less

effective in DCH patients (75 %). The authors concluded that

radiotherapy is effective in treating choroidal hemangiomas with

respect to visual acuity and tumor thickness; but a benefit of

PBRT could not be detected.

In a retrospective review, Levy‐Gabriel et al (2009) evaluated the

long‐term effectiveness and outcome of low‐dose PBRT in the

treatment of symptomatic CCH. A total of 71 patients with


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symptomatic CCH were treated by PBRT between September

1994 and October 2002 using a total dose of 20 CGE. The median

follow‐up was 52 months (range of 8 to 133 months). Retinal re‐

attachment was obtained in all cases. Tumor thickness

decreased in all cases and a completely flat scar was obtained in

65 patients (91.5 %). Visual acuity was improved by 2 lines or

more in 37 of the 71 patients (52 %), and in 30 of the 40 patients

(75 %) treated within 6 months after onset of the first symptoms.

The main radiation complications detected during follow‐up were

cataract (28 %) and radiation‐induced maculopathy (8 %). None

of the 71 patients developed eyelid sequelae or neovascular

glaucoma. The authors concluded that PBRT with a total dose of

20 CGE appeared to be a valid treatment for CCH, inducing

definitive retinal re‐attachment and decreasing tumor thickness.

However, delayed radiation‐induced maculopathy may occur. A

successful functional outcome is dependent on a short interval

between onset of the first symptoms and initiation of therapy.

In a retrospective chart review, Chan et al (2010) described the

clinical outcomes of patients (n = 19) with CCH and DCH treated

by PBRT using a non‐surgical light‐field technique. Choroidal

hemangiomas were treated with PBRT using a light‐field

technique and doses ranging from 15 to 30 CGE in 4 fractions.

Patients with at least 6 months' follow‐up were included in the

study. Tumor regression, visual acuity, absorption of sub‐retinal

fluid, and treatment‐associated complications were evaluated by

clinical examination and ultrasonography. Visual acuity improved

or remained stable in 14 of 18 eyes (78 %). Sub‐retinal fluid was

initially present in 16 of 19 eyes (84 %), and completely resolved

in all 16 eyes. Tumor height, as measured by B‐scan

ultrasonography, decreased in 18 of 19 eyes and remained stable

in 1 of 19, as of the last examination. Complications of radiation

developed in 9 of 19 eyes (47 %) with the total applied dose

ranging from 15 to 30 CGE for these 9 eyes. The authors

concluded that PBRT using a light‐field technique without surgical

tumor localization is an effective treatment option in managing

both CCH and DCH associated with Sturge‐Weber syndrome. A

total proton dose as low as 15 CGE applied in 4 fractions

appeared to be sufficient to reduce tumor size, promote

absorption of sub‐retinal fluid, and improve or stabilize vision in


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most patients.

Published studies of proton beam therapy for Hodgkin lymphoma

are limited to dosimetric planning studies; there is a lack of

published clinical outcome studies of proton beam therapy

demonstrating improvements over photon therapy modalities.

Guidelines on Hodgkin Lymphoma from the National

Comprehensive Cancer Network state, in under the section

Principles of Radiation Therapy, “RT can be delivered with

photons or protons. Preliminary results from single‐institution

studies have shown that significant dose reduction to organs at

risk (OAR; e.g., lung, heart, breasts) can be achieved with proton

beam RT, which can reduce the risk of late effects. Long‐term

follow‐up is needed to confirm the efficacy of proton beam RT.”

Guidelines on radiation therapy for Hodgkin lymphoma from the

International Lymphoma Radiation Oncology Group (2014) state:

“The role of proton therapy has not yet been defined, and it is

not widely available.” National Cancer Institute Guidelines (2014)

and American College of Radiology Appropriateness Criteria

(2010) for adult Hodgkin lymphoma have no recommendation for

proton beam therapy in Hodgkin lymphoma. European Society for

Medical Oncology guidelines on Hodgkin disease (Eichenauer, et

al., 2014) have no recommendation for proton beam therapy.

Other international Hodgkin disease guidelines (British

Committee for Standards in Haematology, 2014; BC Cancer

Agency, 2013; Alberta Health Services, 2013) have no

recommendation for proton beam radiation therapy. Guidelines

on proton beam therapy from Alberta Health Services (2013) do

not recommend proton beam therapy for lymphomas in adults

“due to an insufficient evidence base.”

A technology assessment of proton beam therapy for the

Washington State Health Care Authority (2014) found no

comparative studies of proton beam therapy for lymphomas that

met inclusion criteria for the systematic evidence review. The

assessment concluded that the evidence for proton beam therapy

for lymphomas was “insufficient” based on no evidence, and

reported that their review of guidelines and coverage policies on

proton beam found lymphoma was not recommended or not

covered.


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Meyer et al (2012) noted that chemotherapy plus radiation

treatment is effective in controlling stage IA or IIA non‐bulky

Hodgkin's lymphoma in 90 % of patients but is associated with

late treatment‐related deaths. Chemotherapy alone may improve

survival because it is associated with fewer late deaths. These

researchers randomly assigned 405 patients with previously

untreated stage IA or IIA non‐bulky Hodgkin's lymphoma to

treatment with doxorubicin, bleomycin, vinblastine, and

dacarbazine (ABVD) alone or to treatment with subtotal nodal

radiation therapy, with or without ABVD therapy. Patients in the

ABVD‐only group, those with a favorable risk profile as well as

those with an unfavorable risk‐profile, received 4 to 6 cycles of

ABVD. Among patients assigned to subtotal nodal radiation

therapy, those who had a favorable risk‐profile received subtotal

nodal radiation therapy alone and those with an unfavorable risk‐

profile received 2 cycles of ABVD plus subtotal nodal radiation

therapy. The primary end‐point was 12‐year OS. The median

length of follow‐up was 11.3 years. At 12 years, the rate of OS

was 94 % among those receiving ABVD alone, as compared with

87 % among those receiving subtotal nodal radiation therapy

(hazard ratio [HR] for death with ABVD alone, 0.50; 95 % CI: 0.25

to 0.99; p = 0.04); the rates of freedom from disease progression

were 87 % and 92 % in the 2 groups, respectively (HR for disease

progression, 1.91; 95 % CI: 0.99 to 3.69; p = 0.05); and the rates of

event‐free survival were 85 % and 80 %, respectively (HR for

event, 0.88; 95 % CI: 0.54 to 1.43; p = 0.60). Among the patients

randomly assigned to ABVD alone, 6 patients died from Hodgkin's

lymphoma or an early treatment complication and 6 died from

another cause; among those receiving radiation therapy, 4 deaths

were related to Hodgkin's lymphoma or early toxic effects from

the treatment and 20 were related to another cause. The authors

concluded that among patients with Hodgkin's lymphoma, ABVD

therapy alone, as compared with treatment that included subtotal

nodal radiation therapy, was associated with a higher

rate of OS owing to a lower rate of death from other causes. This

study did not address the use of PBT for the treatment of Hodgkin

lymphoma; in fact it argued against the combination use of

chemo‐ and radiation‐therapy.

National Comprehensive Cancer Network’s clinical practice


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guideline on “Head and neck cancers” (Version 2.2013) stated

that “the role of proton therapy is being investigated”.

The Alberta Health Services, Cancer Care’s clinical practice

guideline on “Proton beam radiation therapy” (2013) noted that

“Members of the working group do not currently recommend

that patients with prostate cancer, non‐small cell lung cancer, or

most lymphomas be referred for proton beam radiotherapy, due

to an insufficient evidence base”.

The European Society for Medical Oncology’s guidelines on biliary

cancers (Eckel et al, 2011) made no recommendation regarding

the use of PBT in the treatment of cholangiocarcinoma.

Furthermore, NCCN guidelines on “Hepatobiliary cancers”

(Version 2.2013) made no recommendation for use PBT in

cholangiocarcinoma.

A systematic evidence review of proton beam therapy prepared

for the Washington State Healthcare Authority (2014) reviewed

studies comparing proton beam therapy to photon therapies. The

investigators identified two poor‐quality retrospective

comparative cohort studies of primary PBT for brain, spinal, and

paraspinal tumors. One was an evaluation of proton beam

therapy versus photon therapy in 40 adults who received surgical

and radiation treatment of medulloblastoma at MD Anderson

Cancer Center (citing Brown, et al., 2013). No statistical

differences between radiation modalities were seen in Kaplan‐

Meier assessment of either overall or progression‐free survival at

two years. A numeric difference was seen in the rate of local or

regional failure (5% for PBT vs. 14% for photon), but this was not

assessed statistically. The second study involved 32 patients

treated for intramedullary gliomas at Massachusetts General

Hospital (citing Kahn, et al., 2011) with either proton beam

therapy (n=10) or IMRT (n=22). While explicit comparisons were

made between groups, the proton beam therapy population was

primarily pediatric (mean age 14 years), while the IMRT

population was adult (mean age 44 years). Patients in both

groups were followed for a median of 24 months. While the crude

mortality rate was lower in the proton beam therapy group

(20% vs. 32% for IMRT), in multivariate analyses controlling for


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age, tumor pathology, and treatment modality, proton beam

therapy was associated with significantly increased mortality risk

(Hazard Ratio 40.0, p = 0.02). The rate of brain metastasis was

numerically higher in the proton beam therapy group (10% vs. 5%

for IMRT), but this was not statistically tested. Rates of local or

regional recurrence did not differ between groups.

NCCN guidelines on central nervous system cancers (2014) have

no recommendation for proton beam therapy. International

guidelines on CNS malignancies (ESMO, 2010; Alberta Cancer

Care, 2012; Cancer Council Australia, 2009) have no

recommendation for proton beam therapy. An ASTRO Technology

Review of proton beam therapy (2012) stated that, for CNS

malignancies other than skull base and cervical spine chordomas

and chondrosarcomas, “the potential benefit of proton beam

therapy remains theoretical and deserving of further study.”

Dermatofibrosarcoma protuberans is an uncommon tumor that

arises in the skin. The tumor is firm and often flesh‐colored

although it can be reddish, bluish, or purplish. The tumor is often

found on the chest or shoulders, but it can be found on other

parts of the body. Dermatofibrosarcoma protuberans may cause

no symptoms, and the initial size of the tumor tends to be around

1 to 5 centimeters. This tumor has a low potential to spread to

other tissues (metastasize). Treatment often involves surgery to

remove the tumor, such as by Mohs’ micrographic surgery.

https://rarediseases.info.nih.gov/GARD/Condition

/9569/Dermatofibrosarcoma_protuberans.aspx

(https://rarediseases.info.nih.gov/GARD/Condition

/9569/Dermatofibrosarcoma_protuberans.aspx). Moreover,

NCCN’s clinical practice guideline on “Dermatofibrosarcoma

protuberans” (Version 1.2014) does not mention proton or

neutron beam therapy as a therapeutic option.

Plastaras et al (2014) stated that the dose distributions that can

be achieved with protons are usually superior to those of

conventional photon external‐beam radiation. There are special

cases where proton therapy may offer a substantial potential

benefit compared to photon treatments where toxicity concerns

dominate. Re‐irradiation may theoretically be made safer with


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proton therapy due to lower cumulative lifetime doses to

sensitive tissues, such as the spinal cord. Proton therapy has

been used in a limited number of patients with rectal, pancreatic,

esophageal, and lung cancers. Chordomas and soft tissue

sarcomas require particularly high radiation doses, posing

additional challenges for re‐irradiation. Lymphoma is another

special case where proton therapy may be advantageous. Late

toxicities from even relatively low radiation doses, including

cardiac complications and second cancers, are of concern in

lymphoma patients with high cure rates and long life

expectancies. Proton therapy has begun to be used for

consolidation after chemotherapy in patients with Hodgkin and

non‐Hodgkin lymphoma. Breast cancer is another emerging area

of proton therapy development and use. Proton therapy may

offer advantages compared to other techniques in the setting of

breast boosts, accelerated partial breast irradiation, and post‐

mastectomy radiotherapy. In these settings, proton therapy may

decrease toxicity associated with breast radiotherapy. The

authors concluded that as techniques are refined in proton

therapy, one may be able to improve the therapeutic ratio by

maintaining the benefits of radiotherapy while better minimizing

the risks.

Mendenhall et al (2014) reported 5‐year clinical outcomes of 3

prospective trials of image‐guided proton therapy for prostate

cancer. A total of 211 prostate cancer patients (89 low‐risk, 82

intermediate‐risk, and 40 high‐risk) were treated in institutional

review board‐approved trials of 78 cobalt gray equivalent (CGE) in

39 fractions for low‐risk disease, 78 to 82 CGE for intermediate‐

risk disease, and 78 CGE with concomitant docetaxel therapy

followed by androgen deprivation therapy for high‐risk disease.

Toxicities were graded according to Common Terminology Criteria

for Adverse Events (CTCAE), version 3.0.

Median follow‐up was 5.2 years. Five‐year rates of biochemical

and clinical freedom from disease progression were 99 %, 99 %,

and 76 % in low‐, intermediate‐, and high‐risk patients,

respectively. Actuarial 5‐year rates of late CTCAE, version 3.0 (or

version 4.0) grade 3 gastrointestinal and urologic toxicity were 1.0

% (0.5 %) and 5.4 % (1.0 %), respectively. Median pre‐treatment

scores and International Prostate Symptom Scores at greater than


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4 years post‐treatment were 8 and 7, 6 and 6, and 9 and 8,

respectively, among the low‐, intermediate‐, and high‐risk

patients. There were no significant changes between median

pre‐treatment summary scores and Expanded Prostate Cancer

Index Composite scores at greater than 4 years for bowel, urinary

irritation and/or obstructive, and urinary continence. The

authors concluded that 5‐year clinical outcomes with image‐

guided proton therapy included extremely high efficacy, minimal

physician‐assessed toxicity, and excellent patient‐reported

outcomes. Moreover, they stated that further follow‐up and a

larger patient experience are needed to confirm these favorable

outcomes.

Furthermore, NCCN’s clinical practice guideline on “Prostate

cancer” (Version 1.2015) states that “An ongoing prospective

randomized trial is accruing patients and comparing prostate

proton therapy to prostate IMRT. The NCCN panel believes that

there is no clear evidence supporting a benefit or decrement to

proton therapy over IMRT for either treatment efficacy or long‐

term toxicity”.

Amsbaugh (2012) reported acute toxicities and preliminary

outcomes for pediatric patients with ependymomas of the spine

treated with proton beam therapy at the MD Anderson Cancer

Center. A total of 8 pediatric patients received proton beam

irradiation between October 2006 and September 2010 for spinal

ependymomas. Toxicity data were collected weekly during

radiation therapy and all follow‐up visits. Toxicities were graded

according to the Common Terminology Criteria for Adverse Events

version 3.0. All patients had surgical resection of the tumor

before irradiation (7 subtotal resection and 1 gross total

resection). Six patients had World Health Organization Grade I

ependymomas, and 2 had World Health Organization Grade II

ependymomas. Patients had up to 3 surgical interventions before

radiation therapy (range of 1 to 3; median, 1). Three patients

received proton therapy after recurrence and 5 as part of their

primary management. The entire vertebral body was treated in

all but 2 patients. The mean radiation dose was 51.1 cobalt gray

equivalents (range of 45 to 54 cobalt gray equivalents). With a

mean follow‐up of 26 months from the radiation therapy start


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date (range of 7 to 51 months), local control, event‐free survival,

and overall survival rates were all 100 %. The most common

toxicities during treatment were Grade 1 or 2 erythema (75 %)

and Grade 1 fatigue (38 %). No patients had a Grade 3 or higher

adverse event. Proton therapy dramatically reduced dose to all

normal tissues anterior to the vertebral bodies in comparison to

photon therapy. The authors concluded that preliminary

outcomes showed the expected control rates with favorable

acute toxicity profiles. They noted that proton beam therapy

offers a powerful treatment option in the pediatric population,

where adverse events related to radiation exposure are of

concern. Moreover, they stated that extended follow‐up will be

required to assess for late recurrences and long‐term adverse

effects.

The American College of Radiology’s “Appropriateness Criteria®

retreatment of recurrent head and neck cancer after prior

definitive radiation” (McDonald et al, 2014) stated that “Newer

conformal radiation modalities, including stereotactic body

radiation therapy and proton therapy, may be appropriate in

select cases. Additional data are needed to determine which

patient subsets will most likely benefit from these modalities”.

In a review on “Promise and pitfalls of heavy‐particle therapy”,

Mitin and Zietman (2014) stated that “Particle therapy [including

proton beam], on a relatively thin evidence base, has established

itself as the standard of care for these rare malignancies

[chordoma and chondrosarcoma]”.

An UpToDate review on “Ependymoma” (Kieran, 2014) does not

mention proton beam as a therapeutic option.

Greenberger et al (2014) reported their experience with pediatric

patients treated with PBT. A total of 32 pediatric patients with

low‐grade gliomas of the brain or spinal cord were treated with

PBT from 1995 to 2007; 16 patients received at least 1 regimen of

chemotherapy before definitive radiotherapy (RT). The median

radiation dose was 52.2 GyRBE (48.6 to 54 GyRBE). The median

age at treatment was 11.0 years (range of 2.7 to 21.5 years), with

a median follow‐up time of 7.6 years (range of 3.2 to 18.2 years).


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The 6‐year and 8‐year rates of progression‐free survival were 89.7

% and 82.8 %, respectively, with an 8‐year overall survival of 100

%. For the subset of patients who received serial neurocognitive

testing, there were no significant declines in Full‐Scale Intelligence

Quotient (p = 0.80), with a median neurocognitive

testing interval of 4.5 years (range of 1.2 to 8.1 years) from

baseline to follow‐up, but subgroup analysis indicated some

significant decline in neurocognitive outcomes for young children

(less than 7 years) and those with significant dose to the left

temporal lobe/hippocampus. The incidence of endocrinopathy

correlated with a mean dose of greater than or equal to 40 GyRBE

to the hypothalamus, pituitary, or optic chiasm. Stabilization or

improvement of visual acuity was achieved in 83.3 % of patients

at risk for radiation‐induced injury to the optic pathways. The

authors concluded that this report of late effects in children with

low‐grade gliomas after PBT is encouraging. Proton beam therapy

appears to be associated with good clinical outcome, especially

when the tumor location allows for increased sparing of the left

temporal lobe, hippocampus, and hypothalamic‐pituitary axis.

The authors also stated that larger cohorts are likely needed to

enable accurate assessment of the incidence of moyamoya

disease after PBT.

In a review on “Promise and pitfalls of heavy‐particle therapy”,

Mitin and Zietman (2014) stated that “In others, the benefits are

likely to be small or non‐existent such as with skin cancer; and

proton beam therapy should not be considered”.

Li et al (2011) stated that the papillary tumor of the pineal region

(PTPR) is a distinct entity that is particularly rare in the pediatric

population. The authors documented the youngest reported

patient with this clinicopathological entity to date. These

researchers described the case of PTPR in a 15‐month old boy.

Initially thought to be a tectal glioma, the tumor was later

identified as a pineal region tumor after demonstrating growth on

routine imaging. Diagnosis of PTPR was established by

histopathological evaluation of biopsy samples, which revealed

papillary, cystic, and solid tumor components. The patient's post‐

operative course was complicated by tumor growth despite

several debulking procedures and chemotherapy, as well as


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persistent hydrocephalus requiring 2 endoscopic third

ventriculostomies and eventual ventriculo‐peritoneal shunt

placement. After a 15‐month follow‐up period, the patient has

received proton‐beam therapy (PBT) and has a stable tumor size.

The PTPR is a recently described tumor of the CNS that must be

included in the differential diagnosis of pineal region masses. The

biological behavior, prognosis, and appropriate treatment of PTPR

have yet to be fully defined.

An UpToDate review on “Pineal gland masses” (Moschovi and

Chrousos, 2014) does not mention PBT as a therapeutic option.

Clivio et al (2013) evaluated intensity modulated proton therapy

(IMPT) in patients with cervical cancer in terms of coverage,

conformity, and DVH parameters correlated with

recommendations from magnetic resonance imaging (MRI)‐

guided brachytherapy. A total of 11 patients with histologically

proven cervical cancer underwent primary chemo‐radiation for

the pelvic lymph nodes, the uterus, the cervix, and the

parametric region, with a symmetric margin of 1 cm. The

prescription was for 50.4 Gy, with 1.8 Gy per fraction. The

prescribed dose to the parametria was 2.12 Gy up to 59.36 Gy in

28 fractions as a simultaneous boost. For several reasons, the

patients were unable to undergo brachytherapy. As an

alternative, IMPT was planned with 5 fractions of 6 Gy to the

cervix, including the macroscopic tumor with an MRI‐guided

target definition, with an isotropic margin of 5 mm for PTV

definition. Groupe‐Europeen de Curietherapie and European

society for Radiotherapy and Oncology (GEC‐ESTRO) criteria were

used for DVH evaluation. Reference comparison plans were

optimized for volumetric modulated rapid arc (VMAT) therapy

with the RapidArc (RA). The dose to the high‐risk volume was

calculated with α/β = 10 with 89.6 Gy. For IMPT, the clinical

target volume showed a mean dose of 38.2 ± 5.0 Gy (35.0 ± 1.8

Gy for RA). The D98% was 31.9 ± 2.6 Gy (RA: 30.8 ± 1.0 Gy). With

regard to the organs at risk, the 2Gy Equivalent Dose (EQD2) (α/β

= 3) to 2 cm(3) of the rectal wall, sigmoid wall, and bladder wall

was 62.2 ± 6.4 Gy, 57.8 ± 6.1 Gy, and 80.6 ± 8.7 Gy (for RA: 75.3 ±

6.1 Gy, 66.9 ± 6.9 Gy, and 89.0 ± 7.2 Gy, respectively). For the

IMPT boost plans in combination with external beam radiation


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therapy, all DVH parameters correlated with less than 5 % risk for

grades 2 to 4 late gastro‐intestinal and genitourinary toxicity. The

authors concluded that in patients who are not eligible for

brachytherapy, IMPT as a boost technique additionally to external

beam radiation therapy provides good target coverage and

conformity and superior DVH parameters, compared with

recommendations to MRI‐guided brachytherapy. They stated that

for selected patients, IMPT might be a valid alternative to

brachytherapy and also superior to reference VMAT plans. (These

preliminary findings from a small study [n = 11] need to be

validated by well‐designed studies).

UpToDate reviews on “Approach to adjuvant treatment of

endometrial cancer” (Plaxe and Mundt, 2014) and “Treatment of

recurrent or metastatic endometrial cancer” (Campos and Cohn,

2014) do not mention proton beam therapy as a therapeutic

option.

Moreover, the National Comprehensive Cancer Network’s clinical

practice guideline on “Uterine cancer” (Version 1.2015) does not

list proton beam therapy as a therapeutic option.

An UpToDate review on “Management of anaplastic

oligodendroglial tumors” (van den Bent, 2014) does not mention

proton beam therapy as a therapeutic option.

Romesser et al (2016) stated that re‐irradiation therapy (re‐RT) is

the only potentially curative treatment option for patients with

locally recurrent head and neck cancer (HNC). Given the

significant morbidity with head and neck re‐RT, interest in proton

beam radiation therapy (PBRT) has increased. These investigators

reported the first multi‐institutional clinical experience using

curative‐intent PBRT for re‐RT in recurrent HNC. A retrospective

analysis of ongoing prospective data registries from 2 hybrid

community practice and academic proton centers was

conducted. Patients with recurrent HNC who underwent at least

1 prior course of definitive‐intent external beam radiation therapy

(RT) were included. Acute and late toxicities were assessed with

the National Cancer Institute Common Te rminology Criteria for

Adverse Events version 4.0 and the Radiation Therapy Oncology


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Group late radiation morbidity scoring system, respectively. The

cumulative incidence of loco‐regional failure was calculated with

death as a competing risk. The actuarial 12‐month freedom‐

from‐distant metastasis and overall survival (OS) rates were

calculated with the Kaplan‐Meier method. A total of 92

consecutive patients were treated with curative‐intent re‐RT with

PBRT between 2011 and 2014. Median follow‐up among

surviving patients was 13.3 months and among all patients was

10.4 months. The median time between last RT and PBRT was

34.4 months. There were 76 patients with 1 prior RT course and

16 with 2 or more courses. The median PBRT dose was 60.6 Gy

(relative biological effectiveness, [RBE]); 85 % of patients

underwent prior HNC RT for an oropharynx primary, and 39 %

underwent salvage surgery before re‐RT. The cumulative

incidence of loco‐regional failure at 12 months, with death as a

competing risk, was 25.1 %. The actuarial 12‐month freedom‐

from‐distant metastasis and OS rates were 84.0 % and 65.2 %,

respectively. Acute toxicities of grade 3 or greater included

mucositis (9.9 %), dysphagia (9.1 %), esophagitis (9.1 %), and

dermatitis (3.3 %). There was 1 death during PBRT due to disease

progression. Grade 3 or greater late skin and dysphagia toxicities

were noted in 6 patients (8.7 %) and 4 patients (7.1 %),

respectively; 2 patients had grade 5 toxicity due to treatment‐

related bleeding. The authors concluded that proton beam re‐RT

of the head and neck can provide effective tumor control with

acceptable acute and late toxicity profiles likely because of the

decreased dose to the surrounding normal, albeit previously

irradiated, tissue, although longer follow‐up is needed to confirm

these findings.

McDonald et al (2016) reported the clinical outcomes of head and

neck re‐RT with proton therapy. From 2004 to 2014, a total of 61

patients received curative‐intent proton re‐irradiation, primarily

for disease involving skull base structures, at a median of 23

months from the most recent previous course of radiation. Most

had squamous cell (52.5 %) or adenoid cystic (16.4 %) carcinoma.

Salvage surgery before re‐irradiation was undertaken in 47.5 %.

Gross residual disease was present in 70.5 %. For patients with

microscopic residual disease, the median dose of re‐irradiation

was 66 Gy (relative biological effectiveness), and for gross disease


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was 70.2 Gy (relative biological effectiveness). Concurrent

chemotherapy was given in 27.9 %. The median follow‐up time

was 15.2 months and was 28.7 months for patients remaining

alive. The 2‐year OS estimate was 32.7 %, and the median OS

was 16.5 months. The 2‐year cumulative incidence of local failure

with death as a competing risk was 19.7 %; regional nodal failure,

3.3 %; and distant metastases, 38.3 %. On multi‐variable analysis,

Karnofsky performance status less than or equal to 70 %, the

presence of a gastrostomy tube before re‐irradiation, and an

increasing number of previous courses of radiation therapy were

associated with a greater hazard ratio for death. A cutaneous

primary tumor, gross residual disease, increasing gross tumor

volume, and a lower radiation dose were associated with a

greater hazard ratio for local failure. Grade greater than or equal

to 3 toxicities were seen in 14.7 % acutely and 24.6 % in the late

setting, including 3 treatment‐related deaths. The authors

concluded that re‐irradiation with proton therapy, with or

without chemotherapy, provided reasonable loco‐regional

disease control, toxicity profiles, and survival outcomes for an

advanced‐stage and heavily pre‐treated population. Moreover,

they stated that additional data are needed to identify which

patients are most likely to benefit from aggressive efforts to

achieve local disease control and to evaluate the potential benefit

of proton therapy relative to other modalities of re‐irradiation.

Desmoid Fibromatosis:

UpToDate reviews on “Desmoid tumors: Epidemiology, risk

factors, molecular pathogenesis, clinical presentation, diagnosis,

and local therapy” (Ravi et al, 2016) and “Desmoid tumors:

Systemic therapy” (Ravi and Patel, 2016) do not mention PBT as a

therapeutic option.

Hemangioendothelioma:

Hemangioendothelioma refers to a group of vascular neoplasms

that may be considered benign as well as malignant, depending

on the specific group member's activity. The primary treatment

of intra‐cranial hemangioendothelioma is surgical excision.

Although some have advocated adjuvant radiotherapy or


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chemotherapy, there is insufficient evidence on the use of PBT for

hemangioendotheliomas. The “Consensus‐derived practice

standards plan for complicated Kaposiform

hemangioendothelioma” (Drolet et al, 2013) had no

recommendation for PBT.

An UpToDate review on “Tufted angioma, kaposiform

hemangioendothelioma, and the Kasabach‐Merritt phenomenon”

(Adams and Frieden, 2016) does not mention PBT as a therapeutic

option.

Mesothelioma:

Cao and colleagues (2014) noted that IMPT is commonly

delivered via the spot‐scanning technique. To “scan” the target

volume, the proton beam is controlled by varying its energy to

penetrate the patient's body at different depths. Although

scanning the proton beamlets or spots with the same energy can

be as fast as 10 to 20 m s(‐1), changing from one proton energy to

another requires approximately 2 additional seconds. The total

IMPT delivery time thus depends mainly on the number of proton

energies used in a treatment. Current treatment planning

systems typically use all proton energies that are required for the

proton beam to penetrate in a range from the distal edge to the

proximal edge of the target. The optimal selection of proton

energies has not been well‐studied. In this study, these

researchers sought to determine the feasibility of optimizing and

reducing the number of proton energies in IMPT planning. They

proposed an iterative mixed‐integer programming optimization

method to select a subset of all available proton energies while

satisfying dosimetric criteria. They applied their proposed

method to 6 patient datasets: 4 cases of prostate cancer, 1 case of

lung cancer, and 1 case of mesothelioma. The numbers of

energies were reduced by 14.3 % to 18.9% for the prostate cancer

cases, 11.0 % for the lung cancer cases and 26.5 % for the

mesothelioma case. The results indicated that the number of

proton energies used in conventionally designed IMPT plans can

be reduced without degrading dosimetric performance. The

IMPT delivery efficiency could be improved by energy layer

optimization leading to increased throughput for a busy proton


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center in which a delivery system with slow energy switch is

employed. This was a small (n = 6; 1 case of mesothelioma)

feasibility study; it did not provide any data regarding the

effectiveness of PBRT for the treatment of mesothelioma.

In a case‐series study, Pan et al (2015) described their experience

implementing IMPT for lung‐intact malignant pleural

mesothelioma (MPM), including patient selection, treatment

planning, dose verification, and process optimization. A total of 7

patients with epithelioid MPM were reviewed; 6 underwent

pleurectomy, whereas 1 had biopsy alone. Four patients received

IMPT and 3 received intensity modulated radiation therapy.

Treatment plans for the other modality were created for

dosimetric comparisons. Quality assurance processes included

dose verification and robustness analysis. Image‐guided set‐up

was performed with the first isocenter, and couch shifts were

applied to reposition to the second isocenter. Treatment with

IMPT was well‐tolerated and completed without breaks. IMPT

plans were designed with 2 isocenters, 4 beams, and ≤64 energy

layers per beam. Dose verification processes were completed in 3

hours. Total daily treatment time was approximately 45 minutes

(20 minutes for set‐up and 25 minutes for delivery). IMPT

produced lower mean doses to the contralateral lung, heart,

esophagus, liver, and ipsilateral kidney, with increased

contralateral lung sparing when mediastinal boost was required

for nodal disease. The authors concluded that their initial

experience showed that IMPT was feasible for routine care of

patients with lung‐intact MPM. This was a small (n = 4) feasibility

study; it did not provide any data regarding the effectiveness of

PBRT for the treatment of mesothelioma.

Retroperitoneal/Pelvic Sarcoma:

Kelly et al (2015) compared outcomes of patients with

retroperitoneal or pelvic sarcoma treated with peri‐operative (RT

versus those treated without peri‐operative RT. Prospectively

maintained databases were reviewed to retrospectively compare

patients with primary retroperitoneal or pelvic sarcoma treated

during 2003 to 2011. Multivariate Cox regression models were

used to assess associations with the primary end‐points: local


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recurrence‐free survival (LRFS) and disease‐specific survival. At 1

institution, 172 patients were treated with surgery alone,

whereas at another institution 32 patients were treated with

surgery and peri‐operative PBRT or IMRT with or without intra‐

operative RT. The groups were similar in age, tumor size, grade,

and margin status (all p > 0.08). The RT group had a higher

percentage of pelvic tumors (p = 0.03) and a different distribution

of histologies (p = 0.04). Peri‐operative morbidity was higher in

the RT group (44 % versus 16 % of patients; p = 0.004). After a

median follow‐up of 39 months, 5‐year LRFS was 91 % (95 % CI:

79 % to 100 %) in the RT group and 65 % (57 % to 74 %) in the

surgery‐only group (p = 0.02). On multivariate analysis, RT was

associated with better LRFS (HR, 0.26; p = 0.03); 5‐year disease‐

specific survival was 93 % (95 % CI: 82 % to 100 %) in the RT

group and 85 % (78 % to 92 %) in the surgery‐only group (p = 0.3).

The authors concluded that the addition of advanced‐

modality RT to surgery for primary retroperitoneal or pelvic

sarcoma was associated with improved LRFS, although this did

not translate into significantly better disease‐specific survival.

They stated that this treatment strategy warrants further

investigation in a randomized trial.

Salivary Gland Tumors:

An UpToDate review on “Salivary gland tumors: Treatment of

locoregional disease” (Lydiatt and Quivey, 2016) mentions

neutrons and carbon ions, but not protons, for the treatment of

salivary gland tumors.

Choroidal Melanoma:

In a retrospective review, Patel and colleagues (2016) reported

visual outcomes in patients undergoing PBRT of tumors located

within 1 disc diameter of the fovea. Patients with choroidal

melanoma involving the fovea treated with proton beam therapy

between 1975 and 2009 were included in this analysis. A total of

351 patients with choroidal melanomas located 1 disc diameter

(DD) or less from the fovea and more than 1 DD away from the

optic nerve were included in this study. In a subgroup of 203 of

the patients with small and medium choroidal melanomas, the


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effect of a reduced dose of radiation, 50 Gy (relative biological

effectiveness [RBE]) versus 70 Gy (RBE), on visual outcomes was

analyzed. The Kaplan‐Meier method and Cox regression analysis

were performed to calculate cumulative rates of vision loss and to

assess risk factors for vision loss, respectively. Visual acuity (VA)

and radiation complications, which included radiation

maculopathy, papillopathy, retinal detachment, and rubeosis,

were assessed. This study had a mean follow‐up time of 68.7

months. More than 1/3 of patients (35.5 %) retained 20/200 or

better vision 5 years after PBRT. For those patients with a

baseline VA of 20/40 or better, 16.2 % of patients retained this

level of vision 5 years after PBRT. Tu mor height less than 5 mm

and baseline VA 20/40 or better were associated significantly with

a better visual outcome (p < 0.001). More than 2/3 (70.4 %) of

patients receiving 50 Gy (RBE) and nearly half (45.1 %) of patients

receiving 70 Gy (RBE) retained 20/200 or better vision 5 years

after treatment, but this difference was not significant.

Approximately 20 % of patients with these smaller macular

tumors retained 20/40 vision or better 5 years after irradiation.

The authors concluded that the results of this retrospective

analysis demonstrated that despite receiving a full dose of

radiation to the fovea, many patients with choroidal melanoma

with foveal involvement maintain useful vision. A radiation dose

reduction from 70 to 50 Gy (RBE) did not appear to increase the

proportion of patients who retain usable vision. The major

drawbacks of this study were: (i) its retrospective design, and (ii)

despite decreasing the risk of coincidental maculopathy and

papillopathy by choosing tumors more than 1 DD away from the

optic nerve, there is still a definite overlap in the incidence of

maculopathy and papillopathy occurring in these patients. These

researchers were unable to distinguish whether the cause of

vision loss in individual patient was the result of radiation effects

on the macula or the optic nerve. The authors stated that further

elucidation of factors that distinguish the small minority of

patients able to retain excellent vision is needed for future

improvement of visual outcomes.

Desmoid Tu mor (Aggressive Fibromatosis):

UpToDate reviews on “Desmoid tumors: Epidemiology, risk


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factors, molecular pathogenesis, clinical presentation, diagnosis,

and local therapy” (Ravi et al, 2016) and “Desmoid tumors:

Systemic therapy” (Ravi and Patel, 2016) do not mention PBT as a

therapeutic option.

Multiple Myeloma:

UpToDate reviews on “Overview of the management of multiple

myeloma” (Rajkumar, 2016a) and “Treatment of relapsed or

refractory multiple myeloma” (Rajkumar, 2016b) do not mention

proton beam therapy as a therapeutic option.

Furthermore, National Comprehensive Cancer Network’s clinical

practice guideline on “Multiple myeloma” (Version 3.2017) does

not mention proton beam therapy as a therapeutic option.

Thymic Tu mor:

Vogel et al (2016) stated that radiation is an important modality

in treatment of thymic tumors. However, toxicity may reduce its

overall benefit. These researchers hypothesized that double‐

scattering proton beam therapy (DS‐PT) can achieve excellent

local control with limited toxicity in patients with thymic

malignancies. Patients with thymoma or thymic carcinoma

treated with DS‐PT between 2011 and 2015 were prospectively

analyzed for toxicity and patterns of failure on an IRB‐approved

study. A total of 27 consecutive patients were evaluated.

Patients were a median of 56 years and had thymoma (85 %).

They were treated with definitive (22 %), salvage (15 %) or

adjuvant (63 %) DS‐PT to a median of 61.2/1.8 Gy [CGE]. No

patient experienced grade greater than or equal to 3 toxicity.

Acute grade 2 toxicities included dermatitis (37 %), fatigue (11 %),

esophagitis (7 %), and pneumonitis (4 %). Late grade 2 toxicity

was limited to 1 patient with chronic dyspnea. At a median

follow‐up of 2 years, 100 % local control was achieved; 3‐year

regional control, distant control, and overall survival (OS) rates

were 96 % (95 % confidence interval [CI]: 76 to 99 %), 74 % (95 %

CI: 41 to 90 %), and 94 % (95 % CI: 63 to 99 %), respectively. The

authors concluded that this was the first cohort and prospective

series of proton therapy to treat thymic tumors, demonstrating


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low rates of early toxicity and excellent initial outcomes.

Parikh et al (2016) evaluated the dosimetric differences between

proton beam therapy (PBT) and intensity modulated radiation

therapy (IMRT) for resected thymoma. These investigators

simultaneously reported their early clinical experience with PBT

in this cohort. These researchers identified 4 patients with

thymoma or thymic carcinoma treated at their center from 2012

to 2014 who completed adjuvant PBT to a median dose of 57.0

cobalt Gy equivalents (CGE; range of 50.4 to 66.6 CGE) after

definitive resection. Adjuvant radiation was indicated for positive

(n = 3) or close margin (n = 1). Median age was 45 (range of 32 to

70) years. Stages included II (n = 2), III (n = 1), and IVA (n = 1).

Analogous IMRT plans were generated for each patient for

comparison, and pre‐set dosimetric end‐points were evaluated.

Early toxicities were assessed according to retrospective chart

review. Compared with IMRT, PBT was associated with lower

mean doses to the lung (4.6 versus 8.1 Gy; p = 0.02), esophagus

(5.4 versus 20.6 Gy; p = 0.003), and heart (6.0 versus 10.4 Gy; p =

0.007). Percentages of lung, esophagus, and heart receiving

radiation were consistently lower in the PBT plans over a wide

range of radiation doses. There was no difference in mean breast

dose (2.68 versus 3.01 Gy; p = 0.37). Of the 4 patients treated

with PBT, 3 patients experienced grade 1 radiation dermatitis, and

1 patient experienced grade 2 dermatitis, which resolved after

treatment. With a median follow‐up of 5.5 months, there were

no additional grade greater than or equal to 2 acute or sub‐acute

toxicities, including radiation pneumonitis. The authors

concluded that PBT is clinically well‐tolerated after surgical

resection of thymoma, and was associated with a significant

reduction in dose to critical structures without compromising

coverage of the target volume. Moreover, they stated that

prospective evaluation and longer follow‐up is needed to assess

clinical outcomes and late toxicities.

Furthermore, National Comprehensive Cancer Network’s clinical

practice guideline on “Thymomas and thymic carcinomas”

(Version 3.2016) does not mention proton beam radiotherapy as

a therapeutic option.


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Yo lk Cell Tu mor:

Park et al (2015) performed dosimetric comparisons between

proton beam therapy and intensity modulated radiotherapy

(IMRT) of intra‐cranial germ cell tumors (ICGCTs) arising in various

locations of the brain. IMRT, passively scattered proton therapy

(PSPT), and spot scanning proton therapy (SSPT) plans were

performed for 4 different target volumes: (i) the whole ventricle

(WV), (ii) pineal gland (PG), (iii) supra‐sellar (SS), and (iv) basal

ganglia (BG); 5 consecutive clinical cases were selected from the

patients treated between 2011 and 2014 for each target volume.

A total 20 cases from the 17 patients were included in the

analyses with 3 overlap cases which were used in plan

comparison both for the whole ventricle and boost targets. The

conformity index, homogeneity index, gradient index, plan quality

index (PQI), and doses applied to the normal substructures of the

brain were calculated for each treatment plan. The PQI was

significantly superior for PSPT and SSPT than IMRT for ICGCTs in

all locations (median; WV: 2.89 and 2.37 versus 4.06, PG: 3.38

and 2.70 versus 4.39, SS: 3.92 and 2.49 versus 4.46, BG: 3.01 and

2.49 versus 4.45). PSPT and SSPT significantly reduced the mean

dose, and the 10 and 15 Gy dose volumes applied to the normal

brain compared with IMRT (p ≤ 0.05). PSPT and SSPT saved

significantly greater volumes of the temporal lobes and

hippocampi (p < 0.05) in the SS and PG targets than IMRT. For

tumors arising in the BG, PSPT and SSPT also saved greater

volumes of the contralateral temporal lobes. The authors

concluded that PSPT and SSPT provided superior target volume

coverage and saved more normal tissue compared with IMRT for

ICGCTs in various locations. Moreover, they stated that future

studies should examine if the extent of normal tissue saved has

clinical benefits in children with ICGCTs.

Furthermore, an UpToDate review on “Diagnosis and treatment

of relapsed and refractory testicular germ cell tumors” (Gilligan

and Kantoff, 2016) does not mention proton beam radiotherapy

as a therapeutic option.

Neutron Beam Therapy:


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Most radiation therapies utilize photons ‐‐ lightweight particles

that damage cancerous cells. Neutron beam therapy (NBT) uses

neutrons, which are much heavier than photons and appear to be

more effective in destroying very dense tumors. Compared to

roentgen ray (X‐ray), neutrons are characterized by several

properties: (i) reduced oxygen enhancement factor, (ii) less or no

repair of sub‐lethal or potentially lethal cell damage, and (iii) less

variation of sensitivity through cell cycle.

Neutron beam radiation therapy (NBRT) is a specialized type of

EBRT that uses high energy neutrons (neutral charged subatomic

particles). The neutrons are targeted toward tissue masses that

are characterized by lower tumor oxygen levels and a slower cell

cycle, since neutrons require less oxygen and are less dependent

on the cell’s position in the cell division cycle. Neutrons impact

with approximately 20 to 100 times more energy than

conventional photon radiation and may be more damaging to

surrounding tissues. For that reason, the radiation is delivered

utilizing a sophisticated planning and delivery system.

Neutron beam therapy entails the use of a particle accelerator;

protons from the accelerator are deflected by a magnet to a

target which creates the neutron beam. Neutron bean therapy

has been employed mainly for the treatment of the salivary gland

cancers. It has also been used to treat other malignancies such as

soft tissue sarcoma (STS) as well as lung, pancreatic, colon, kidney

and prostate cancers. Nevertheless, NBT has not gained wide

acceptance because of the clinical difficulty in generating neutron

particles. It should be noted that NBT is different from boron

neutron capture therapy (BNCT), which is a radiotherapy based

on the preferential targeting of tumor cells with non‐radioactive

isotope (10)B and subsequent activation with thermal neutrons

to produce a highly localized radiation, and is often used to treat

brain tumors. In BNCT, the patient is given a drink containing

boron, which is taken up by tumor cells. The tumor is then

irradiated with a neutron beam, causing the boron to split into

two highly energetic particles (helium and lithium) that destroy

the cancerous cells while largely sparing adjacent healthy cells.

Salivary Gland Cancer:


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In the treatment of patients with salivary gland cancer, primary

radiation including NBT may play a role in certain histological

types or non‐operative patients (Day, 2004). Neutron beam

therapy has been most extensively used either for an

incompletely excised primary tumor or for recurrent disease.

In a randomized clinical study, Laramore and associates (1993)

compared the effectiveness of fast neutron radiotherapy versus

conventional photon and/or electron radiotherapy for

unresectable, malignant salivary gland tumors. Eligibility criteria

included either inoperable primary or recurrent major or minor

salivary gland tumors. Patients were stratified by surgical status

(primary versus recurrent), tumor size (less than or greater than 5

cm), and histology (squamous or malignant mixed versus other).

After a total of 32 patients were entered into this study, it

appeared that the group receiving fast neutron radiotherapy had

a significantly improved local/regional control rate and also a

borderline improvement in survival and the study was stopped

earlier than planned for ethical reasons. Twenty‐five patients

were study‐eligible and analyzable. Ten‐year follow‐up data for

this study was presented. On an actuarial basis, there was a

statistically‐significant improvement in local/regional control for

the neutron radiotherapy group (56 % versus 25 %, p = 0.009),

but there was no statistically significant improvement in OS (15 %

versus 25 %). Patterns of failure were analyzed and it was

demonstrated that distant metastases account for the majority of

failures on the neutron radiotherapy arm and local/regional

failures account for the majority of failures on the

photon/electron radiotherapy arm. Long‐term, treatment‐related

morbidity was analyzed and while the incidence of morbidity

graded "severe" was greater on the neutron arm, there was no

significant difference in "life‐threatening" complications. These

investigators concluded that fast neutron radiotherapy appeared

to be the treatment‐of‐choice for patients with inoperable

primary or recurrent malignant salivary gland tumors.

Prott et al (2000) reported their findings of fast neutron therapy

in 72 patients with adenoid cystic carcinoma (ACC) of the salivary

glands. The median age was 54 years; and the median follow‐up

was 50 months. This study showed that 39.1 % of the patients


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achieved a complete remission and 48.6 % achieved partial

remission. The survival probability was 86 % after 1 year, 73 %

after 2 years and 53 % after 5 years. The recurrence‐free survival

was 83 % after 1 year, 71 % after 2 years and 45 % after 5 years.

These investigators concluded that NBT appeared to have been

an effective treatment in these selected patients.

Huber and colleagues (2001) compared retrospectively

radiotherapy with neutrons, photons, and a photon/neutron

mixed beam in patients (n = 75) with advanced ACC of the head

and neck. Local control, survival, distant failure, and

complications were analyzed. Follow‐up ranged from 1 to 160

months (median 51 months), and the surviving patients had a

minimum follow‐up of 3 years at the time of analysis. The

actuarial 5‐year local control was 75 % for neutrons, and 32 % for

both mixed beam and photons (p = 0.015, log‐rank). This

advantage for neutrons in local control was not transferred to

significant differences in survival (p > 0.1). In multi‐variate

analysis post‐operative radiotherapy (p = 0.003) and small tumor

size (p = 0.01) were associated with high local control, while

primary therapy (p = 0.006) and negative lymph nodes (p = 0.01)

were associated with longer survival. While acute toxicity was

similar in all 3 radiotherapy groups, severe late grade 3 and 4

toxicity tended to be more prevalent (p > 0.1) with neutrons (19

%) than with mixed beam (10 %) and photons (4 %). These

researchers concluded that fast neutron radiotherapy provides

higher local control rates than a mixed beam and photons in

advanced, recurrent or not completely resected ACC of the major

and minor salivary glands. Neutron radiotherapy can be

recommended in patients with bad prognosis with

gross/macroscopic residual disease (R2 resection), with

unresectable tumors, or inoperable tumors.

Douglas et al (2003) evaluated the effectiveness of fast neutron

radiotherapy for the treatment of salivary gland neoplasms. Of

the 279 patients, 263 had evidence of gross residual disease at

the time of treatment, while16 had no evidence of gross residual

disease; 141 had tumors of a major salivary gland, and 138 had

tumors of minor salivary glands. The median follow‐up period

was 36 months (range of 1 to 142 months). The main outcome


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measures were local‐regional control, cause‐specific survival, and

freedom from metastasis. The 6‐year actuarial cause‐specific

survival rate was 67 %. Multi‐variate analysis revealed that low

group stage (I ‐ II) disease, minor salivary sites, lack of skull base

invasion, and primary disease were associated with a statistically

significant improvement in cause‐specific survival. The 6‐year

actuarial local‐regional control rate was 59 %. Multi‐variate

analysis revealed size 4 cm or smaller, lack of base of skull

invasion, prior surgical resection, and no previous radiotherapy to

have a statistically significant improved local‐regional control.

Patients without evidence of gross residual disease had a 100 %

6‐year actuarial local‐regional control. The 6‐year actuarial

freedom from metastasis rate was 64 %. Factors associated with

decreased development of systemic metastases included negative

lymph nodes at the time of treatment and lack of base of skull

involvement. The 6‐year actuarial rate of development of grade 3

or 4 long‐term toxicity (using the Radiation Therapy Oncology

Group and European Organization for Research on the Treatment

of Cancer criteria) was 10 %. No patient experienced grade 5

toxic effects. The authors concluded that NBT is an effective

treatment for patients with salivary gland neoplasms who have

gross residual disease and achieves excellent local‐regional

control in patients without evidence of gross disease.

Other Types of Cancer:

Russell et al (1994) evaluated the effectiveness of fast neutron

radiation therapy in treatment of locally advanced carcinomas of

the prostate (n = 178). Median follow‐up was 68 months (range

of 40 to 86 months). The 5‐year actuarial clinical local‐regional

failure rate was significantly better for neutron‐treated patients

than photon‐treated patients (11 % versus 32 %). When findings

of routine post‐treatment prostate biopsies were incorporated,

the resulting "histological" local‐regional tumor failure rates were

13 % for the neutron‐treated group versus 32 % for the photon‐

treated group (p = 0.01). Moreover, actuarial survival and cause‐

specific survival rates were statistically indistinguishable for the 2

patient cohorts, with 32 % of the neutron‐treated patient deaths

and 41 % of the photon‐treated patient deaths caused by

prostate cancer. Prostate specific antigen values were elevated in


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17 % of neutron‐treated patients and 45 % of photon‐treated

patients at 5 years (p < 0.001). Severe late complications of

treatment were higher for the neutron‐treated patients (11 %

versus 3 %), and were inversely correlated with the degree of

neutron beam shaping available at the participating institutions.

The authors concluded that high energy fast neutron

radiotherapy is safe and effective when adequate beam delivery

systems and collimation are available, and it is significantly

superior to external beam photon radiotherapy in the local‐

regional treatment of large prostate tumors.

In a review on the use of fast neutron radiation for the treatment

of prostatic adenocarcinomas, Lindsley et al (1998) stated that the

Radiation Therapy Oncology Group performed a multi‐

institutional randomized trial comparing mixed beam (neutron

plus photon) irradiation to conventional photon irradiation for the

treatment of locally advanced prostate cancer. A subsequent

randomized trial by the Neutron Therapy Collaborative Working

Group compared pure neutron irradiation to standard photon

irradiation. Both studies reported significant improvement in

loco‐regional control with neutron irradiation compared to

conventional photon irradiation in the treatment of locally

advanced prostate carcinoma. To date, only the mixed beam

study has demonstrated a significant survival benefit. Future

analysis of the larger Neutron Therapy Collaborative Working

Group trial at the 10‐year follow‐up should confirm whether or

not improved loco‐regional control translates into a survival

advantage.

Lindsley et al (1996) noted that a phase III clinical study

comparing NBT to photon radiotherapy for inoperable regional

non‐small cell lung cancer showed no overall improvement in

survival. However, a statistically significant improvement in

survival was observed in the subset of patients with squamous

cell histology. Engenhart‐Cabillic and colleagues (1998) discussed

the use of NBT in the management of locally advanced non‐

resectable primary or recurrent rectal cancer. They noted that

the value of radiation therapy in managing such patients is being

appreciated, although up to 40 % of the treated patients have no

symptomatic response. The authors also stated that over


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350 patients were entered in studies comparing NBT alone and

mixed‐beam treatments. At present, no therapeutic gain for

long‐lasting survival has been achieved. However, local control

and pain improvement seems to be better with NBT than with

photon therapy. There is insufficient evidence regarding the

effectiveness of NBT for rectal and lung cancers.

Strander et al (2003) stated that there is some evidence that

adjuvant radiation therapy in combination with conservative

surgery improves the local control rate in the treatment of STS of

extremities and trunk in patients with negative, marginal or

minimal microscopic positive surgical margins. A local control

rate of 90 % has been achieved. Improvement is obtained with

radiation therapy added in the case of intralesional surgery, but

the local control rate is somewhat lower. More studies are

needed on this issue. For STS in other anatomical sites,

retroperitoneum, head and neck, breast and uterus, there is only

weak indication of a benefit for the local control rate, with the use

of adjuvant radiation therapy. There is still insufficient data to

establish that pre‐operative radiotherapy is favorable compared

to post‐operative radiotherapy for local control in patients

presenting primarily with large tumors. One small study has

shown a possible survival benefit for pre‐operative radiotherapy.

There is fairly good evidence to suggest that the pre‐operative

setting results in more wound complications. There is no

randomized study comparing external beam radiotherapy and

brachytherapy. The data suggested that external beam

radiotherapy and low‐dose rate brachytherapy result in

comparable local control for high‐grade tumors. Some patients

with low‐grade STS benefit from external beam radiotherapy in

terms of local control. Brachytherapy with low‐dose rate for low‐

grade tumors seems to be of no benefit, but data are sparse. The

available data are inconclusive concerning the effect of intra‐

operative high‐dose rate radiotherapy for retroperitoneal STS.

Further studies are needed. Neutron radiotherapy might be

beneficial for patients with low‐grade and intermediate‐grade

tumors considered inoperable and for those operated with

intralesional margins. More severe adverse effects for NBT have

been reported.


47 of 73 5/9/17, 11:20 AM


Murray (2004) noted that the commonest STS of the upper

extremity are the epithelioid sarcoma, synovial cell sarcoma, and

malignant fibrous histiocytoma. Limb salvage surgery is the

treatment of choice for STS to preserve upper extremity

function. Following wide tumor resection, adjuvant therapies

such as chemotherapy, external beam radiation therapy, and

brachytherapy may lessen local recurrence rates, but their effect

on overall survival remains unclear.

A review by Hassen‐Khodja and Lance (2003) stated that the

efficacy of NBT is well‐established only for the treatment of

inoperable or unresectable salivary gland tumors, regardless of

their degree of malignancy or stage of progression, and for the

treatment of large residual tumors after surgical resection. The

authors also examined the data on the effectiveness of for NBT in

the treatment of malignant prostate tumors, STS and central

nervous system tumors. However, these data are insufficient to

rule on its therapeutic efficacy.

An assessment of the evidence for neutron beam radiotherapy

prepared by the Australia and New Zealand Horizon Scanning

Network (Purins et al, 2007) found that NBT is a promising

technology. The assessment cautioned, however, that "[t]he

studies identified in this prioritising summary were not of high

quality and, as such, the conclusions must be taken as preliminary

in nature."

In a phase I study, Kankaanranta and colleagues (2011) examined

the safety of BNCT in the treatment of malignant gliomas that

progress after surgery and conventional external beam radiation

therapy. Adult patients who had histologically confirmed

malignant glioma that had progressed after surgery and external

beam radiotherapy were included in this study, provided that

greater than 6 months had elapsed from the last date of radiation

therapy. The first 10 patients received a fixed dose, 290 mg/kg, of

l‐boronophenylalanine‐fructose (l‐BPA‐F) as a 2‐hour infusion

before neutron irradiation, and the remaining patients were

treated with escalating doses of l‐BPA‐F, either 350 mg/kg, 400

mg/kg, or 450 mg/kg, using 3 patients on each dose level.

Adverse effects were assessed using National Cancer Institute


48 of 73 5/9/17, 11:20 AM


Common Toxicity Criteria version 2.0. A total of 22 patients

entered the study. Twenty subjects had glioblastoma, and 2

patients had anaplastic astrocytoma, and the median cumulative

dose of prior external beam radiotherapy was 59.4 Gy. The

maximally tolerated l‐BPA‐F dose was reached at the 450 mg/kg

level, where 4 of 6 patients treated had a grade 3 adverse event.

Patients who were given more than 290 mg/kg of l‐BPA‐F

received a higher estimated average planning target volume dose

than those who received 290 mg/kg (median of 36 versus 31 Gy

[W, i.e., a weighted dose]; p = 0.018). The median survival time

following BNCT was 7 months. The authors concluded that BNCT

administered with an l‐BPA‐F dose of up to 400 mg/kg as a 2‐hour

infusion is feasible in the treatment of malignant gliomas that

recur after conventional radiation therapy.

Ghost Cell Odontogenic Carcinoma:

Martos‐Fernandez et al (2014) noted that ghost cell odontogenic

carcinoma is a rare condition characterized by ameloblastic‐like

islands of epithelial cells with aberrant keratinitation in the form

of ghost cell with varying amounts of dysplastic dentina. These

investigators reported a case of a 70‐year old woman with a rapid

onset of painful swelling right maxillary tumor. Magnetic

resonance showed a huge tumor dependent on the right half of

the right hard palate with invasion of the pterygoid process and

focally to the second branch of the trigeminal. Radiological stage

was T4N0. The patient underwent a right subtotal maxillectomy

with clear margins. Adjuvant radiotherapy was given. The patient

was free of residual or recurrent disease 12 months after

surgery. The tumor was 3.9 cm in diameter. It was spongy and

whitish gray. Microscopically the tumor was arranged in nets and

trabeculae, occasionally forming palisade. Tumoral cells had clear

cytoplasm with vesicular nuclei. There was atipia and mitosi with

vascular and peri‐neural invasion. The excised tumor was

diagnosed as a GCOC. The authors concluded that ghost cell

carcinoma is a rare odontogenic carcinoma. Its course is

unpredictable, ranging from locally invasive tumors of slow

growth to highly aggressive and infiltrative ones. Wide surgical

excision with clean margins is the treatment of choice although

its combination with post‐operative radiation therapy, with or


49 of 73 5/9/17, 11:20 AM


without chemotherapy, remains controversial. This was a single‐

case study, and it’s unclear whether NBT was used as adjuvant

radiotherapy. Moreover the authors stated that post‐operative

radiation therapy, with or without chemotherapy, remains

controversial.

Li et al (2014) stated that the diagnosis of ameloblastic carcinoma

is often difficult and the optimal treatment methods remain

controversial. The current study retrospectively investigated the

optimal diagnosis and treatment methods of 12 ameloblastic

carcinoma patients at the West China Hospital of Stomatology,

Sichuan University (Chengdu, China), and 20 patients selected

from the PubMed database, were reviewed. The clinical features,

diagnosis and outcome of the different treatments were

evaluated. Ameloblastic carcinoma occurred in 12 out of a total

of 538 ameloblastoma patients; the majority were of the primary

type. Of the 538 ameloblastoma patients, 294 were males, 244

were females with a male to female ratio of 1.2:1. The

predilection age is 20 to 30 years, which accounts for 40 % of the

total. In total, 461 cases were in the mandible and 77 were

located in the maxilla. The cure rate of the primary type and the

recurrence rate of the secondary type tumors were higher in the

patients from the West China Hospital of Stomatology compared

with those reported in the literature. In particular, a case with a

long‐term survival of 30 years was presented, which was

considered to be relatively rare. The evolution of the clinical

course has experienced 3 stages: Ameloblastoma (1978) followed

by metastatic ameloblastoma (2000) and finally ameloblastic

carcinoma (2008). To avoid recurrence, wide local excision with

post‐operative radiation therapy was required. While novel

therapeutic regimens should also be considered as appropriate,

including carbon ion therapy and Gamma Knife stereotactic

radiosurgery. However, controlled studies with larger groups of

patients are required to increase the accuracy of results. This

study did not mention ghost cell odontogenic carcinoma and NBT.

Furthermore, reviews on “Ghost cell odontogenic carcinoma”

(Martos‐Fernandez et al, 2014; Ahmed et al, 2015) do not

mention NBT as a therapeutic option.


50 of 73 5/9/17, 11:20 AM


CPT Codes / HCPCS Codes / ICD‐10 Codes

Informa'tion in the [brackets] below has been added for clarifica'tion

purposes. Codes requiring a 7th character are represented by "+":

Proton Beam Radiotherapy (PBRT):

CPT codes covered if selection criteria are met:

77520 Proton treatment delivery; simple, without

compensation

77522 simple, with compensation

77523 intermediate

77525 complex

Other CPT codes related to the CPB:

61796 Stereotactic radiosurgery (particle beam, gamma ray

or linear accelerator); 1 simple cranial lesion

+61797 each additional cranial lesion, simple (List separately

in addition to code for primary procedure)

61798 1 complex cranial lesion

+61799 each additional cranial lesion, complex (List

separately in addition to code for primary procedure)

63620 Stereotactic radiosurgery (particle beam, gamma ray,

or linear accelerator); 1 spinal lesion

+63621 each additional spinal lesion, complex (List


77432 Stereotactic radiation treatment management of

cranial lesion(s) (complete course of treatment

consisting of 1 session)

Other HCPCS codes related to the CPB:

S8030 Scleral application of tantalum ring(s) for localization

of lesions for proton beam therapy

ICD‐10 codes covered if selection criteria are met for adults:

C41.0 Malignant neoplasm of bones of skull and face

[Chordomas or chondrosarcomas arising at the base of

the skull or cervical spine without distant metastases]


51 of 73 5/9/17, 11:20 AM


C41.2 Malignant neoplasm of vertebral column [Chordomas

or chondrosarcomas arising at the base of the skull or

cervical spine without distant metastases]

C69.30 ‐

C69.32

Malignant neoplasm of choroid

C69.40 ‐ Malignant neoplasm of ciliary body [confined to globe

C69.42 ‐ not distant metastases]

C75.1 Malignant neoplasm of pituitary gland and

craniopharyngeal duct

C75.2 Malignant neoplasm of craniopharyngeal duct

D33.4 Benign neoplasm of spinal cord [Chordomas or

chondrosarcomas arising at the base of the skull or

cervical spine without distant metastases]

D43.0 ‐ Neoplasm of uncertain behavior of brain and spinal

D43.2, D43.4 cord [Chordomas or chondrosarcomas arising at the

base of the skull or cervical spine without distant

metastases]

ICD‐10 codes not covered for indications listed in the CPB for adults

(not all‐inclusive):

C01 ‐ C02.9 Malignant neoplasm of tongue [squamous cell

carcinoma]

C06.9 Malignant neoplasm of mouth, unspecified [Malignant

neoplasm of minor salivary gland, unspecified site]

C07 ‐ C08.9 Malignant neoplasm of major salivary glands

C09.0 ‐

C09.9

Malignant neoplasm of tonsil

C11.0 ‐

C11.9

Malignant neoplasm of nasopharynx [adenoid cystic

carcinoma] [nasopharngeal carcinoma]

C14.0 ‐

C14.8

Malignant neoplasm of other and ill‐defined sites

within the lip, oral cavity, and pharynx

C15.3 ‐

C15.9

Malignant neoplasm of esophagus

C17.0 ‐

C17.9

Malignant neoplasm of small intestine


52 of 73 5/9/17, 11:20 AM


C19 ‐ C21.8 Malignant neoplasm of rectum, rectosigmoid,

rectosigmoid junction, and anus

C22.0 ‐

C22.9

Malignant neoplasm of liver and intrahepatic bile

ducts [hepatocellular] [cholangiocarcinoma]

C25.0 ‐

C25.9

Malignant neoplasm of pancreas

C30.0 ‐

C31.9

Malignant neoplasm of nasal cavity, middle ear, and

accessory sinuses

C32.0 ‐

C32.9

Malignant neoplasm of larynx [squamous cell

carcinoma]

C34.00 ‐ Malignant neoplasm of bronchus and lung [including

C34.92 non‐small‐cell lung carcinoma]

C37 Malignant neoplasm of thymus

C40.0 ‐ Malignant neoplasm of bone and articular cartilage of

C40.92, limbs [Ewing's sarcoma] [hemangioendothelioma]

C31.1, C41.3

‐ C41.9

C43.0 ‐

C43.9

Malignant melanoma of skin

C44.01, Squamous cell carcinoma of skin of lip, eyelid including

C44.121 ‐ canthus, ear and external auditory canal, other and

C44.129 unspecified parts of face, or scalp and skin of neck

C44.221 ‐

C44.229,

C44.320 ‐

C44.329

C44.42

C44.42 Squamous cell carcinoma of skin of scalp and neck

C44.90 Unspecified malignant neoplasm of skin, unspecified

[Dermatofibrosarcoma protuberans]

C45.0 ‐

C45.9

Mesothelioma

C48.0 Malignant neoplasm of retroperitoneum

[retroperitoneal sarcoma]


53 of 73 5/9/17, 11:20 AM


C49.0 ‐

C49.9

Malignant neoplasm of connective and soft tissue [soft

tissue sarcoma] [desmoid fibrosarcoma] [fibrosarcoma

of extremities] [squamous cell carcinoma of the head

and neck][leiomyosarcoma of extremities]

[angiosarcoma] [hemangioendothelioma]

C50.01 ‐

C50.929

Malignant neoplasm of breast [male and female]

C53.0 ‐

C53.9

Malignant neoplasm of cervix uteri

C55 Malignant neoplasm of uterus, part unspecified

C57.4 Malignant neoplasm of uterine adnexa, unspecified

C61 Malignant neoplasm of prostate

C62.10 ‐

C62.92

Malignant neoplasm of testis

C67.0 ‐

C67.9

Malignant neoplasm of bladder

C70.0 ‐

C70.1

Malignant neoplasm of cerebral or spinal meninges

C71.0 ‐

C71.9

Malignant neoplasm of brain [not covered for glioma

or oligodendroglioma]

C72.0 ‐

C72.9

Malignant neoplasm of spinal cord, cranial nerves and

other parts of central nervous system

C75.0 Malignant neoplasm of pituitary gland and

craniopharyngeal duct

C75.3 Malignant neoplasm of pineal gland [pineal tumor]

C75.4 Malignant neoplasm of carotid body

C76.0 Malignant neoplasm of head, face and neck

C78.00 ‐

C78.02

Secondary malignant neoplasm of lung

C78.7 Secondary malignant neoplasm of liver and

intrahepatic bile duct

C79.31 ‐

C79.49

Secondary malignant neoplasm of brain, cerebral

meninges, and other and unspecified parts of nervous

system

C79.82 Secondary malignant neoplasm of genital organs


54 of 73 5/9/17, 11:20 AM


C79.89 Secondary malignant neoplasm of other specified sites

[carotid body] [submandibular gland]

C81.00 ‐

C81.99

Hodgkin's lymphoma

C82.00 ‐ Malignant neoplasms of lymphoid, hematopoietic and

C91.92 related tissue [non‐Hodgkin lymphoma]

D00.00 ‐

D00.08

Carcinoma in situ of lip, oral cavity, and pharynx

D02.3 Carcinoma in situ of other parts of respiratory system

[maxillary sinus tumor]

D10.39 Benign neoplasm of other parts of mouth [Benign

neoplasm of minor salivary gland NOS]

D10.6 Benign neoplasm of nasopharynx

D11.0 ‐

D11.9

Benign neoplasm of major salivary glands

D14.0 Benign neoplasm of middle ear, nasal cavity and

accessory sinuses [maxillary sinus tumor]

D18.00 ‐ Hemangioma [hemangioendothelioma]

D18.01,

D18.03

D18.02 Hemangioma of intracranial structures [cavernous

hemangioma]

D18.09 Hemangioma of other sites

D19.0 ‐

D19.9

Benign neoplasm of mesothelial tissue [benign

mesothelioma NOS]

D32.0 Benign neoplasm of cerebral meninges

D33.0 ‐

D33.2

Benign neoplasm of brain

D35.2 ‐

D35.3

Benign neoplasm of pituitary gland or

craniopharyngeal duct (pouch)

D35.4 Benign neoplasm of pineal gland [pineal tumor]

D35.5 Benign neoplasm of carotid body

D37.030 ‐ Neoplasm of uncertain behavior of major salivary

D37.039 glands


55 of 73 5/9/17, 11:20 AM


D38.5 Neoplasm of uncertain behavior of other and

unspecified respiratory organs [maxillary sinus tumor]

D44.6 ‐

D44.7

Neoplasm of uncertain behavior of paraganglia

[carotid body]

D48.1 Neoplasm of uncertain behavior of connective and

other soft tissue [desmoid fibromatosis]

D49.0 Neoplasm of unspecified behavior of digestive system

D49.1 Neoplasm of unspecified behavior of respiratory

system

D49.6 Neoplasm of unspecified behavior of brain

H35.051 ‐

H35.059

Retinal neovascularization, unspecified

H35.30 ‐

H35.3293

Macular degeneration (age‐related)

Q27.9 Congenital malformation of peripheral vascular

system, unspecified [cerebrovascular system] [arterio‐

venous malformations]

Q28.2 Arteriovenous malformation of cerebral vessels [Spinal

vessel anomaly] [arterio‐venous malformations]

ICD‐10 codes covered if selection criteria are met for children:

C00.0 ‐

C7a.8

D00.00 ‐

D09.9

Malignant neoplasm [radiosensitive]

Neutron Beam Therapy (NBT):

CPT codes covered if selection criteria are met:

61796 Stereotactic radiosurgery (particle beam, gamma ray

or linear accelerator); 1 simple cranial lesion

+ 61797 each additional cranial lesion, simple (List separately

in addition to code for primary procedure)

61798 1 complex cranial lesion

+ 61799 each additional cranial lesion, complex (List



56 of 73 5/9/17, 11:20 AM


77422 High energy neutron radiation treatment delivery;

single treatment area using a single port or parallel‐

opposed ports with no blocks or simple blocking

77423 1 or more isocenter(s) with coplanar or non‐

coplanar geometry with blocking and/or wedge,

and/or compensator(s)

ICD‐10 codes covered if selection criteria are met:

C07 ‐ C08.9 Malignant neoplasm of major salivary glands [locally

advanced, unresectable, or inoperable]

ICD‐10 codes not covered for indications listed in the CPB (not

all‐inclusive):

C00.0 ‐

C06.9

C09.0 ‐

C80.2

Malignant neoplasms [other than salivary gland]

[includes ghost cell odontogenic carcinoma]

The above policy is based on the following references:

Proton Beam Therapy:

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safe therapeutic option using proton irradiation for

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compared with conventional dose irradiation using protons

alone. Int J Radio Oncol Biol Phys. 1995;32:3‐12.

3. Raju MR. Proton radiobiology, radiosurgery and

radiotherapy. Int J Radiat Biol. 1995;67:237‐259.

4. Levin VA, Gutin PH, Leibel S. Neoplasms of the central

nervous system. In: Cancer: Principles and Practice of

Oncology. VT DeVita, S Hellman, AS Rosenberg, eds.

Philadelphia, PA: JB Lippincott; 1993: 1723‐1724.

5. Nahum AE, Dearnaley DP, Steel GG. Prospects for proton

beam radiotherapy. Eur J Canc. 1994;30A:1577‐1583.


57 of 73 5/9/17, 11:20 AM


6. Hanks GE. A question filled future for dose escalation in

prostate cancer. In J Radiation Oncol Biol Phys.

1995;32:267‐269.

7. Suit H, Urie M. Proton beams in radiation therapy. J Natl

Cancer Inst. 1992;84:155‐164.

8. Rossi CJ Jr, Slater JD, Reyes‐Molyneux N, et al. Particle beam

radiation therapy in prostate cancer: Is there an advantage?

Semin Radiat Oncol. 1998;8(2):115‐123.

9. Zelefsky MJ, Leibel SA, Kutcher GJ, Fuks Z. Three‐

dimensional conformal radiotherapy and dose escalation:

Where do we stand? Semin Radiat Oncol. 1998;8(2):107‐

114.

10. Fleurette F. Charvet‐Protat S. Proton and neutron radiation

in cancer treatment: Clinical and economic outcomes.

French National Agency for Medical Evaluation (ANDEM).

Bull Cancer Radiother. 1996;83(Suppl):223s‐227s.

11. Rossi CJ. Conformal proton beam therapy of prostate

cancer – update on the Loma Linda University medical

center experience. Strahlenther Onkol. 1999;175(Suppl

2):82‐84.

12. Yonemoto LT, Slater JD, Rossi CJ Jr, et al. Combined proton

and photon conformal radiation therapy for local advanced

carcinoma of the prostate: Preliminary results of a phase

I/II study. Int J Radiat Oncol Bio Phys. 1997;37(1):21‐29.

13. Slater JD, Yonemoto LT, Rossi CJ Jr, et al. Conformal proton

therapy for prostate carcinoma. Int J Radiat Oncol Bio Phys.

1998;42(2):229‐304.

14. Krengli M, Liebsch NJ, Hug EB, et al. Review of current

protocols for proton therapy in USA. Tumori.

1998;84(2):209‐216.

15. Hart KB, Porter AT. A rational approach to the treatment of

prostate cancer with radiation therapy: Lessons for the

future. Semin Oncol. 1997;24(6):745‐755.

16. Carroll PR, Presti JC Jr, Small E, et al. Focal therapy for

prostate cancer 1996: Maximizing outcome. Urology.

1997;49(3A Suppl):84‐94.

17. Habrand JL, Schlienger P, Schwartz L, et al. Clinical

applications of proton therapy. Experiences and ongoing

studies. Radiat Environ Biophys. 1995;34(1):41‐44.

18. Tsuji H, Inada T, Maruhashi A, et al. Clinical results of


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fractionated proton therapy. Int J Radiat Oncol Bio Phys.

1993;25(1):49‐60.

19. Bush DA, Slater JD, Bonnet R, et al. Proton‐beam

radiotherapy for early‐stage lung cancer. Chest.

1999;116(5):1313‐1319.

20. Habrand JL, Mammar H, Ferrand R, et al. Proton beam

therapy (PT) in the management of CNS tumors in

childhood. Strahlenther Onkol. 1999;175 Suppl 2:91‐94.

21. Hug EB, Slater JD. Proton radiation therapy for chordomas

and chondrosarcomas of the skull base. Neurosurg Clin N

Am. 2000;11(4):627‐638.

22. Krisch EB, Koprowski CD. Deciding on radiation therapy for

prostate cancer: The physician's perspective. Semin Urol

Oncol. 2000;18(3):214‐225.

23. Gragoudas ES, Lane AM, Regan S, et al. A randomized

controlled trial of varying radiation doses in the treatment

of choroidal melanoma. Arch Ophthalmol.

2000;118(6):773‐778.

24. Munzenrider JE. Uveal Melanomas. Conservation

treatment. Hematol Oncol Clin North Am.

2001;15(2):389‐402.

25. Bonnet RB, Bush D, Cheek GA, et al. Effects of proton and

combined proton/photon beam radiation on pulmonary

function in patients with resectable but medically

inoperable non‐small cell lung cancer. Chest.

2001;120(6):1803‐1810.

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cervical spine. Prognostic factors and patterns of failure.

Strahlenther Onkol. 2003;179(4):241‐248.

27. Egger E, Zografos L, Schalenbourg A, et al. Eye retention

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28. Noel G, Habrand JL, Helfre S, et al. Proton beam therapy in

the management of central nervous system tumors in

childhood: The preliminary experience of the Centre de

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29. Robertson DM. Changing concepts in the management of

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2003;136(1):161‐170.

30. Li W, Gragoudas ES, Egan KM. Tumor basal area and

metastatic death after proton beam irradiation for

choroidal melanoma. Arch Ophthalmol.

2003;121(1):68‐72.

31. Ciulla TA, Danis RP, Klein SB, et al. Proton therapy for

exudative age‐related macular degeneration: A

randomized, sham‐controlled clinical trial. Am J

Ophthalmol. 2002;134(6):905‐906.

32. Spatola C, Privitera G, Raffaele L, et al. Clinical application

of proton beams in the treatment of uveal melanoma: The

first therapies carried out in Italy and preliminary results

(CATANA Project). Tumori. 2003;89(5):502‐509.

33. Kagei K, Tokuuye K, Okumura T, et al. Long‐term results of

proton beam therapy for carcinoma of the uterine cervix.

Int J Radiat Oncol Biol Phys. 2003;55(5):1265‐1271.

34. Silander H, Pellettieri L, Enblad P, et al. Fractionated,

stereotactic proton beam treatment of cerebral

arteriovenous malformations. Acta Neurol Scand.

2004;109(2):85‐90.

35. Sivagnanavel V, Evans JR, Ockrim Z, Chong V. Radiotherapy

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36. Bush DA, Hillebrand DJ, Slater JM, Slater JD. High‐dose

proton beam radiotherapy of hepatocellular carcinoma:

Preliminary results of a phase II trial. Gastroenterology.

2004;127(5 Suppl 1):S189‐S193.

37. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of

conventional‐dose vs high‐dose conformal radiation

therapy in clinically localized adenocarcinoma of the

prostate: A randomized controlled trial. JAMA.

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38. Kawashima M, Furuse J, Nishio T, et al. Phase II study of

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carcinoma. J Clin Oncol. 2005;23(9):1839‐1846.

39. Nihei K, Ogino T, Ishikura S, et al. Phase II feasibility study of

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40. Al‐Shahi R, Warlow CP. Interventions for treating brain

arteriovenous malformations in adults. Cochrane Database

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41. Nihei K, Ogino T, Ishikura S, Nishimura H. High‐dose proton

beam therapy for Stage I non‐small‐cell lung cancer. Int J


42. Fitzek MM, Linggood RM, Adams J, Munzenrider JE.

Combined proton and photon irradiation for

craniopharyngioma: Long‐term results of the early cohort

of patients treated at Harvard Cyclotron Laboratory and

Massachusetts General Hospital. Int J Radiat Oncol Biol

Phys. 2006;64(5):1348‐1354.

43. Kozak KR, Smith BL, Adams J, et al. Accelerated partial‐

breast irradiation using proton beams: Initial clinical

experience. Int J Radiat Oncol Biol Phys.

2006;66(3):691‐698.

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45. Konski A, Speier W, Hanlon A, et al. Is proton beam therapy

cost effective in the treatment of adenocarcinoma of the

prostate? J Clin Oncol. 2007;25(24):3603‐3608.

46. Almefty K, Pravdenkova S, Colli BO, et al. Chordoma and

chondrosarcoma: Similar, but quite different, skull base

tumors. Cancer. 2007;110(11):2457‐2467.

47. Hata M, Tokuuye K, Kagei K, et al. Hypofractionated high‐

dose proton beam therapy for stage I non‐small‐cell lung

cancer: Preliminary results of a phase I/II clinical study. Int

J Radiat Oncol Biol Phys. 2007;68(3):786‐793.

48. Nishimura H, Ogino T, Kawashima M, et al. Proton‐beam

therapy for olfactory neuroblastoma. Int J Radiat Oncol Biol

Phys. 2007;68(3):758‐762.

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