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.

For individuals who have uveal melanoma(s) who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes randomized controlled trials 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 a meaningful 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 2016, a systematic review of observational studies found 5-year survival rates after PBT ranging from 67% to 94%. The evidence is sufficient to determine that the technology results in a meaningful 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 the effects of the technology on health outcomes.

Clinical input obtained in 2013 strongly supported the use of charged-particle radiotherapy for treating pediatric central nervous system tumors. This modality of treatment of pediatric central nervous system tumors has the potential to reduce long-term adverse events (e.g., damage to nearby normal central nervous system tissue, development of radiation-induced secondary tumors).

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 the effects of the technology on health outcomes.

For individuals who have localized prostate cancer who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes 2 randomized controlled trials and systematic reviews. 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 randomized controlled trials, only one of which had a comparison group of patients that did not receive PBT. No data on the use of PBT for prostate cancer published since 2010 would alter the conclusions of the TEC Assessment. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have non-small-cell lung cancer who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes 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. No subsequent randomized or nonrandomized comparative studies were identified that would alter the conclusions of the TEC Assessment. The evidence is insufficient to determine the effects of the technology on health outcomes.

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 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 head-to-head trials comparing charged-particle therapy with other treatments. The evidence is insufficient to determine the effects of the technology on health outcomes. 

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 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. 
• 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, is 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. Senior staff at the FDA’s Center for Devices and Radiological Health have 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 1 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:  

• Ocular tumors, including intraocular melanomas 
• Tumors that approach or are located at the base of skull, including but not limited to: Chordoma 
• 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 CNS tumors 
• Advanced (e.g., T4) and/or unresectable head and neck cancers 
• Cancers of the paranasal sinuses and other accessory sinuses 
• Non-metastatic retroperitoneal sarcomas 
• Re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose) 

All other applications of charged-particle irradiation with proton beams are considered NOT MEDICALLY NECESSARY because there is no evidence of long-term durable benefit to health outcomes as compared to other methods of delivering radiation therapy, and charged-particle irradiation with proton beams is more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the patient's illness, injury or disease. This includes but is not limited to the following examples, which are considered NOT MEDICALLY NECESSARY:  

• Non-T4 and resectable head and neck cancers 
• Thoracic malignancies, including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas 
• Abdominal malignancies, including non-metastatic primary pancreatic, biliary and adrenal cancers 
• Pelvic malignancies, including non-metastatic rectal, anal, bladder and cervical cancers 
• Non-metastatic prostate cancer 
• Breast cancer

Policy Guidelines
There are no data to define age parameters for the use of proton beam therapy in pediatric patients. Some studies using proton beam therapy in pediatric central nervous system (CNS) tumors mostly included patients 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).

The use of proton beam or helium ion radiation therapy typically consists of a series of CPT codes describing the individual steps required: medical radiation physics, clinical treatment planning, treatment delivery and clinical treatment management. It should be noted that the code for treatment delivery primarily reflects the costs related to the energy source used and not physician work. The following CPT codes have been used:

Medical Radiation Physics
77399: Unlisted procedure, medical radiation physics, dosimetry and treatment devices

Clinical Treatment Planning
77299: Unlisted procedure, therapeutic radiology clinical treatment planning

Treatment delivery
The codes used for treatment delivery will depend on the energy source used, typically either photons or protons. For photons (i.e., with a Gamma Knife or LINAC device) nonspecific radiation therapy treatment delivery, CPT codes may be used based on the voltage of the energy source (i.e., codes 77402 – 77416). When proton beam therapy is used, the following specific CPT codes are available:
77520: Proton treatment delivery; simple, without compensation
77522: Proton treatment delivery; simple with compensation
77523: Proton treatment delivery; intermediate
77525: Proton treatment delivery; complex

Note: Codes for treatment delivery primarily reflect the costs related to the energy source used, and not physician work.

Clinical Treatment Management
77499: Unlisted procedure, therapeutic radiology clinical treatment management

Stereotactic charged particle radiosurgery would be reported with the following CPT codes:
61796: Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); 1 simple cranial lesion
61797: Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); each additional cranial lesion, simple (List separately in addition to code for primary procedure)
61798: Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); 1 complex cranial lesion
61799: Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); each additional cranial lesion, complex (List separately in addition to code for primary procedure)
63620: Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); 1 spinal lesion
63621: Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); each additional spinal lesion (List separately in addition to code for primary procedure)

Benefit Application
BlueCard/National Account Issues
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 MEDLINE database. The most recent literature update was performed through May 24, 2018.

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 function — including 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, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses 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. 

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

The question addressed in this evidence review is: Does charged-particle RT improve the net health outcome in patients who have uveal melanoma(s)?

The following PICOTS were used to select literature to inform this review. 

Patients 
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, 0.9 among Hispanics, and 0.24 among blacks. 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. 

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 proton beam therapy (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.

Timing 
RT is used as part of first-line treatment for uveal melanoma. One- and 5-year outcomes are indicators of successful treatment. 

Setting 
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

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

More recently, 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, 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 (odds ratio, 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 = 0.006). 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 = 0.02). 

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 = 0.008). 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 < 0.02); tumor diameter of 12 to 18 mm (HR = 2.48; 95% CI, 1.40 to 4.42; p < 0.02); tumor diameter greater than 18 mm (HR = 6.41; 95% CI, 1.45 to 28.35; p < 0.02); and proton treatment (HR = 1.89; 95% CI, 1.06 to 3.37; p < 0.02). 

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) RT for individuals with Skull-Based Tumors 
Clinical Context and Test Purpose 
The purpose of charged-particle (proton or helium ion) RT in patients who have skull-based tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does charged-particle RT improve the net health outcome in individuals with skull-based tumors?

The following PICOTS were used to select literature to inform this review. 

Patients 
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. 

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. 

Timing 
Local control and survival outcomes for charged-particle therapy for skull-base tumors have been reported at 1 year and 5 years. 

Setting 
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

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.⁴ More recently, 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.^8. 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 systematic review by Matloob et al. (2016) evaluated the literature on PBT for skull-based chordomas.⁹ Reviewers selected controlled trials and case series with more than 5 patients, with 12 studies meeting eligibility criteria. Reviewers did not report study type, but it appears they only identified case series. Sample sizes ranged from 9 to 367 patients and 6 studies reported 5-year survival rates that ranged from 67% to 94%. 

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%.

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

The question addressed in this evidence review is: Does charged-particle RT improve the net health outcome in children with CNS tumors?

The following PICOTS were used to select literature to inform this review. 

Patients 
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. 

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. 

Timing 
Local tumor control and OS would be assessed at 1 and 3 years. 

Setting 
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

Systematic Reviews
Leroy et al. (2016) published a systematic review of the literature on PBT for the treatment of pediatric cancers.¹⁰ Their findings included the following:

• For craniopharyngioma, three studies were identifiedtwo retrospective case series and one 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.

Case Series 
Representative case series of PBT used to treat multiple pediatric CNS tumor types are described next. For example, Bishop et al. (2014) reported on 52 children with craniopharyngioma treated at 2 centers; 21 received PBT and 31 received IMRT.¹¹ 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 = 0.742). 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..¹² 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 2009.¹³ 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 < 0.05). There was partial sparing of mean postradiation 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.¹⁴ 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.¹⁵ 

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. 

charged-particle (proton or helium ion) RT for Pediatric Non-CNS Tumors 
Clinical Context and Test 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 question addressed in this evidence review is: Does charged-particle RT improve net health outcomes in children with non-CNS tumors?

The following PICOTS were used to select literature to inform this review. 

Patients
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.

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.

Outcomes 
The general outcomes of interest are OS, disease-free survival, change in disease status (local recurrence), and treatment-related morbidity. 

Timing 
Local control and OS would be assessed at 1 and 3 years. 

Setting 
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

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 rhabdomyosarcoma¹⁶ and late toxicity outcomes in other solid tumors of childhood.^17,18

Vogel et al. (2018) published a retrospective case series of proton-based radiotherapy to treat nonhematologic head and neck malignancies in 69 pediatric patients.¹⁹ 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 mucosities (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 Ewin sarcoma, in addition to other histologies. The current evidence base is not sufficiently robust to draw conclusions about the efficacy of PBT for pediatric non-CNS tumors. 

charged-particle (proton or helium ion) RT for Localized Prostate Cancer 
Clinical Context and Test 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 question addressed in this evidence review is: Does charged-particle RT improve the net health outcome in individuals with localized prostate cancer?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients who have locally advanced prostate cancer (i.e., stages C or D1 without distant metastases., also classified as T3 or T4). These tumors may be associated with a high rate of local recurrence despite maximal doses of conventional RT.

Interventions
The test being considered is charged-particle (proton or helium ion) RT.

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.

Outcomes
The general outcomes of interest are OS, disease-free survival, change in disease status (local recurrence), and treatment-related morbidity.

Timing
Local control and OS would be assessed at 1 and 5 years.

Setting
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

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.²⁰ Nine 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.²¹ 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. Actuarial 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).²² 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.²³ 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.²⁴ 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.²⁵ 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- dimensional 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.²⁶ 

Section Summary: Localized Prostate Cancer 
The evidence on PBT for treating localized prostate cancer includes 2 RCTs and systematic reviews. 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. 

Charged-particle (proton or helium ion) RT for Non-Small-Cell Lung Cancer 
Clinical Context and Test Purpose
The purpose of charged-particle (proton or helium ion) RT in patients 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 question addressed in this evidence review is: Does charged-particle RT improve the net health outcome for patients with NSCLC?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with NSCLC. NSCLC is the most common cause 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.

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.

Outcomes
The general outcomes of interest are OS, disease-free survival, change in disease status (local recurrence), and treatment-related morbidity.

Timing
Local control and OS would be assessed at 1 and 5 years. 

Setting 
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

Systematic Reviews 
A TEC Assessment (2010) assessed the use of PBT for NSCLC.²⁷ 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 (total 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 (e.g., 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.²⁸ 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.²⁹ 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 patients) and 6, C-ions (n = 210 patients). 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. 

Nonrandomized Studies 
To date, no RCTs comparing health outcomes in patients treated with PBT or with an alternative treatment have been identified.

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).^30. 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 = 0.004). 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 = 0.04), and a pretreatment tumor size greater than 7 cm (p = 0.03). The use of non-standardized 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 2015.³¹ 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 as 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 = 0.109), 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. No subsequent randomized or nonrandomized comparative studies have been published. Final results from a 2017 open-label phase 2 study included 5-year survival rates for patients who had PBT with concurrent chemotherapy. 

charged-particle (proton or helium ion) RT for Head and Neck Tumors, Other Than Skull-Based 
Clinical Context and Test Purpose
The purpose of charged-particle (proton or helium ion) RT in patients 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 question addressed in this evidence review is: Does charged-particle RT improve the net health outcome in patients with head and neck tumors, other than skull-based?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients 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.

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.

Outcomes
The general outcomes of interest are OS, disease-free survival, change in disease status (local recurrence), and treatment-related morbidity.

Timing 
Local control and OS would be assessed at 1 and 5 years. 

Setting
Charged-particle therapy is administered in specially equipped treatment centers. PBT can be administered with or without stereotactic techniques. 

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.³² Reviewers identified 41 observational studies that included 13 cohorts treated with charged- particle therapy (n = 286 patients) and 30 cohorts treated with PBT (n = 1186 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 timeframes (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 < 0.001), 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.

Zenda et al. (2015) reported on late toxicity in 90 patients after PBT for nasal cavity, paranasal sinuses, or skull-based malignancies.³³ 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. 

Summary of Evidence 
For individuals who have uveal melanoma(s) who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes 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 a meaningful 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 PBT compared with 44% with surgery plus photon therapy. In 2016, a systematic review of observational studies found 5-year survival rates after PBT ranging from 67% to 94%. The evidence is sufficient to determine that the technology results in a meaningful 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 the effects of the technology on health outcomes.

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 the effects of the technology on health outcomes.

For individuals who have localized prostate cancer who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes 2 RCTs and systematic reviews. 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. No data on the use of PBT for prostate cancer published since 2010 would alter the conclusions of the TEC Assessment. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have non-small-cell lung cancer who receive charged-particle (proton or helium ion) radiotherapy, the evidence includes 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. No subsequent randomized or nonrandomized comparative studies were identified that would alter the conclusions of the TEC Assessment. The evidence is insufficient to determine the effects of the technology on health outcomes.

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 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 head-to-head trials comparing charged-particle therapy with other treatments. The evidence is insufficient to determine the effects of the technology on health outcomes.

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.

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 
International Particle Therapy Co-operative Group 
A 2016 consensus statement by the International Particle Therapy Co-operative Group 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..."³⁴ 

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.³⁵

National Comprehensive Cancer Network 
Prostate Cancer 
National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (v.3.2018) 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."³⁶ 

Non-Small-Cell Lung Cancer 
NCCN guidelines for NSCLC (v.4.2018) have been updated with the following for advanced-stage disease or palliation: “When higher doses ( > 30 Gy) are warranted, technologies to reduce normal tissue irradiation (at least 3D-CRT 3-dimensioal conformal radiotherapy. and including IMRT and proton therapy as appropriate) may be used."³⁷ 

Head and Neck Cancer 
NCCN guidelines for head and neck cancers (v.2.2018) indicate 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."³⁸ The guidelines suggest that proton therapy can be considered for cancers of the paranasal sinuses and salivary glands if normal tissue constraints cannot be met by conventional photon radiotherapy. 

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.³⁹ 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 (e.g., 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 1. 

Table 1. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
NCT01230866	Study of Hypo-fractionated Proton Radiation for Low Risk Prostate Cancer	150	Dec 2018
NCT01993810	Comparing Photon Therapy To Proton Therapy To Treat Patients With Lung Cancer	560	Dec 2020
NCT02838602	Randomized Carbon Ions vs Standard Radiotherapy for Radioresistant Tumors (ETOILE)	250	May 2024
NCT01617161	Proton Therapy vs. IMRT for Low or Intermediate Risk Prostate Cancer (PARTIQoL)	400	Dec 2026
NCT02603341	Pragmatic Randomized Trial of Proton vs. Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial	1,720	Nov 2030

NCT: national clinical Trial.

References:

1. Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer Treat Rev. Aug 2012;38(5):549-553. PMID 22270078
2. Hawkins BS. Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials. Oct 2011;8(5):661-673. PMID 22013172
3. Pereira PR, Odashiro AN, Lim LA, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol. 2013;7:1669-1682. PMID 24003303
4. Blue Cross and Blue Shield Association 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.
5. 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 1 2013;86(1):18-26. PMID 23040219
6. 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 1 2015;92(2):376-383. PMID 25841624
7. 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. Nov - Dec 2017;16(6):1225-1231. PMID 28966081
8. 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):110-122. PMID 17502116
9. Matloob SA, Nasir HA, Choi D. Proton beam therapy in the management of skull base chordomas: systematic review of indications, outcomes, and implications for neurosurgeons. Br J Neurosurg. May 13 2016:1-6. PMID 27173123
10. 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 1 2016;95(1):267-278. PMID 27084646
11. 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 1 2014;90(2):354-361. PMID 25052561
12. 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 1 2011;79(1):121-129. PMID 20452141
13. 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
14. Hug EB, Muenter MW, Archambeau JO, et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol. Jan 2002;178(1):10-17. PMID 11977386
15. 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 1 1999;45(5):1117-1126. PMID 10613303
16. 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 1 2009;74(1):179-186. PMID 19019562
17. Merchant TE. Proton beam therapy in pediatric oncology. Cancer J. Jul-Aug 2009;15(4):298-305. PMID 19672146
18. Timmermann B. Proton beam therapy for childhood malignancies: status report. Klin Padiatr. May 2010;222(3):127-133. PMID 20514614
19. 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
20. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Proton beam therapy for prostate cancer. TEC Assessments 2010;Volume 25:Tab 10.
21. 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
22. 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):1233-1239. PMID 16160131
23. 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):477-485. PMID 23398594
24. 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.
25. Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol. Aug 2004;43(4):316-381. PMID 15303499
26. Kuban D, Pollack A, Huang E, et al. Hazards of dose escalation in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys. Dec 1 2003;57(5):1260-1268. PMID 14630260
27. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Proton beam therapy for non-small-cell lung cancer. TEC Assessments. 2010;Volume 25:Tab 7.
28. 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
29. 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. Jan 2010;15(1):93-103. PMID 20067947
30. 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
31. 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
32. 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):1027-1038. PMID 24980873
33. 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):447-454. PMID 25135461
34. 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 1 2016;95(1):505-516. PMID 27084663
35. Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria(R) Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014;37(3):278-288. PMID 25180754
36. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 3.2018. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed June 27, 2018.
37. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 4.2018. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed June 27, 2018.
38. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Head and neck cancers. Version 2.2018. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed June 27, 2018.
39. 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_Policie s/Content_Pieces/ASTROPBTModelPolicy.pdf. Accessed June 27, 2018.

Coding Section

Codes	Number	Description
CPT	See Policy Guidelines
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 (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
	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
	C72.0	Malignant neoplasm of spinal cord
ICD-10-PCS (effective 10/01/15)
	D8004ZZ	Radiation oncology, eye, beam radiation, eye, 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, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology^© American Medical Association. All Rights Reserved." 

History From 2013 Forward     

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.