Charged-Particle (Proton or Helium Ion) Radiotherapy for Neoplastic Conditions - CAM 80110

Description
Charged-particle beams consisting of protons or helium ions are a type of particulate radiotherapy. Treatment with charged-particle radiotherapy is proposed for a large number of tumors that would benefit from the delivery of a high dose of radiation with limited scatter, minimizing the radiation dose to surrounding normal tissues and critical structures.

Summary of Evidence
For individuals who have uveal melanoma(s) who receive charged-particle (proton or helium ion) radiotherapy, evidence includes long-term studies, randomized controlled trials (RCTs), and systematic reviews. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. Systematic reviews, including a 1996 TEC Assessment and a 2013 review of randomized and nonrandomized studies, concluded that the technology is at least as effective as alternative therapies for treating uveal melanomas and is better at preserving vision. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a skull-based tumor(s) (i.e., cervical chordoma, chondrosarcoma) who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes observational studies and systematic reviews. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. A 2007 systematic review found a 5-year overall survival rate of 81% with proton beam therapy (PBT) compared with 44% with surgery plus photon therapy. In 2018, a meta-analysis found 5-year and 10-year overall survival rates for proton beam therapy of 78% and 60% compared with 46% and 21% for conventional radiotherapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have pediatric central nervous system tumor(s) who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes case series, nonrandomized comparative studies, and systematic reviews. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. There are few comparative studies, and they tend to have small sample sizes. The available observational studies do not provide sufficient evidence on the efficacy of charged-particle therapy compared with other treatments (e.g., intensity-modulated radiotherapy). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have pediatric non-central nervous system tumor(s) who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes dosimetric planning studies in a small number of patients. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. For this population, there is a lack of randomized and observational studies evaluating the efficacy and safety of this technology. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have localized prostate cancer who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes two RCTs, systematic reviews, a single-arm study, and a database analysis. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. A 2010 TEC Assessment addressed the use of PBT for prostate cancer and concluded that it had not been established whether PBT improves outcomes in any setting for clinically localized prostate cancer. The TEC Assessment included 2 RCTs , only one of which had a comparison group of patients that did not receive PBT. A 2021 analysis of the National Cancer Database reported inferior survival outcomes with EBRT compared to PBT, but no significant survival difference when compared to brachytherapy.A large, ongoing phase 3 RCT comparing proton therapy to IMRT in prostate cancer may alter the conclusions of the TEC Assessment. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have non-small cell lung cancer who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes one RCT, case series and systematic reviews. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. A 2010 TEC Assessment, which included 8 case series, concluded that the evidence was insufficient to permit conclusions about PBT for any stage of non-small-cell lung cancer. A 2018 RCT failed to demonstrate superiority of passive scattering proton therapy (PSPT) to IMRT on the combined primary outcome of grade ≥3 radiation pneumonitis or local failure. An ongoing RCT comparing proton versus photon chemoradiation may alter the conclusions of the TEC Assessment.The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have head and neck tumors other than skull-based who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes case series, nonrandomized comparative studies, and a systematic review. Relevant outcomes are overall survival, disease-free survival, change in disease status, and treatment-related morbidity. The systematic review noted that the studies on charged-particle therapy were heterogenous in terms of the types of particles and delivery techniques used; further, there are no prospective head-to-head trials comparing charged-particle therapy with other treatments. Ongoing RCTs comparing intensity-modulated proton therapy (IMPT) to IMRT may elucidate effects on net health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information
In response to requests while this policy was under review in 2019, clinical input on use of charged-particle (proton or helium ion) beam therapy for various tumor indications was received from 3 respondents, including 2 specialty society-level responses and 1 physician-level response identified by an academic health system. In addition, the specialty society responses included multiple physicians with academic medical center affiliations.

Pediatric central nervous system tumors.

Clinical input and published guidelines support that the use of charged-particle beam therapy provides a clinically meaningful improvement in net health outcomes and is consistent with generally accepted medical practice in the following clinical scenarios, where treatment planning with conventional or advanced photon-based radiotherapy cannot meet dose-volume constraints for normal tissue radiation tolerance (see Policy Guidelines):

Curative treatment of primary or benign solid pediatric non-central nervous system tumors, including Ewing sarcoma;
Curative treatment of nonmetastatic primary non-small cell lung cancer;
Head and neck cancers.

Clinical input suggests a possible role of charged-particle beam therapy for the treatment of localized prostate cancer, but broad support for this use is pending until the results of an ongoing RCT comparing proton therapy to intensity-modulated radiotherapy (IMRT) become available.

Further details from clinical input are included in the Appendix.

Background
Charged-particle beams consisting of protons or helium ions are a type of particulate radiotherapy. They have several unique properties that distinguish them from conventional electromagnetic (i.e., photon) radiotherapy, including minimal scatter as particulate beams pass through tissue, and deposition of ionizing energy at precise depths (i.e., the Bragg peak). Thus, radiation exposure of surrounding normal tissues and critical structures is minimized. The theoretical advantages of protons and other charged-particle beams may improve outcomes when the following conditions apply:

Conventional treatment modalities do not provide adequate local tumor control;
Evidence shows that local tumor response depends on the dose of radiation delivered; and
Delivery of adequate radiation doses to the tumor is limited by the proximity of vital radiosensitive tissues or structures.

Regulatory Status
Radiotherapy is a procedure and, therefore, not subject to U.S. Food and Drug Administration (FDA) regulations. However, the accelerators and other equipment used to generate and deliver charged-particle radiation (including proton beam) are devices that require FDA oversight. The FDA’s Center for Devices and Radiological Health has indicated that the proton beam facilities constructed in the United States prior to enactment of the 1976 Medical Device Amendments were cleared for use in the treatment of human diseases on a “grandfathered” basis, while at least one that was constructed subsequently received a 510(k) marketing clearance. There are 510(k) clearances for devices used for delivery of proton beam therapy and devices considered to be accessory to treatment delivery systems, such as the Proton Therapy Multileaf Collimator (which was cleared in December 2009). Since 2001, several devices classified as medical charged-particle radiation therapy systems have received 510(k) marketing clearance. FDA product code LHN.

Related Policies:
60110 Stereotactic Radiosurgery and Stereotactic body Radiation Therapy
80146 Intensity-Modulated Radiation Therapy (IMRT) of the Breast and Lung
80147 Intensity-Modulated Radiation Therapy (IMRT) of the Prostate
80148 Intensity-Modulated Radiation Therapy (IMRT): Cancer of the Head and Neck or Thyroid
80149 Intensity-Modulated Radiation Therapy (IMRT): Abdomen and Pelvis

Policy:
Charged-particle irradiation with proton or helium ion beams may be considered MEDICALLY NECESSARY in the following clinical situations:

primary therapy for melanoma of the uveal tract (iris, choroid, or ciliary body), with no evidence of metastasis or extrascleral extension, and with tumors up to 24 mm in largest diameter and 14 mm in height;
postoperative therapy (with or without conventional high-energy X-rays) in patients who have undergone biopsy or partial resection of chordoma or low-grade (I or II) chondrosarcoma of the basisphenoid region (skull-base chordoma or chondrosarcoma) or cervical spine. Patients eligible for this treatment have residual localized tumor without evidence of metastasis;
pediatric central nervous system tumors.

Charged-particle irradiation with proton or helium ion beams may be considered MEDICALLY NECESSARY where treatment planning with conventional or advanced photon-based radiotherapy cannot meet dose-volume constraints for normal tissue radiation tolerance (see Policy Guidelines section) in the following clinical situations:

in the curative treatment of primary or benign solid pediatric non-central nervous system tumors, including Ewing sarcoma;
in the curative treatment of nonmetastatic primary non-small cell lung cancer;
head and neck cancers.

Other applications of charged-particle irradiation with proton or helium ion beams may be considered investigational and NOT MEDICALLY NECESSARY. This includes, but may not be limited to:

clinically localized prostate cancer;
non-curative treatment of primary or benign solid pediatric non-central nervous system tumors, including Ewing sarcoma;
non-curative treatment of non-small cell lung cancer.

Policy Guidelines
Policy criteria are informed by clinical input and published guidelines. Further details from clinical input are included in the Appendix.

Evidence is lacking on the definition of age parameters for the use of proton beam therapy in pediatric individuals. Some studies using proton beam therapy in pediatric central nervous system tumors have mostly included individuals younger than 3 years of age. However, experts cite the benefit of proton beam therapy in pediatric patients of all ages (< 21 years of age).

Organs at risk are defined as normal tissues whose radiation sensitivity may significantly influence treatment planning and/or prescribed radiation dose. These organs at risk may be particularly vulnerable to clinically important complications from radiation toxicity. Table PG1 outlines radiation doses that are generally considered tolerance thresholds for these normal structures in various organ regions. Clinical documentation based on dosimetry plans may be used to demonstrate that radiation by conventional or advanced photon-based radiotherapy, including intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), stereotactic radiosurgery (SRS), or stereotactic body radiation therapy (SBRT), would exceed tolerance doses to structures at risk. For patients with radiation-sensitizing genetic syndromes such as neurofibromatosis type 1 (NF-1) or retinoblastoma, clinical documentation of the condition may be used to demonstrate increased risk from exposure during treatment.

Table PG1. Radiation Tolerance Doses for Normal Tissues

Site	TD 5/5 (Gray)^a			TD 50/5 (Gray)^b			Complication End Point
	Portion of Organ Involved			Portion of Organ Involved
	1/3	2/3	3/3	1/3	2/3	3/3
Heart	60	45	40	70	55	50	Pericarditis
Lung	45	30	17.5	65	40	24.5	Pneumonitis
Spinal cord	50	50	47	70	70	NP	Myelitis/necrosis
Salivary glands	32	32	32	46	46	46	Xerostemia
Kidney	50	30	23	NP	40	28	Clinical nephritis
Liver	50	35	30	55	45	40	Liver failure
Esophagus	60	58	55	72	70	68	Stricture, perforation
Stomach	60	55	50	70	67	65	Ulceration, perforation
Small intestine	50	NP	40	60	NP	55	Obstruction, perforation
Colon	55	NP	45	65	NP	55	Obstruction, perforation, ulceration, fistula
Rectum	NP	NP	60	NP	NP	80	Severe proctitis, necrosis, stenosis, fistula
Femoral head	NP	NP	52	NP	NP	65	Necrosis

Compiled from 2 sources: (1) Morgan MA (2011). Radiation Oncology. In DeVita, Lawrence, and Rosenberg, Cancer (p. 308). Philadelphia: Lippincott Williams and Wilkins; and (2) Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic equation to estimate normal tissue complication probability. Available online at http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm.
NP: not provided; TD: tolerance dose.
a TD 5/5 is the average dose that results in a 5% complication risk within 5 years.
b TD 50/5 is the average dose that results in a 50% complication risk within 5 years.

For charged-particle radiotherapy (proton or helium ion) therapy to provide outcomes superior to photon-based radiotherapy, there must be a clinically meaningful decrease in the radiation exposure to normal structures. There is no standard definition for a clinically meaningful decrease in radiation dose. In principle, a clinically meaningful decrease would signify a significant reduction in anticipated complications of radiation exposure. To document a clinically meaningful reduction in dose, dosimetry planning studies should demonstrate a significant decrease in the maximum dose of radiation delivered per unit of tissue, and/or a significant decrease in the volume of normal tissue exposed to potentially toxic radiation doses. While radiation tolerance dose levels for normal tissues are well-established, the decrease in the volume of tissue exposed that is needed to provide a clinically meaningful benefit has not been standardized. Therefore, precise parameters for a clinically meaningful decrease cannot be provided.

IMRT of the lung is addressed in evidence review 8.01.46. IMRT of the prostate is addressed in evidence review 8.01.47. IMRT of the head or neck is addressed in evidence review 8.01.48.

Benefit Application
Charged particle radiation therapy is a specialized procedure that may need out-of-network referral.

Because proton beam therapy is generally more costly than alternative therapies but has not been shown to lead to improved outcomes compared to those obtained with alternatives, it is considered not medically necessary, using the MPRM medical necessity definition.

For contracts that do not use this definition of medical necessity, other contract provisions, including contract language concerning use of out-of-network providers and services, may be applied. That is, if the alternative therapies (e.g., IMRT or conformal treatments) are available in network, but proton beam therapy is not, proton beam therapy would not be considered an in-network benefit. In addition, benefit or contract language describing the "least costly alternative" may also be applicable for this choice of treatment.

Rationale
The evidence review was created in July 1996 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 3, 2023.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, two domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (lesbian, gay, bisexual, transgender, queer, intersex, asexual); women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Uveal Melanomas
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) radiotherapy (RT) in individuals who have uveal melanoma(s) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with uveal melanoma(s). Uveal melanoma, although rare, is the most common primary intraocular malignancy in adults. Mean age-adjusted incidence of uveal melanoma in the United States is 6.3 per million people among whites people, 0.9 among Hispanic people, and 0.24 among Black people. Uveal melanoma has a progressively rising, age-specific, incidence rate that peaks near age 70.¹

Interventions
The therapy being considered is charged-particle (proton or helium ion) RT. Charged-particle therapy is administered in specially equipped treatment centers. Proton beam therapy can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about the treatment of uveal melanoma(s): plaque RT, surgical resection, and transpupillary thermotherapy. Primary, localized uveal melanoma can be treated by surgery or RT. In general, larger tumors require enucleation surgery and smaller tumors can be treated with RT, but specific treatment parameters are lacking. The most common treatment of localized uveal melanoma is RT, which is preferred because it can spare vision in most cases. For smaller lesions, RCTs have shown that patients receiving RT or enucleation progress to metastatic disease at similar rates after treatment.² RT can be delivered by various mechanisms, most commonly brachytherapy and PBT. Treatment of primary uveal melanoma improves local control and spares vision; however, the 5-year survival rate (81.6%) has not changed over the last 3 decades, suggesting that life expectancy is independent of successful local eye treatment.³

Outcomes
The general outcomes of interest are overall survival (OS), disease-free survival, change in disease status (local recurrence), and treatment-related morbidity. RT is used as part of first-line treatment for uveal melanoma. One- and 5-year outcomes are indicators of successful treatment.

Systematic Reviews
This section was informed by a TEC Assessment (1996) that concluded proton therapy was at least as effective as alternative therapies for treating uveal melanoma.⁴

Subsequently, Wang et al. (2013) published a systematic review of the literature on charged-particle (proton, helium, carbon ion) RT for uveal melanoma.⁵ Reviewers included 27 controlled and uncontrolled studies that reported health outcomes (e.g., mortality, local recurrence). Three studies were RCTs. One RCT compared helium ion therapy with an alternative treatment (brachytherapy). The other 2 RCTs compared different proton beam protocols and so cannot be used to draw conclusions about the efficacy of charged-ion particle therapy relative to other treatments. The overall quality of the studies was low; most of the observational studies did not adjust for potential confounding variables. The analysis focused on studies of treatment-naive patients (all but one of the identified studies). In a pooled analysis of data from 9 studies, there was no statistically significant difference in mortality rates with charged-particle therapy compared with brachytherapy (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.01 to 1.63). However, there was a significantly lower rate of local recurrence with charged-particle therapy compared with brachytherapy in a pooled analysis of 14 studies (OR , 0.22; 95% CI, 0.21 to 0.23). There were also significantly lower rates of radiation retinopathy and cataract formation in patients treated with charged-particle therapy than brachytherapy (pooled rates of 0.28 vs 0.42 and 0.23 vs. 0.68, respectively). Reviewers concluded there was low-quality evidence that charged-particle therapy is at least as effective as alternative therapies for the primary treatment of uveal melanoma and is better at preserving vision.

Randomized Controlled Trials
An RCT by Mishra et al. (2015) compared charged-particle therapy using helium ions and iodine 125 (I-125) plaque therapy in 184 patients with uveal melanoma.⁶ The primary end point was local tumor control. Median follow-up was 14.6 years in the charged-particle therapy group and 12.3 years in the I-125 plaque therapy group. The rate of local control at 12 years was significantly higher in the helium ion group (98%; 95% CI, 88% to 100%) than in the I-125 plaque therapy group (79%; 95% CI, 68% to 87%; p = .006). The OS rate at 12 years was 67% (95% CI, 55% to 76%) in the helium ion group and 54% (95% CI, 43% to 63%) in the I-125 plaque therapy group (p = .02).

Comparative Observational Studies
Lin et al. (2017) published a retrospective review of 1224 patients in the National Cancer Database who had choroid melanoma and were treated with brachytherapy (n = 996) or proton therapy (n = 228) between 2004 and 2013.⁷ For the brachytherapy group, median follow-up was 37 months; for proton-treated patients, median follow-up was 29 months. Proton-treated patients were propensity-matched with a smaller cohort of brachytherapy-treated patients (n = 228 each). The OS rate at 2 years was 97% for brachytherapy-treated patients and 93% for proton-treated patients. The 5-year OS rates were 77% and 51% for brachytherapy- and proton-treated groups, respectively (p = .008). Factors likely to predict poorer survival rates included the following: older age (hazard ratio [HR], 1.06; 95% CI, 1.03 to 1.09; p < .02); tumor diameter of 12 to 18 mm (HR, 2.48; 95% CI, 1.40 to 4.42; p < .02); tumor diameter greater than 18 mm (HR, 6.41; 95% CI, 1.45 to 28.35; p < .02); and proton treatment (HR, 1.89; 95% CI, 1.06 to 3.37; p < .02).

Long-Term Studies

Toutee et al. (2019) reported 5-year visual outcomes for patients with stage T1 uveal melanoma (N = 424) treated by proton therapy, as a function of their distance to the fovea-optic disc in a long-term retrospective study. 8,With a mean follow-up duration of 122 months, no tumor recurrences were observed. Mean baseline and final best corrected visual acuities were measured for patients with posterior edge of tumor located at ≥ 3 mm (n = 75) or < 3 mm (n = 317) as 20/25 & 20/32 and 20/40 & 20/80. The frequency of a 20/200 or greater conservation was 93.2% and 60.1%, respectively (p < .001). Thus, PBT for stage T1 uveal melanoma was shown to yield excellent tumor control and good long-term visual outcomes, particularly for tumors located ≥ 3 mm from the fovea-optic disc.

Section Summary: Uveal Melanoma
Systematic reviews, including a 1996 TEC Assessment, have concluded that charged-particle RT is at least as effective as alternative therapies for treating uveal melanomas and is better at preserving vision. A 2013 systematic review of charged-particle therapy for uveal melanoma identified 3 RCTs and a number of observational studies. This systematic review found that charged-particle therapy was associated with a significantly lower rate of local recurrence than brachytherapy and fewer adverse events to vision. A 2017 database review found comparable 2-year OS rates but lower 5-year OS rates for PBT than for brachytherapy.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Individuals With Skull-Based Tumors
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) RT in individuals who have skull-based tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with skull-based tumors. The skull base is the anatomic area that supports the brain and includes the entry and exit passages for nerve and vascular bundles. Tumors located near these vital structures such as chordoma and chondrosarcoma that arise in the skull base may not be amenable to complete surgical excision or adequate doses of conventional RT are impossible.

Interventions
The therapy being considered is charged-particle (proton or helium ion) RT. Charged-particle irradiation theoretically affords protection from radiation damage to surrounding structures. Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about skull-based tumors: other types of RT including conventional and high-dose photon therapies, surgical resection, and other therapeutic modalities for localized tumor control.

Outcomes
The general outcomes of interest are OS, disease-free survival, change in disease status (local recurrence), and treatment-related morbidity. Local control and survival outcomes for charged-particle therapy for skull-base tumors have been reported at 1 year and 5 years.

Systematic Reviews
This section was informed by a TEC Assessment (1996) that concluded, compared with treatment using conventional RT after partial resection or biopsy, charged-particle irradiation yields greater rates of local control, OS, and disease-free survival at 5 years after therapy.⁴Subsequently, Lodge et al. (2007) published a systematic review of charged-particle therapy and found local tumor control and 5-year OS rates of 63% and 81%, respectively, for skull-based chordomas treated with surgery and PBT.⁹ Comparable local tumor control and 5-year OS rates were 25% and 44% for postsurgical photon therapy. For chondrosarcomas of the skull-base, proton therapy achieved a 5-year tumor control rate of 95% and photon therapy a rate of 100%

A meta-analysis by Zhou et al. (2018) compared the effectiveness of photon- and particle-based RT for the treatment of chordoma after surgery.¹⁰ A fixed-effects model was used to perform an analysis of 3-, 5-, and 10-year OS rates. A total of 25 studies were included, 11 on the use of conventional RT (CRT) or stereotactic RT (SRT), 9 on the use of PBT, and 5 on the use of carbon-ion RT (CIRT). A total of 21 studies reported 3-yr OS data, 15 studies reported 5-yr OS data, and 9 studies reported 10-yr OS data. Characteristics and results are summarized in Tables 1 and 2. PBT was found to have a statistically significant benefit on 10-yr OS rates compared to both CRT (p < .001) and SRT (p = .004).

Table 1. SR & M-A Characteristics

Study	Dates	Trials	Participants¹	N (Range)	Design	Duration (Range)
Zhou et al. (2018)¹⁰	1983 – 2016 (All) 1995 – 2016 (Proton) 2003 – 2014 (Carbon)	25 (All) 9 (Proton) 5 (Carbon)	Studies containing OS rates for patients with chordoma. Patients with chordoma that received at least one surgery prior to RT. Exact RT type used is described.	N = 996 (All) N = 351 (13-100) (Proton) N = 361 (32-155) (Carbon)	Single-arm trials	15-72 months

M-A: meta-analysis; OS: overall survival; RT: radiotherapy; SR: systematic review
1 Key eligibility criteria.

Table 2. SR & M-A Results

Study	3-yr Outcomes		5-yr Outcomes		10-yr Outcomes
Zhou et al. (2018)¹⁰	OS, % (95% CI)	p -value¹	OS, % (95% CI)	p -value¹	OS, % (95% CI)	p -value¹
CRT	70 (60 – 81)	---	46 (36-56)	---	21 (10 – 33)	---
SRT	92 (88 – 96)	< .001	81 (75-86)	< .001	40 (30 – 55)	.004
PBT	89 (85 – 93)	< .001	78 (23-84)	< .001	60 (43 – 77)	< .001
CIRT	93 (90 – 95)	< .001	87 (84-91)	< .001	45 (36 – 55)	< .001

CI: confidence interval; CIRT: carbon-ion radiotherapy; CRT: conventional radiotherapy; PBT: proton beam therapy; SRT: stereotactic radiotherapy.
1p -value indicates significance for difference compared to CRT.

Section Summary: Skull-Based Tumors
Several systematic reviews, including a TEC Assessment, have been published. A 2007 systematic review found 5-year OS rates of 81% with PBT compared with 44% with surgery and photon therapy. A 2016 systematic review of observational studies found 5-year survival rates after PBT ranging from 67% to 94%. In 2018, a meta-analysis found 5-year and 10-year OS rates for PBT of 78% and 60% compared with 46% and 21% for conventional radiotherapy. The published evidence supports a meaningful improvement in the net health outcome.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Pediatric Central Nervous System Tumors
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) RT in children who have central nervous system (CNS) tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with pediatric CNS tumors. Primary malignant tumors of the CNS are the second most common childhood malignancies after hematologic malignancies. Specific types include craniopharyngioma, astrocytoma, ependymoma, glioblastoma, and medulloblastoma. There are multiple genetic syndromes that confer additional risk for the development of CNS tumors: neurofibromatosis, tuberous sclerosis, as well as von Hippel-Lindau, basal cell nevus and Li Fraumeni and Turcot syndromes.

Interventions
The therapy being considered is charged-particle (proton or helium ion) RT. Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about pediatric CNS tumors: other types of RT, surgical resection, and other therapeutic modalities for localized tumor control.

Outcomes
The general outcomes of interest are OS, disease-free survival, change in disease status (local recurrence), and treatment-related morbidity. Local tumor control and OS would be assessed at 1 and 3 years.

Systematic Reviews
Leroy et al. (2016) published a systematic review of the literature on PBT for the treatment of pediatric cancers.¹¹ Their findings included the following:

For craniopharyngioma, 3 studies were identified: 2 retrospective case series and 1 retrospective comparative study of PBT and intensity-modulated radiotherapy (IMRT). They found very low level evidence that survival outcomes with PBT and IMRT are similar.
For ependymoma, 1 prospective case series and another retrospective case series were identified. They concluded that the evidence did not support or refute the use of PBT for this condition.
For medulloblastoma, 1 prospective case series and 2 retrospective case series were identified. They concluded that the evidence did not support or refute the use of PBT for this condition.
For CNS germinoma, 1 retrospective case series was identified. They concluded that the evidence did not support or refute the use of PBT for this condition.

Upadhyay et al. (2022) conducted a systematic review and meta-analysis of secondary malignant neoplasm risk in children treated with proton versus photon radiotherapy for primary CNS tumors.¹² Twenty-four studies were included for analysis representing 418 secondary malignancies among 38,163 patients. Most common secondary malignancies included gliomas (40.6%), meningioma (38.7%), sarcoma (4.8%), thyroid cancer (4.2%), and basal cell carcinoma (1.3%). The incidence of secondary malignancies with photons was 1.8% (95% CI, 1.1 to 2.6; I2 = 94%) compared to 1.5% (95% CI, 0 to 4.5; I2 = 81%) with protons, and this difference was not significantly different (p = .91). The overall cumulative incidence of secondary malignancies at 10 years ranged from 1.4% to 8.9% for photons versus 0% to 5.4% with protons. A shorter latency to secondary cancers was also observed in proton treated patients (5.9 years vs 11.9 years, respectively). The median follow-up was slightly shorter in the proton group, at 6.9 years compared to 8.8 years in patients treated with photons. The authors suggest this may bias observed outcomes, in addition to general study heterogeneity and potentially confounding effects of concurrent treatment with chemotherapy.

Peterson et al. (2022) published a systematic review of neuropsychological outcomes with proton versus photon radiation therapy in the treatment of pediatric brain tumors.¹³ Eight studies were included for analysis. Photon radiation therapy was associated with decreased neuropsychological functioning over time whereas proton radiation therapy was generally associated with stable neuropsychological function across all domains except working memory and processing speed. However, study interpretation is limited by methodological limitations concerning collection and reporting of sociodemographic characteristics for each treatment group.

Case Series
Representative case series of PBT used to treat multiple pediatric CNS tumor types are described next. For example:

Baliga et al. (2022) reported on 178 pediatric medulloblastoma patients treated with PBT between 2002 and 2016.¹⁴, Median longitudinal follow-up was 9.3 years with156 patients (89.3%) undergoing a gross total resection. Ten-year OS for the whole cohort, standard-risk cohort, and intermediate/high-risk cohort was 79.3% (95% CI, 73.1 to 85.9), 86.9% (95% CI, 79.9 to 94.4), and 68.9% (95% CI, 58.7 to 80.8) respectively. Corresponding rates of 10-year event-free survival (EFS) were 73.8% (95% CI, 67.1 to 81.1), 79.5% (95% CI, 71.1 to 88.9), and 66.2% (95% CI, 56.3 to 78.0), respectively. Intermediate/high-risk status was associated with inferior EFS and OS in univariate analysis. The 10-year cumulative incidence of any secondary tumors, secondary malignancies, or secondary benign tumors was 5.6% (95% CI, 2.2 to 11.3), 2.1% (95% CI, 0.6 to 5.8), and 3.4% (95% CI, 0.9 to 8.9), respectively. Two patients who developed in-field secondary glioblastoma died. The cumulative incidence rates of brainstem injury at 5 and 10 years were 1.1% (95% CI, 0.2 to 3.7) and 1.9% (95% CI, 0.5 to 5.1). The authors noted that the 5-year EFS of 83% for standard-risk and 70% for high-risk patients in the St. Jude Medulloblastoma-86 Study which used 3-dimensional conformal RT was comparable to the 5-year EFS rates of 87.3% and 68.9% in this study. Additionally, the rate of secondary malignancies in the proton-treated cohort was nearly half the rate historically observed in patients treated with photons (2.1% vs 3.7%).

Indelicato et al. (2018) reported on 179 children with nonmetastatic grade II/III intracranial ependymoma who were treated with proton therapy at a single institution.¹⁵ Three-year local control, progression-free survival, and OS rates were 85%, 76%, and 90%, respectively. The authors noted that these disease control rates were comparable to photon series. The 3-year grade 2+ brainstem toxicity rate was 5.5% (95% CI, 2.9 to 10.2). Subtotal resection and male sex were associated with inferior disease control rates.

Bishop et al. (2014) reported on 52 children with craniopharyngioma treated at 2 centers; 21 received PBT and 31 received IMRT.¹⁶ Patients received a median dose of 50.4 gray (Gy). At 3 years, the OS rate was 94.1% in the PBT group and 96.8% in the IMRT group (p = .742). Three-year nodular and cystic failure-free survival rates were also similar between groups. Based on imaging, 17 (33%) patients had cyst growth within 3 months of RT, and 14 patients had late cyst growth (> 3 months after therapy); rates did not differ significantly between groups. In 14 of the 17 patients with early cyst growth, enlargement was transient.

MacDonald et al. (2011) reported on the use of protons to treat germ cell tumors in 22 patients, 13 with germinoma and 9 with nongerminomatous germ cell tumors.¹⁷ Radiation doses ranged from 30.6 to 57.6 cobalt Gray equivalents (CGE). All nongerminomatous germ cell tumor patients also received chemotherapy before RT. Median follow-up was 28 months. There were no CNS recurrences or deaths. Following RT, 2 patients developed growth hormone deficiency and 2 other patients developed central hypothyroidism. The authors indicated that longer follow-up was necessary to assess the neurocognitive effects of therapy. In the same study, a dosimetric comparison of photons and protons was performed. PBT provided substantial sparing to the whole brain and temporal lobes, and reduced doses to the optic nerves.

Moeller et al. (2011) reported on 23 children enrolled in a prospective series and treated with PBT for medulloblastoma between 2006 and 2009.¹⁸ Because hearing loss is common after chemoradiotherapy for children with medulloblastoma, the authors evaluated whether PBT led to a clinical benefit in audiometric outcomes (because, compared with photons, protons reduce radiation dose to the cochlea for these patients). The children underwent pre- and 1-year post-RT pure-tone audiometric testing. Ears with moderate-to-severe hearing loss before therapy were censored, leaving 35 ears in 19 patients available for analysis. The predicted mean cochlear radiation dose was 30 CGE (range, 19 – 43 CGE). Hearing sensitivity significantly declined following RT across all frequencies analyzed (p < .05). There was partial sparing of mean post radiation hearing thresholds at low- to mid-range frequencies; the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was 5%, which compared favorably to the rate of grade 3 or 4 toxicity following IMRT (18%) reported in a separate case series.

Hug et al. (2002) reported on proton radiation in the treatment of low-grade gliomas in 27 pediatric patients.¹⁹ Six patients experienced local failure; acute adverse events were minimal. After a median follow-up of 3 years, all children with local control maintained performance status. In a dosimetric comparison of protons to photons for 7 optic pathway gliomas treated, Fuss et al. (1999) showed a decrease in radiation dose to the contralateral optic nerve, temporal lobes, pituitary gland, and optic chiasm with the use of protons.²⁰

Section Summary: Pediatric Central Nervous System Tumors
A 2016 systematic review identified several case series evaluating PBT for several types of pediatric CNS tumors including craniopharyngioma, ependymoma, medulloblastoma, and CNS germinoma. One small comparative observational study was identified. It compared PBT with IMRT for children with craniopharyngioma and found similar outcomes with both types of treatment. The current evidence base is not sufficiently robust to draw conclusions about the efficacy of PBT for pediatric CNS tumors. A systematic review of neuropsychological outcomes with proton versus photon radiation therapy for pediatric brain tumors suggests more stable neuropsychologically functioning across time with PBT for most domains, but study interpretation is complicated by incomplete baseline sociodemographic data for each group. Ten-year data in children with medulloblastoma reported OS and event-free survival rates comparable to historical photon-treated cohorts, with reduced incidence of secondary malignancies. While some studies suggest sparing of normal tissues and reduced toxicities, limitations of the published evidence preclude determining the effects of the technology on net health outcome.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Pediatric Non-CNS Tumors
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) RT in children who have non-CNS tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with pediatric non-CNS tumors. Tumors of the axial skeleton require conformal radiotherapy with the intent of avoiding damage to vital structures.

Interventions
The therapy being considered is charged-particle (proton or helium ion) RT. Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about pediatric non-CNS tumors: other types of RT, surgical resection, and other types of therapy for localized tumor control.

Case Series
There are scant data on the use of PBT in pediatric non-CNS tumors. Data include dosimetric planning studies in a small number of pediatric patients with parameningeal rhabdomyosarcoma21, and late toxicity outcomes in other solid tumors of childhood.^22,23

Vogel et al. (2018) published a retrospective case series of proton-based radiotherapy to treat nonhematologic head and neck malignancies in 69 pediatric patients.²⁴ Thirty-five of the patients had rhabdomyosarcoma and were treated with a median dose of 50.4 Gy (range 36.0 – 59.4 Gy) in 1.8 Gy fractions. A number of patients had Ewing sarcoma (n = 10; median dose, 55.8 Gy; range, 55.8 – 65.6 Gy), and there were other histologies (n = 24; median dose, 63.0 Gy). For the overall cohort, 92% (95% CI, 80% to 97%) were free from local recurrence at 1 year; at 3 years, 85% (95% CI, 68% to 93%). The OS rate at 1 year was 93% (95% CI, 79% to 98%); at 3 years, it was 90% (95% CI, 74% to 96%). Incidences of grade 3 toxicities were as follows: oral mucositis (4%), anorexia (22%), dysphagia (7%), dehydration (1%), and radiation dermatitis (1%). Despite the small and heterogenous sample, and the varying dosages and modalities administered, reviewers concluded that PBT was safe for the population in question, given the low rates of toxicity.

Section Summary: Pediatric Non-CNS Tumors
There are few data on charged-particle therapy for treating pediatric non-CNS tumors. A 2018 case series evaluated pediatric patients treated with PBT for rhabdomyosarcoma and Ewing sarcoma. The current evidence base is not sufficiently robust to draw conclusions about the efficacy of PBT for pediatric non-CNS tumors. While this modality of treatment has the potential to reduce toxicity to organs at risk and may minimize the development of radiation-induced secondary malignancies, limitations of the published evidence preclude determining the effects of the technology on net health outcome.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Localized Prostate Cancer
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) RT in patients who have locally advanced prostate cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have locally advanced prostate cancer (i.e., stages T3 or T4). These tumors may be associated with a high rate of local recurrence despite maximal doses of conventional RT.

Interventions
The therapy being considered is charged-particle RT. Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about localized prostate cancer: other types of radiotherapy, surgical resection, and other types of therapy for localized tumor control.

Systematic Reviews
A TEC Assessment (2010) addressed the use of PBT for prostate cancer and concluded that it had not been established whether PBT improves outcomes in any setting for clinically localized prostate cancer.²⁵Nine studies were included in the review; 4 were comparative and 5 were noncomparative. There were 2 RCTs, and only one included a comparison group that did not receive PBT. This trial, by Shipley et al. (1995), compared treatment with external-beam radiotherapy (EBRT) using photons and either a photon or proton beam boost.²⁶ After a median follow-up of 61 months, the investigators found no statistically significant differences in OS, disease-specific survival, or recurrence-free survival. In a subgroup of patients with poorly differentiated tumors, there was superior local control with PBT vs photon boost, but survival outcomes did not differ. Actutimes incidence of urethral stricture and freedom from rectal bleeding were significantly better in the photon boost group. The TEC Assessment noted that higher doses were delivered to the proton beam boost group and, thus, better results on survival and tumor control outcomes would be expected. Moreover, the trial was published in the mid-1990s and used 2-dimensional methods of RT, which are now outmoded. The other RCT, known as Proton Radiation Oncology Group, was reported by Zietman et al. (2005).²⁷ They compared conventional- and high-dose conformal therapy using both conformal proton beams, proton boost, and EBRT. After a median follow-up of 8.9 years, there was no statistically significant difference between groups in survival. Biochemical failure (an intermediate outcome) was significantly lower in the high-dose proton beam group than in the conventional-dose proton beam group. The TEC Assessment noted that the outcome (biochemical failure) has an unclear relation to the more clinically important outcome, survival. The rate of acute gastrointestinal tract toxicity was worse with the high-dose proton beam boost.

Kim et al. (2013), reported on an RCT of men with androgen-deprivation therapy-naive stage T1, T2, and T3 prostate cancer that compared different protocols for administering hypofractionated PBT.²⁸ However, without an alternative intervention, conclusions cannot be drawn about the efficacy and safety of PBT. The 5 proton beam protocols used were as follows: arm 1, 60 CGE in 20 fractions for 5 weeks; arm 2, 54 CGE in 15 fractions for 5 weeks; arm 3, 47 CGE in 10 fractions for 5 weeks; arm 4, 35 CGE in 5 fractions for 2.5 weeks; or arm 5, 35 CGE in 5 fractions for 5 weeks. Eighty-two patients were randomized, with a median follow-up of 42 months. Patients assigned to arm 3 had the lowest rate of acute genitourinary toxicity, and those assigned to arm 2 had the lowest rate of late gastrointestinal toxicity. However, without an alternative intervention, conclusions cannot be drawn about the efficacy and safety of PBT.

Sun et al. (2014) assessed therapies for localized prostate cancer, for the Agency for Healthcare Research and Quality.²⁹ Reviewers compared the risk and benefits of a number of treatments, including: radical prostatectomy, EBRT (standard therapy as well as PBT, 3-dimensional conformal radiotherapy, IMRT, stereotactic body radiotherapy [SBRT]), interstitial brachytherapy, cryotherapy, watchful waiting, active surveillance, hormonal therapy, and high-intensity focused ultrasound. They concluded that the evidence for most treatment comparisons was inadequate to draw conclusions about comparative risks and benefits. Limited evidence appeared to favor surgery over surveillance or EBRT, and RT plus hormonal therapy over RT alone. Reviewers noted that advances in technologies for many of the treatment options for clinically localized prostate cancer (e.g., current RT protocols permit higher doses than those administered in many of the trials included in the report). Moreover, the patient population had changed since most of the studies were conducted. More recently, most patients with localized prostate cancer have been identified using prostate-specific antigen testing and may be younger and healthier than prostate cancer patients identified before such testing existed. Thus, reviewers recommended additional studies to validate the comparative effectiveness of emerging therapies such as PBT, robotic-assisted surgery, and SBRT.

From the published literature, it appears as if dose escalation is an accepted treatment strategy for organ-confined prostate cancer.³⁰ PBT, using CRT planning or IMRT, is used to provide dose escalation to a more well-defined target volume. However, dose escalation is more commonly offered with conventional EBRT using 3-dimentional conformal radiotherapy or IMRT. Morbidity related to RT of the prostate is focused on the adjacent bladder and rectal tissues; therefore, dose escalation is only possible if these tissues are spared. Even if IMRT or 3-dimentional conformal radiotherapy permits improved delineation of the target volume, if the dose is not accurately delivered, perhaps due to movement artifact, the complications of dose escalation can be serious, because the bladder and rectal tissues are exposed to even higher doses. The accuracy of dose delivery applies to both conventional and PBT.³¹

Liu et al. (2021) conducted an analysis of the National Cancer Database (NCDB) for cases of localized prostate cancer treated with definitive radiotherapy between 2004 and 2015.³² Patients with T1-T3, N0, M0 disease who received first-line treatment to the prostate and/or pelvis were included for analysis. Inclusion of individuals treated with EBRT or PBT was restricted to doses ≥ 60 Gy. The EBRT treatment cohort included individuals receiving 3D-CRT or IMRT and the brachytherapy (BT) treatment cohort allowed for monotherapy or a boost with EBRT. A total of 276,880 patients were identified with median age 68 years and median follow-up of 80.9 months. Patients treated with PBT generally had more favorable prognostic characteristics, including age, comorbidity score, tumor grade, risk group. Ten-year survival rates were 85.6%, 60.1%, and 74% for PBT, EBRT, and BT groups, respectively. In the multivariable analysis, the HR for death was 1.72 (95% CI, 1.51 to 1.96) for EBRT and 1.38 (95% CI, 1.21 to 1.58) for BT compared to PBT (p < .001 for all). Generalized propensity score matching of 1,860 matched cases from each treatment cohort identified no statistically significant difference in OS between PBT and BT (HR, 1.18; 95% CI, 0.93 to 1.48; p = .168). However, EBRT continued to be associated with inferior OS (HR, 1.65; 95% CI, 1.32 to 2.04; p < .001) compared to PBT with propensity score matching. Ten-year survival rates in the matched samples were 80.2%, 71.3%, and 78.3% for PBT, EBRT, and BT groups, respectively. EBRT was also associated with inferior OS compared to BT. Older and higher-risk patients were associated with a decreased magnitude of improvement in OS with PBT. A sensitivity analysis determined that the observed difference in OS between PBT and EBRT cohorts was robust to an unmeasured confounder, with a > 400% effect size needed to drive the estimate to nonsignificance. However, the authors note that unmeasured socioeconomic differences and other factors impacting access to proton centers are expected to underpin considerable selection biases. Additionally, the authors conclude that these findings support the rationale for ongoing studies comparing PBT to IMRT such as the PARTIQoL RCT and the COMPPARE prospective study (see Table 3).

Single-Arm Studies
In 2019, Grewal et al. published 4-year outcomes from a prospective phase 2 trial of moderately hypofractionated proton therapy (70 Gy in 28 fractions) for localized prostate cancer.³³ A total of 184 men were followed for a median of 49.2 months. Four-year rates of biochemical-clinical failure-free survival were 93.5% (95% CI, 88 to 100) overall and 94.4% (95% CI, 89 to 100), 92.5% (95% CI, 86 to 100), and 93.8% (95% CI, 88 to 100) among subjects with low-risk, favorable intermediate-risk, and unfavorable, intermediate-risk, respectively. Overall survival was 95.8% (95% CI, 92 to 100) at 4 years, with no statistically significant differences by risk group (log-rank p > .7). Four-year cumulative incidence rates of late grade 2 or higher urologic or gastrointestinal toxicities were 7.6% (95% CI, 4 to 13) and 13.6% (95% CI, 9 to 20), respectively. One late grade 3 toxicity occurred, and all late toxicities were transient. Changes in urinary incontinence, irritation, and bowel function were minimal as reflected by International Prostate Symptom Score survey (IPSS) and Expanded Prostate Cancer Index Composite (EPIC) questionnaire scores. Patients receiving anticoagulation reported worse EPIC bowel scores over time (p < .01) and patients receiving androgen deprivation therapy reported worse International Index of Erectile Function (IIEF) (p < .01) and EPIC sexual (p = .01) and hormonal domain (p = .05) scores over time.

Section Summary: Localized Prostate Cancer
The evidence on PBT for treating localized prostate cancer includes 2 RCTs, systematic reviews, a single-arm study, and a comparative effectiveness analysis of the National Cancer Database (NCDB). A 2010 TEC Assessment addressed the use of PBT for prostate cancer and concluded that it had not been established whether PBT improves outcomes in any setting for clinically localized prostate cancer. The TEC Assessment included 2 RCTs, only one of which included a comparison group that did not receive PBT. A 2014 comparative effectiveness review concluded that the evidence on PBT for prostate cancer is insufficient. A 2021 comparative effectiveness analysis of the NCDB reported 10-year survival rates of 85.6%, 60.1%, and 74% for PBT, EBRT, and brachytherapy groups, respectively. With propensity score matching, EBRT was associated with inferior survival compared to PBT, and differences between PBT and brachytherapy were not significantly different. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. Ongoing prospective studies comparing PBT to IMRT may alter the conclusions of the TEC Assessment.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Non-Small-Cell Lung Cancer
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) RT in individuals who have non-small-cell lung cancer (NSCLC) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with NSCLC. NSCLC is the most common form of lung cancer, and RT is an essential component of treatment for many patients. The potential benefit of PBT is to reduce radiation toxicity to normal lung tissue and the heart.

Interventions
The therapy being considered is charged-particle (proton or helium ion) RT. Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about NSCLCs: other types of radiotherapy, surgical resection, or other types of therapy for localized tumor control.

Systematic Reviews
A TEC Assessment (2010) assessed the use of PBT for NSCLC.³⁴ This assessment compared health outcomes (OS, disease-specific survival, local control, disease-free survival, adverse events) between PBT and SBRT, which is an accepted approach for using RT to treat NSCLC. Eight PBT case series were identified (N = 340 patients). No comparative studies, randomized or nonrandomized, were found. For these studies, stage I comprised 88.5% of all patients, and only 39 patients had other stages or recurrent disease. Among 7 studies reporting 2-year OS rates, probabilities ranged between 39% and 98%. At 5 years, the range across 5 studies was 25% to 78%.

The review concluded that the evidence was insufficient to permit conclusions about PBT outcomes for any stage of NSCLC. All PBT studies were case series; no studies directly compared PBT with SBRT. 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 PBT regimens. The PBT studies were similar in patient age, but there was great variability in percentages with stage IA cancer, the sex ratio, and the percentage of medically inoperable tumors. There was a high degree of treatment heterogeneity among the PBT studies, particularly with respect to planning volume, total dose, the number of fractions, and the number of beams. Survival results were highly variable. It is unclear whether the heterogeneity of results could be explained by differences in patient and treatment characteristics. In addition, indirect comparisons between PBT and SBRT (eg, comparing separate sets of single-arm studies on PBT and SBRT) might have been distorted by confounding. Absent RCTs, the comparative effectiveness of PBT and SBRT was found to be uncertain. The Assessment noted that adverse events reported after PBT generally fell into several categories: rib fracture, cardiac, esophageal, pulmonary, skin, and soft tissue. Adverse events data in PBT studies are difficult to interpret due to lack of consistent reporting across studies, lack of detail about observation periods, and lack of information about rating criteria and grades.

An indirect meta-analysis by Grutters et al. (2010) reviewed in the TEC Assessment found a nonsignificant difference of 9 percentage points between pooled 2-year OS estimates favoring SBRT over PBT for the treatment of NSCLC.³⁵ The nonsignificant difference of 2.4 percentage points at 5 years also favored SBRT over PBT. Based on separate groups of single-arm studies on SBRT and PBT, it is unclear whether this indirect meta-analysis adequately addressed the possible influence of confounding on the comparison of SBRT and PBT.

Pijls-Johannesma et al. (2010) conducted a systematic literature review examining the use of particle therapy in lung cancer.³⁶ Study selection criteria included having at least 20 patients and a follow-up of 24 months or more. Eleven studies, all dealing with NSCLC, were selected, 5 investigating protons (n = 214 and 6 C-ions (n = 210). The proton studies included 1 phase 2 study, 2 prospective studies, and 2 retrospective studies. The C-ion studies were all prospective and conducted at the same institution in Japan. No phase 3 studies were identified. Most patients had stage I disease, but because a wide variety of radiation schedules were used, comparisons of results were difficult, and local control rates were defined differently across studies. For proton therapy, 2-year local control rates were 74% and 85%, respectively, in the 2 studies reporting this outcome; 5-year local control rates ranged from 57% to 96% (4 studies). The 2-year OS rates ranged from 31% to 74%, and the 5-year OS rates ranged from 31% to 50% (2- and 5-year OS each reported in 4 studies). These local control and survival rates are equivalent or inferior to those achieved with SBRT. Radiation-induced pneumonitis was observed in about 10% of patients. For C-ion therapy, the overall local tumor control rate was 77%, and it was 95% when using a hypofractionated dosing schedule. The 5-year OS and cause-specific survival rates with C-ion therapy were 42% and 60%, respectively. Slightly better results were reported when using hypofractionation (50% and 76%, respectively). Reviewers concluded that, although the results with protons and heavier charged particles were promising, additional well-designed trials would be needed.

Randomized Controlled Studies
Liao et al. (2018) conducted a RCT of PSPT versus IMRT in patients with inoperable NSCLC who were candidates for concurrent chemotherapy.³⁷ Patients were eligible for randomization only if both treatment plans satisfied prespecified dose-volume constraints for organs at risk at the same tumor dose. The majority of enrolled patients were stage IIIA/B. The primary study endpoint was first occurrence of severe (grade ≥ 3) radiation pneumonitis or local failure. Compared to treatment with IMRT (n = 92), patients treated with PSPT (n = 57) had less lung tissue exposure to doses of 5 – 10 Gy(RBE [relative biological effectiveness]), increased lung tissue exposure to doses ≥ 20 Gy(RBE), and less heart tissue exposure at all dose levels between 5 – 80 Gy(RBE). Six patients in each group developed grade ≥ 3 radiation pneumonitis. At 1 year, rates of radiation pneumonitis were 6.5% and 10.5% in IMRT and PSPT groups, respectively (p = .537). Two patients in the IMRT group experienced grade 5 radiation pneumonitis, and no patients in the PSPT groups experienced grade 4 or 5 radiation pneumonitis. At 1 year, rates of local failure were 10.9% and 10.5% in IMRT and PSPT groups, respectively (p = 1.0). Combined rates of radiation pneumonitis and local failure were not significantly different between groups (17.4% vs 21.1% for IMRT and PSPT groups, respectively; p = .175). Median OS was 29.5 months and 26.1 months for patients in IMRT and PSPT groups, respectively (p = .297), which is comparable to historical benchmarks. Considerably fewer events occurred in this trial than the 15% rate for radiation pneumonitis and 25% rate for local failure expected from historical data. In an exploratory analysis, the investigators evaluated whether a possible learning curve in the design or delivery of radiation with IMRT or PSPT over time influenced outcomes. Study participants enrolled before and after the trial midpoint in September 2011 were compared. No differences in clinical characteristics were noted for those treated with IMRT whereas the later PSPT group had a higher rate of adenocarcinoma and smaller gross tumor volumes. Combined rates of radiation pneumonitis and local failure at 12 months significantly differed according to time of enrollment in both IMRT (21.1% [early] vs 18.2% [late]) and PSPT groups (31.0% [early] vs 13.1% [late]). PSPT group radiation pneumonitis events occurred exclusively in the early cohort, whereas IMRT group radiation pneumonitis events occurred throughout the trial. Authors attributed the clinical effectiveness of IMRT in this trial to the introduction of an automated IMRT optimization system during the first year after trial activation. New treatment plans for the 6 patients who developed radiation pneumonitis in the PSPT group were generated post hoc and demonstrated lower mean lung doses for 3 individuals. The authors note that the importance of heart sparing for OS benefit is being elucidated in the ongoing Radiation Therapy Oncology Group (RTOG) 1308 RCT comparing photon versus proton chemoradiation (see Table 3).

Nonrandomized Studies
Chang et al. (2017) published final results from an open-label phase 2 study of 64 patients with stage III unresectable NSCLC treated with PBT plus concurrent chemotherapy (carboplatin and paclitaxel).³⁸ Median OS was 26.5 months; at 5 years, the OS rate was 29% (95% CI, 18% to 41%). Median progression-free survival was 12.9 months; the 5-year progression-free survival rate was 22% (95% CI, 12% to 32%). At 5 years, 54% of patients had distant metastasis, 28% had locoregional recurrence, and 64% had a recurrence of any type. No grade 5 adverse events were observed, and grade 3 or 4 adverse events were rare. Poor OS was predicted by Karnofsky Performance Status score of 70 to 80, compared with of 90 to 100 (HR, 2.48; 95% CI, 1.33 to 4.65; p = .004). Other predictors of poor OS were stage III cancer (p = 0.03), the presence of a tumor in the left lung or right lower lobe (p = .04), and a pretreatment tumor size greater than 7 cm (p = .03). The use of nonstandardized induction and adjuvant chemotherapy as well as the heterogeneity across study populations limit conclusions about treatment efficacy.

Ono et al. (2017) published a retrospective case series of 20 patients with lung cancer treated with PBT at a single center between 2009 and 2015.³⁹ In 14 (70%) patients, tumors were clinically inoperable; overall median tumor diameter was 39.5 mm (range, 24 – 81 mm). PBT was administered 3.2 Gy per fraction. Median follow-up was 27.5 months (range, 12 – 72 months), and the 1-year OS rate was 95.0% (95% CI, 87.7 to 100). At 2 years, the OS rate was 73.8% (95% CI, 53.9 to 93.7); no statistically significant difference was found between operable (n = 6) and inoperable patients (n = 14) for 2-year OS (p = .109), although operable patients had better survival rates. At 2 years, local control rate was 78.5% (95% CI, 59.5 to 97.5), and there were no reported toxicities of grade 3 or higher. The study was limited by small sample size and retrospective design.

Section Summary: Non-Small-Cell Lung Cancer
A 2010 TEC Assessment, which included 8 case series, concluded that the evidence was insufficient to permit conclusions about PBT for any stage of NSCLC. Another systematic review, also published in 2010, only identified case series. Final results from a 2017 open-label phase 2 study included 5-year survival rates for patients who had PBT with concurrent chemotherapy. A 2018 RCT failed to demonstrate superiority of PSPT to IMRT on the combined primary outcome of grade ≥ 3 radiation pneumonitis or local failure. The ongoing RTOG 1308 RCT is expected to further elucidate the comparative safety and effectiveness of proton versus photon chemoradiation.

Charged-Particle (Proton or Helium Ion) Radiotherapy for Head and Neck Tumors, Other Than Skull-Based
Clinical Context and Therapy Purpose
The purpose of charged-particle (proton or helium ion) RT in individuals who have head and neck tumors, other than skull-based, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have head and neck malignancies. The histology of the malignancies are predominantly of squamous cell type and may arise from, and involve multiple regions, including the oral cavity, pharynx, larynx, nasal cavity and paranasal sinuses, and the major salivary glands.

Interventions
The therapy being considered is charged-particle (proton or helium ion) RT. Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques.

Comparators
The following practices are currently being used to make decisions about head and neck tumors, other than skull-based: other types of radiotherapy, surgical resection, or other types of therapy for localized tumor control.

Systematic Reviews
A systematic review by Patel et al. (2014) evaluated the literature comparing charged-particle therapy with PBT in the treatment of paranasal sinus and nasal cavity malignant disease.⁴⁰ Reviewers identified 41 observational studies that included 13 cohorts treated with charged-particle therapy (n = 286 patients) and 30 cohorts treated with PBT (n = 1,186 patients). There were no head-to-head trials. In a meta-analysis, the pooled OS event rate was significantly higher with charged-particle therapy than with photon therapy at the longest duration of follow-up (relative risk, 1.27; 95% CI, 1.01 to 1.59). Findings were similar for 5-year survival outcomes (relative risk, 1.51; 95% CI, 1.14 to 1.99). Findings were mixed for the outcomes of locoregional control and disease-free survival; photon therapy was significantly better for one of the 2 time frames (longest follow-up or 5-year follow-up). In terms of adverse events, there were significantly more neurologic toxic effects with charged-particle therapy than with photon therapy (p < .001), but other toxic adverse event rates (e.g., eye, nasal, hematologic) did not differ significantly between groups. Reviewers noted that the charged-particle studies were heterogeneous (e.g., type of charged particles [carbon ion, proton], delivery techniques). In addition, comparisons were indirect, and none of the studies selected actually compared the 2 types of treatment in the same patient sample.

Nonrandomized Comparative Studies
Youssef et al. (2022) conducted a retrospective cohort study comparing outcomes in 292 patients with newly diagnosed nonmetastatic oropharyngeal carcinoma treated with curative-intent intensity-modulated proton therapy (IMPT; n = 58) or IMRT (n = 234).⁴¹ Median follow-up was 26 months and 93% of tumors were HPV-p16-positive. There were no significant differences in 3-year rates of OS (97% IMPT vs 91% IMRT; p = .18), progression-free survival (82% IMPT vs 85% IMRT; p = .62) or locoregional recurrence (5% IMPT vs 4% IMRT; p = .59). Incidence of acute toxicities was significantly higher for IMRT compared with IMPT for grade ≥ 2 oral pain (72% IMPT vs 93% IMRT; p < .001), grade ≥ 2 xerostomia (21% IMPT vs 29% IMRT; p < .001), grade ≥ 2 dysgeusia (28% IMPT vs 57% IMRT; p < .001), grade 3 dysphagia (7% IMPT vs 12% IMRT; p < .001), grade ≥3 mucositis (53% IMPT vs 57% IMRT; p < .003), grade ≥ 2 nausea (0% IMPT vs 8% IMRT; p = .04), and grade ≥ 2 weight loss (37% IMPT vs 59% IMRT; p < .001). There were no significant differences in chronic grade ≥ 3 toxic effects. Four patients treated with IMRT required a G-tube for longer than 6 months compared to none treated with IMPT.

Blanchard et al. (2016) case-matched 50 patients treated with IMPT with 100 patients treated with IMRT who were receiving treatment for oropharyngeal carcinoma.⁴² Patients were followed-up for a median of 32 months. No statistically significant differences in OS (HR, 0.55; 95% CI 0.12 – 2.50; p = 0.44) or PFS (HR, 1.02; 95% CI, 0.41 – 2.54; p = .96) were observed. A pre-planned composite endpoint demonstrated reduced risks of grade 3 weight loss or G-tube presence at 3 months (OR 0.44; 95% CI, 0.19 – 1.0; p = .05) and 1-year after treatment (OR, 0.23; 95% CI, 0.07 – 0.73; p = .01).

Adverse Events
Zenda et al. (2015) reported on late toxicity in 90 patients after PBT for nasal cavity, paranasal sinuses, or skull-based malignancies.⁴³ Eighty-seven of the 90 patients had paranasal sinus or nasal cavity cancer. The median observation period was 57.5 months. Grade 3 late toxicities occurred in 17 (19%) patients, and grade 4 occurred in 6 (7%) patients. Five patients developed cataracts, and 5 developed optic nerve disorders. Late toxicities (other than cataracts) developed a median of 39.2 months after PBT.

Section Summary: Head and Neck Tumors, Other Than Skull-Based
A 2014 systematic review identified only case series and noted that the studies of charged-particle therapy were heterogenous in terms of the types of particle and delivery techniques used. No studies identified compared charged-particle therapy with other treatments. A case-matched cohort study compared outcomes for oropharyngeal cancer patients receiving IMPT or IMRT. No statistically significant differences in OS or PFS were observed, however, a lower risk for treatment-related adverse events was noted with IMPT. A 2022 retrospective cohort study reported similar findings in patients with nonmetastatic oropharyngeal cancer treated with curative-intent IMPT versus IMRT. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. Ongoing RCTs comparing IMPT to IMRT may elucidate effects on net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2019 Input
In response to requests while this policy was under review in 2019, clinical input on use of charged-particle (proton or helium ion) beam therapy for various tumor indications was received from 3 respondents, including 2 specialty society-level responses and 1 physician-level response identified by an academic health system. In addition, the specialty society responses included multiple physicians with academic medical center affiliations.

Pediatric central nervous system tumors.

Curative treatment of primary or benign solid pediatric non-central nervous system tumors, including Ewing sarcoma;
Curative treatment of nonmetastatic primary non-small cell lung cancer;
Head and neck cancers.

Clinical input suggests a possible role of charged-particle beam therapy for the treatment of localized prostate cancer but broad support for this use is pending until the results of an ongoing RCT comparing proton therapy to intensity-modulated radiotherapy (IMRT) are available.

Further details from clinical input are included in the Appendix.

2013 Input

In response to requests, input was received from 2 physician specialty societies (4 responses) and 4 academic medical centers while this policy was under review in 2013. There was uniform support for the use of proton beam therapy in pediatric central nervous system tumors. Two reviewers supported the use of proton beam therapy in pediatric non-central nervous system tumors; data for this use are scant. Input on head and neck tumors (non-skull-based) was mixed.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

International Particle Therapy Co-operative Group
A 2016 consensus statement by the International Particle Therapy Co-operative Group (PTCOG) offered the following conclusion about proton therapy for non-small-cell lung cancer (NSCLC): “... Promising preliminary clinical outcomes have been reported for patients with early-stage or locally advanced NSCLC who receive proton therapy. However, the expense and technical challenges of proton therapy demand further technique optimization and more clinical studies ....”⁴⁴

In 2021, PTCOG published consensus guidelines on particle therapy for the management of head and neck cancer.⁴⁵ The following recommendations were made:

Nasopharynx: "Consider proton therapy whenever feasible. Most advanced treatment, imaging, and adaptation techniques should be used to minimize risk of neurotoxicity, given anatomic location."
Reirradiation: "Careful evaluation required for each patient to determine risks/benefits of reirradiation. Enrollment in clinical trial encouraged whenever possible."
Sinonasal: "Consider proton therapy whenever feasible. Most advanced treatment, imaging, and adaptation techniques should be used to minimize risk of neurotoxicity, given anatomic location."
Postoperative: "Consider proton therapy whenever feasible. Enrollment in clinical trial encouraged whenever possible."
Oropharynx: "Consider proton therapy whenever feasible. Enrollment in clinical trial encouraged whenever possible."

American College of Radiology
The 2014 guidelines from the American College of Radiology on external-beam radiotherapy in stage T1 and T2 prostate cancer stated:

"There are only limited data comparing proton-beam therapy to other methods of irradiation or to radical prostatectomy for treating stage T1 and T2 prostate cancer. Further studies are needed to clearly define its role for such treatment.
There are growing data to suggest that hypofractionation at dose per fraction < 3.0 Gy per fraction is reasonably safe and efficacious, and although the early results from hypofractionation/SBRT [stereotactic body radiation therapy] studies at dose per fraction > 4.0 Gy seem promising, these approaches should continue to be used with caution until more mature, ongoing phase II and III randomized controlled studies have been completed."46,

American Urological Association et al.
In 2022, the American Urological Association (AUA) and American Society for Radiation Oncology (ASTRO) published evidence-based guidelines for the management of clinically localized prostate cancer.⁴⁷ Part III of the guideline discusses principles of radiation therapy. Regarding the use of proton therapy, the guidelines state the following: "Clinicians may counsel patients with prostate cancer that proton therapy is a treatment option, but it has not been shown to be superior to other radiation modalities in terms of toxicity profile and cancer outcomes. (Conditional Recommendation; Evidence Level: Grade C)" The guidelines additionally note that while dosimetric planning studies have indicated that proton therapy can deliver lower integral and mean doses to normal tissues, it has not been established whether these dosimetric differences translate in fewer side effects or improvements in quality of life.

National Comprehensive Cancer Network
Uveal Melanoma
National Comprehensive Cancer Network (NCCN) guidelines for uveal melanoma (v.2.2022) support the use of particle beam therapy for definitive radiotherapy of the primary tumor and that its use is appropriate as upfront therapy after diagnosis, after margin-positive enucleation, or for intraocular or orbital recurrence.⁴⁸ Treatment recommendations for intraocular tumors include:

"Using protons, 50 – 70 cobalt Gray equivalent (CGyE) in 4-5 fractions should be prescribed to encompass the planning target volume surrounding the tumor.
Using carbon ions, 60 – 85 CGyE in 5 fractions should be prescribed to encompass the planning target volume surrounding the tumor."

Prostate Cancer
NCCN guidelines for prostate cancer (v.1.2023) offer the following conclusion on proton therapy: “The NCCN panel believes no clear evidence supports a benefit or decrement to proton therapy over IMRT [intensity-modulated radiotherapy] for either treatment efficacy or long-term toxicity. Conventionally fractionated prostate proton therapy can be considered a reasonable alternative to X-ray-based regimens at clinics with appropriate technology, physics, and clinical expertise.”⁴⁹ The NCCN adds that a prospective randomized trial comparing prostate PBT with X-ray-based IMRT is ongoing and may help to elucidate outcomes, as the evidence to date has not demonstrated a significant difference in benefit, particularly in regard to short and long-term toxicities. The NCCN acknowledges that PBT may deliver less radiation to surrounding tissues (e.g., muscle, bone, vessels, fat), but that these tissues do not routinely contribute to the morbidity of prostate radiation. Of greater clinical relevance, is the volume of rectum and bladder that is exposed to radiation. Higher volume, lower dose exposures may minimize risk of long-term treatment morbidity. While in silico dosimetric studies have suggested that the right treatment planning can make an IMRT plan more favorable compared to a proton therapy plan or vice versa, these studies often do not accurately predict clinically meaningful endpoints.

Non-Small-Cell Lung Cancer
NCCN guidelines for non-small cell lung cancer (NSCLC) (v.2.2023) offer the following recommendations:⁵⁰ "[Radiation therapy] has a potential role in all stages of NSCLC as either definitive or palliative therapy .... More advanced techniques are appropriate when needed to deliver curative [radiation therapy] safely. These techniques include (but are not limited to)4D-CT and/or PET/CT stimulation, IMRT/VMAT, [image-guided radiation therapy], motion management, and proton therapy .... Image-guided radiation therapy is recommended when using proton with steep dose gradients around the target, when [organs at risk] are in close proximity to high-dose regions, and when using complex motion management techniques." NCCN recommends that highly conformal radiation therapies such as proton therapy be used in the setting of prior radiation therapy, potentially with hyperfractionation, to reduce risk of toxicity.

Head and Neck Cancer
NCCN guidelines for head and neck cancers (v.1.2023) indicate that proton therapy may be used per the discretion of the treating physician but is an active area of investigation.⁵¹ Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy. Otherwise, IMRT or 3D conformal RT is recommended. The safety and efficacy of PBT when highly conformal dose distributions are important has been established, and is particularly important for patient with primary periocular tumors, tumors invading the orbit, skull base, cavernous sinus, and for patients with intracranial extension or perineural invasion. These treatment approaches are recommended for those being treated with curative intent and/or those with long life expectancies following treatment. However, NCCN adds that without "high-quality prospective comparative data, it is premature to conclude that proton therapy has been established as superior to other established radiation techniques such as IMRT, particularly with regard to tumor control.”

Pediatric Central Nervous System Cancer
NCCN guidelines for pediatric central nervous system cancers (v.2.2023) indicate that proton therapy offers maximal sparing of normal tissue and may be considered for patients with better prognoses (e.g., IDH1-mutated tumors, 1p/19q-codeletions, or younger age) as most data are derived from studies involving pediatric cases of low-grade glioma.52,

American Society for Radiation Oncology
The American Society for Radiation Oncology (ASTRO) (2017) updated its model policy on the medical necessity requirements for the use of proton therapy.⁵³ ASTRO deemed the following disease sites those for which the evidence frequently supports the use of proton beam therapy:

Ocular tumors, including intraocular melanomas
Tumors that approach or are located at the base of the skull, including but not limited to chordoma and chondrosarcomas
Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated
Hepatocellular cancer
Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors
Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients
Malignant and benign primary central nervous system tumors
Advanced (eg, T4) and/or unresectable head and neck cancers
Cancers of the paranasal sinuses and other accessory sinuses
Nonmetastatic retroperitoneal sarcomas
Re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose).

The model policy also made a specific statement on proton beam therapy for treating prostate cancer: “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.”

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03164460	Phase II Randomized Trial of Stereotactic Onco-Ablative Reirradiation Versus Conventionally Fractionated Conformal Radiotherapy for Patients With Small Inoperable Head and Neck Tumors (SOAR-HN)	100	May 2023
NCT03217188	A Phase II Study of Proton Re-Irradiation for Recurrent Head and Neck Cancer	87	Jul 2023
NCT01629498	Phase I/II Trial of Image-Guided, Intensity-Modulated Photon (IMRT) or Scanning Beam Proton Therapy (IMPT) Both With Simultaneous Integrated Boost (SIB) Dose Escalation to the Gross Tumor Volume (GTV) With Concurrent Chemotherapy for Stage II/III Non-Small Cell Lung Cancer (NSCLC)	100	Sep 2023
NCT01230866	Study of Hypo-fractionated Proton Radiation for Low Risk Prostate Cancer	150	Dec 2023
NCT02923570	A Phase II Randomized Study of Proton Versus Photon Beam Radiotherapy in the Treatment of Unilateral Head and Neck Cancer	108	Oct 2024
NCT01893307	Phase II/III Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck	442	Aug 2025
NCT01993810	Comparing Photon Therapy To Proton Therapy To Treat Patients With Lung Cancer	330	Oct 2025
NCT03561220	A Prospective Comparative Study of Outcomes With Proton and Photon Radiation in Prostate Cancer (COMPPARE)	3000	Apr 2026
NCT02838602	Randomized Carbon Ions vs Standard Radiotherapy for Radioresistant Tumors (ETOILE)	250	Dec 2026
NCT01617161	Proton Therapy vs. IMRT for Low or Intermediate Risk Prostate Cancer (PARTIQoL)	454	Dec 2026
ISRCTN16424014	A Trial of Proton Beam Radiotherapy for Oropharyngeal Cancer (TORPEdO)	183	Sep 2028

References:

Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer Treat Rev. Aug 2012; 38(5): 549-53. PMID 22270078
Hawkins BS. Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials. Oct 2011; 8(5): 661-73. PMID 22013172
Pereira PR, Odashiro AN, Lim LA, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol. 2013; 7: 1669-82. PMID 24003303
Technology Evaluation Center (TEC). Charged particle (proton or helium ion) irradiation for uveal melanoma and for chordoma or chondrosarcoma of the skull base or cervical spine. TEC Assessments 1996;Volume 11:Tab 1.
Wang Z, Nabhan M, Schild SE, et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. May 01 2013; 86(1): 18-26. PMID 23040219
Mishra KK, Quivey JM, Daftari IK, et al. Long-term Results of the UCSF-LBNL Randomized Trial: Charged Particle With Helium Ion Versus Iodine-125 Plaque Therapy for Choroidal and Ciliary Body Melanoma. Int J Radiat Oncol Biol Phys. Jun 01 2015; 92(2): 376-83. PMID 25841624
Lin AJ, Rao YJ, Acharya S, et al. Patterns of care and outcomes of proton and eye plaque brachytherapy for uveal melanoma: Review of the National Cancer Database. Brachytherapy. 2017; 16(6): 1225-1231. PMID 28966081
Toutée A, Angi M, Dureau S, et al. Long-Term Visual Outcomes for Small Uveal Melanoma Staged T1 Treated by Proton Beam Radiotherapy. Cancers (Basel). Jul 24 2019; 11(8). PMID 31344948
Lodge M, Pijls-Johannesma M, Stirk L, et al. A systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer. Radiother Oncol. May 2007; 83(2): 110-22. PMID 17502116
Zhou J, Yang B, Wang X, et al. Comparison of the Effectiveness of Radiotherapy with Photons and Particles for Chordoma After Surgery: A Meta-Analysis. World Neurosurg. Sep 2018; 117: 46-53. PMID 29879512
Leroy R, Benahmed N, Hulstaert F, et al. Proton Therapy in Children: A Systematic Review of Clinical Effectiveness in 15 Pediatric Cancers. Int J Radiat Oncol Biol Phys. May 01 2016; 95(1): 267-278. PMID 27084646
Upadhyay R, Yadav D, Venkatesulu BP, et al. Risk of secondary malignant neoplasms in children following proton therapy vs. photon therapy for primary CNS tumors: A systematic review and meta-analysis. Front Oncol. 2022; 12: 893855. PMID 36033525
Peterson RK, King TZ. A systemic review of pediatric neuropsychological outcomes with proton versus photon radiation therapy: A call for equity in access to treatment. J Int Neuropsychol Soc. Nov 03 2022: 1-14. PMID 36323679
Baliga S, Gallotto S, Bajaj B, et al. Decade-long disease, secondary malignancy, and brainstem injury outcomes in pediatric and young adult medulloblastoma patients treated with proton radiotherapy. Neuro Oncol. Jun 01 2022; 24(6): 1010-1019. PMID 34788463
Indelicato DJ, Bradley JA, Rotondo RL, et al. Outcomes following proton therapy for pediatric ependymoma. Acta Oncol. May 2018; 57(5): 644-648. PMID 29239262
Bishop AJ, Greenfield B, Mahajan A, et al. Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys. Oct 01 2014; 90(2): 354-61. PMID 25052561
MacDonald SM, Trofimov A, Safai S, et al. Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes. Int J Radiat Oncol Biol Phys. Jan 01 2011; 79(1): 121-9. PMID 20452141
Moeller BJ, Chintagumpala M, Philip JJ, et al. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy. Radiat Oncol. Jun 02 2011; 6: 58. PMID 21635776
Hug EB, Muenter MW, Archambeau JO, et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol. Jan 2002; 178(1): 10-7. PMID 11977386
Fuss M, Hug EB, Schaefer RA, et al. Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol Phys. Dec 01 1999; 45(5): 1117-26. PMID 10613303
Kozak KR, Adams J, Krejcarek SJ, et al. A dosimetric comparison of proton and intensity-modulated photon radiotherapy for pediatric parameningeal rhabdomyosarcomas. Int J Radiat Oncol Biol Phys. May 01 2009; 74(1): 179-86. PMID 19019562
Merchant TE. Proton beam therapy in pediatric oncology. Cancer J. 2009; 15(4): 298-305. PMID 19672146
Timmermann B. Proton beam therapy for childhood malignancies: status report. Klin Padiatr. May 2010; 222(3): 127-33. PMID 20514614
Vogel J, Both S, Kirk M, et al. Proton therapy for pediatric head and neck malignancies. Pediatr Blood Cancer. Feb 2018; 65(2). PMID 29058370
Technology Evaluation Center (TEC). Proton beam therapy for prostate cancer. TEC Assessments 2010;Volume 25:Tab 10.
Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. Apr 30 1995; 32(1): 3-12. PMID 7721636
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. Sep 14 2005; 294(10): 1233-9. PMID 16160131
Kim YJ, Cho KH, Pyo HR, et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol. Apr 2013; 52(3): 477-85. PMID 23398594
Sun F, Oyesanmi O, Fontanarosa J, et al. Therapies for Clinically Localized Prostate Cancer: Update of a 2008 Systematic Review (Comparative Effectiveness Review No. 146). Rockville, MD: Agency for Healthcare Research and Quality; 2014.
Nilsson S, Norlén BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol. 2004; 43(4): 316-81. PMID 15303499
Kuban D, Pollack A, Huang E, et al. Hazards of dose escalation in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys. Dec 01 2003; 57(5): 1260-8. PMID 14630260
Liu Y, Patel SA, Jani AB, et al. Overall Survival After Treatment of Localized Prostate Cancer With Proton Beam Therapy, External-Beam Photon Therapy, or Brachytherapy. Clin Genitourin Cancer. Jun 2021; 19(3): 255-266.e7. PMID 32972877
Grewal AS, Schonewolf C, Min EJ, et al. Four-Year Outcomes From a Prospective Phase II Clinical Trial of Moderately Hypofractionated Proton Therapy for Localized Prostate Cancer. Int J Radiat Oncol Biol Phys. Nov 15 2019; 105(4): 713-722. PMID 31199994
Technology Evaluation Center (TEC). Proton beam therapy for non- small-cell lung cancer. TEC Assessments. 2010;Volume 25:Tab 7.
Grutters JP, Kessels AG, Pijls-Johannesma M, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol. Apr 2010; 95(1): 32-40. PMID 19733410
Pijls-Johannesma M, Grutters JP, Verhaegen F, et al. Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review. Oncologist. 2010; 15(1): 93-103. PMID 20067947
Liao Z, Lee JJ, Komaki R, et al. Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. Jun 20 2018; 36(18): 1813-1822. PMID 29293386
Chang JY, Verma V, Li M, et al. Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: Final Results of a Phase 2 Study. JAMA Oncol. Aug 10 2017; 3(8): e172032. PMID 28727865
Ono T, Yabuuchi T, Nakamura T, et al. High Dose Hypofractionated Proton Beam Therapy is a Safe and Feasible Treatment for Central Lung Cancer. Radiol Oncol. Sep 2017; 51(3): 324-330. PMID 28959169
Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. Aug 2014; 15(9): 1027-38. PMID 24980873
Youssef I, Yoon J, Mohamed N, et al. Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy. JAMA Netw Open. Nov 01 2022; 5(11): e2241538. PMID 36367724
Blanchard P, Garden AS, Gunn GB, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer - A case matched analysis. Radiother Oncol. Jul 2016; 120(1): 48-55. PMID 27342249
Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up. Int J Clin Oncol. Jun 2015; 20(3): 447-54. PMID 25135461
Chang JY, Jabbour SK, De Ruysscher D, et al. Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. May 01 2016; 95(1): 505-516. PMID 27084663
Lin A, Chang JHC, Grover RS, et al. PTCOG Head and Neck Subcommittee Consensus Guidelines on Particle Therapy for the Management of Head and Neck Tumors. Int J Part Ther. 2021; 8(1): 84-94. PMID 34285938
Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria® Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014; 37(3): 278-88. PMID 25180754
Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically Localized Prostate Cancer: AUA/ASTRO Guideline. Part III: Principles of Radiation and Future Directions. J Urol. Jul 2022; 208(1): 26-33. PMID 35536141
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Uveal Melanoma. Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/uveal.pdf. Accessed April 3, 2023.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed April 4, 2023.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed April 5, 2023.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed April 6, 2023.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pediatric Central Nervous System Cancers. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf. Accessed April 7, 2023.
American Society for Radiation Oncology (ASTRO). ASTRO Model Policies: Proton Beam Therapy (PBT). 2017; https://www.astro.org/uploadedFiles/_MAIN_SITE/Daily_Practice/Reimbursement/Model_Policies/Content_Piece s/ASTROPBTModelPolicy.pdf. Accessed April 3, 2023.

Coding Section

Codes	Number	Description
CPT	77299	Unlisted procedure, therapeutic radiology clinical treatment planning
	77399	Unlisted procedure, medical radiation physics, dosimetry and treatment devices, and special services
	77499	Unlisted procedure, therapeutic radiology treatment management
	77520-77525	Proton Delivery Treatment; simple, intermediate or complex
	77261-77263	Therapeutic radiology treatment planning; simple, intermediate or complex
	77280,77285, 77290	Therapeutic radiology simulation-aided field setting; simple, intermediate or complex
	90380	Respiratory syncytial virus, monoclonal antibody, seasonal dose; 0.5 mL dosage, for intramuscular use
	90831	Respiratory syncytial virus, monoclonal antibody, seasonal dose; 1 mL dosage, for intramuscular use
ICD-9 Procedure	92.26	Teleradiotherapy or other particulate radiation
ICD-9 Diagnosis	170.0	Malignant neoplasm of skull
	170.2	Chondrosarcoma of cervial spine
	170.9	Chondrosarcoma, basisphenoid region (skull)
	190.0-190.9	Malignant neoplasm of eye code range (190.0 includes uveal tract)
	191.0-191.9	Malignant neoplasm of brain code range (there are no specific codes for pediatric CNS tumors)
	192.0-192.3	Malignant neoplasm of other and unspecified parts of the nervous system (192.2 is specific to the spinal cord)
	198.5	Secondary malignant neoplasm of skull
HCPCS	No Code
ICD-10-CM	C11.0-C11.9	Malignant neoplasm of nasopharynx code range
	C22.0-C22.9	Liver cancer code range
	C30.0-C31.9; C32.0-C32.9	Malignant neoplasm of the sinuses and larynx code range
	C34.00-C39.9	Malignant neoplasm of the lung code range
	C37	Malignant neoplasm of thymus
	C7A.091	Malignant carcinoid tumor of the thymus
	C41.0-C41.9	Malignant neoplasm of bones code range (skull and face, mandible, vertebral column, pelvic, sacrum and coccyx, articular cartilage)
ICD-10-CM (effective 10/01/15)	C41.0	Malignant neoplasm of bones of skull and face
	C41.2	Malignant neoplasm of vertebral column
	C41.9	Malignant neoplasm of bone and articular cartilage, unspecified
	C49.0	Malignant neoplasm of connective and soft tissue of head, face and neck
	50.01-C50.929	Malignant neoplasms of the breast code range
	C61	Malignant neoplasm of the prostate
	C69.30-C69.42	Malignant neoplasm of eye (codes specific to the uveal tract)
	C69.00 – C69.92	Malignant neoplasm of eye and adnexa code range (C69.0-C69.42 are specific to the uveal tract)
	C71.0 – C71.9	Malignant neoplasm of the brain code range
	C71.0-C71.9; C79.31	Malignant neoplasm of the brain code range
	C72.0	Malignant neoplasm of spinal cord
	C72.0-C72.1	Malignant neoplasm of spinal cord and cauda equina
	C72.20-C72.59	Malignant neoplasm of the cranial nerves
	C72.9	Malignant neoplasm of central nervous system, unspecified
	C79.49	Secondary malignant neoplasm of other parts of nervous system
	C81.00-C81.99	Hodgkins lymphoma code range
	C82.00-C88.9	Non-Hodgkins lymphoma code range
	D33.0-D33.2; D43.0-D43.2; D49.6	Benign and uncertain behaviors neoplasm of brain code range
	D33.3; D43.3	Benign and uncertain behaviors neoplasm of the cranial nerves
	D33.4; D43.4	Benign and uncertain behaviors neoplasm of spinal cord
	D33.7; D43.8-D43.9	Benign and uncertain behaviors neoplasm of other specified parts of central nervous system
	D33.9	Benign neoplasm of central nervous system, unspecified
	D42.0-D42.9	Neoplasm of uncertain behavior of meninges
ICD-10-PCS (effective 10/01/15)	D0004ZZ, D0014ZZ, D0064ZZ, D0004ZZ,	Radiation therapy, central and peripheral nervous system, beam radiation, brain, brain stem or spinal cord, heavy particles (protons, ions)
	D7004ZZ, D7014ZZ, D7024ZZ, D7034ZZ, D7044ZZ, D7054ZZ, D7064ZZ, D7074ZZ, D7084ZZ,	Radiation therapy, lymphatic and hematologic system, beam radiation,,heavy particles (protons, ions)
	D8004ZZ	Radiation oncology, eye, beam radiation, eye, heavy particles (protons, ions)
	D9004ZZ, D9014ZZ, D9034ZZ, D9044ZZ, D9054ZZ, D9064ZZ, D9074ZZ, D9084ZZ, D9094ZZ, D90B4ZZ, D90D4ZZ, D90F4ZZ	Radiation therapy, ENT, beam radiation, heavy particles (protons, ions)
	DB004ZZ, DB014ZZ, DB024ZZ, DB054ZZ, DB064ZZ, DB074ZZ, DB084ZZ,	Radiation therapy, Respiratory System, beam radiation, heavy particles (protons, ions)
	DF004ZZ, DF014ZZ, DF024ZZ, DF034ZZ	Radiation therapy, Hepatobiliary system and pancreas, beam radiation, heavy particles (protons, ions)
	DM004ZZ, DM014ZZ	Radiation Therapy, Breast, Beam Radiation, heavy particles (protons, ions)
	DP004ZZ, DP024ZZ, DP034ZZ, DP004ZZ, DP084ZZ,	Radiation therapy, Musculoskeletal system, beam radiation, (skull, maxilla, mandible, pelvic bones,) heavy particles (protons, ions)
	DV004ZZ	Radiation therapy, prostate, beam radiation, heavy particles (protons, ions)
	DW014ZZ, DW024ZZ, DW034ZZ, DW044ZZ, DW054ZZ, DW064ZZ,	Radiation therapy, Anatomical Regions, beam radiation, (head and neck, chest, abdomen, hemibody, whole body, pelvic) heavy particles (protons, ions)
	D0014ZZ, D0064ZZ	Radiation oncology, central and peripheral nervous system, beam radiation, brain stem or spinal cord, heay particles (protons, ions)
Type of Service	Therapy
Place of Service	Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

History From 2013 Forward

01/01/2024	Annual review, entire policy being updated to include coverage statements regarding ewing sarcoma, non metastatic primary non small cell lung cancer and neck cancers.
08/07/2023	Updating coding. Add codes 90380 and 90381. No other changes made.
01/05/2023	Annual review, no change to policy intent.
01/03/2022	Annual review, no change to policy intent.
01/06/2021	Annual review, no change to policy intent.
01/02/2020	Annual review, no change to policy intent.
01/22/2019	Annual review, no change to policy intent. Updating background, description, rationale and references.
05/10/2018	Interim review updating policy to mirror the current ASTRO model in relation to medical necessity. No other changes made.
02/14/2018	Annual review, no change to policy intent. Updating title, description, rationale and references.
01/16/2018	Annual review, no change to policy intent. Updating title, description, rationale and references.
08/29/2017	Interim review updating language related to medical necessity criteria.
08/01/2017	Correcting typographical errors.
03/27/2017	Interim review, updating policy statement to change diagnoses previously considered investigational to not medically necessary. No other changes made.
01/03/2017	Annual review, no change to policy intent. Adding regulatory status. Updating background, description, rationale and references.
01/20/2016	Annual update, changing the status of treatment for localized prostate cancer from not medically necessary to investigational. Updating background, description, rationale and references.
01/29/2015	Annual review, no change to policy intent. Updated rationale and references. Added coding.
01/16/2014	Annual review, adding related policies, updated policy language related to pediatric CNS tumors, expanded verbiage related to investigational uses of this technonlogy, added policy guidelines, updated rationale and references.

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Charged-Particle (Proton or Helium Ion) Radiotherapy for Neoplastic Conditions - CAM 80110