Coverage Policy Manual
Policy #: 2008012
Category: Radiology
Initiated: September 2008
Last Review: June 2024
  Radiation Therapy, Proton Beam or Helium Ion Irradiation

Description:
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.

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
 
Coverage Statement Effective March 13, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Proton beam therapy (PBT) meets member benefit certificate primary coverage criteria in the following clinical situations:
 
Base of Skull Tumors
Chordoma, Chondrosarcoma
For chordoma or chondrosarcoma when the following condition is met:
            • As postoperative therapy for individuals who have undergone biopsy or partial resection of a chordoma or low-grade (I or II) chondrosarcoma of the basisphenoid region (e.g., skull-base chordoma or chondrosarcoma), cervical spine, or sacral/lower spine and have residual, localized tumor without evidence of metastasis
Sinonasal Cancer
For locally advanced sinonasal carcinoma when the following condition is met:
            • Tumor involves the base of skull and proton therapy is needed to spare the orbit, optic nerve, optic chiasm, or brainstem
Central Nervous System
Arteriovenous Malformation (AVM)
For AVM when ANY of the following conditions are met:
            • Intracranial AVM not amenable to surgical excision or other conventional forms of treatment
            • Adjacent to critical structures such as the optic nerve, brain stem or spinal cord
Central Nervous System (CNS) Tumors
For CNS tumors when ALL the following conditions are met:
Including, but not limited to, primary or metastatic CNS malignancies, such as gliomas (BOTH of the following must be met)
            • When adjacent to critical structures such as the optic nerve, brain stem, or spinal cord
            • When other standard radiation techniques such as IMRT or standard stereotactic modalities would not sufficiently reduce the risk of radiation damage to the critical structure
Hepatobiliary Cancer
Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma
For Hepatocellular Cancer or Intrahepatic Cholangiocarcinoma when the following conditions are met:
            • To treat unresectable, non-metastatic hepatocellular cancer or intrahepatic cholangiocarcinoma AND
            • Treatment is given with curative intent
Melanoma
Ocular Melanoma
For ocular melanoma when the following condition is met:
            • To treat melanoma of the uveal tract (including the iris, choroid, or ciliary body) and no evidence of metastasis or extrascleral extension
Pediatric Patients
All Tumor Types
For pediatric patients (age less than 21) when the following condition is met:
            • To treat all pediatric tumors in which radiation therapy is required
Re-irradiation (Repeat Treatment)
        • For the repeat irradiation of previously treated fields where the dose tolerance of surrounding normal structures would be exceeded with 3D conformal radiation or IMRT or stereotactic radiosurgery.
 
Image guidance or image-guided radiation therapy (IGRT), any modality, used with Proton beam therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Proton beam therapy (PBT) for the treatment of all other conditions other than specifically stated above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered including but not limit to:
    • Breast cancer
    • Esophageal cancer
    • Gastric cancer
    • Gynecologic cancer
    • Head and neck cancer
    • Hepatobiliary cancers not listed above
    • Lung cancer
    • Lymphoma (Hodgkin and non-Hodgkin)
    • Pancreatic cancer
    • Prostate cancer
Investigational services are Plan exclusions.
 
For contracts without primary coverage criteria, Proton beam therapy (PBT) for the treatment of all other conditions other than specifically stated above, is considered investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage..
 
 
Coverage Statement Effective Prior to March 13, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Proton beam or helium ion irradiation meets member benefit certificate primary coverage criteria in the following clinical situations:
 
Initial Treatment
    • Primary therapy for melanoma of the uveal tract (iris, choroid, or ciliary body), with no evidence of metastasis or extrascleral extension.
    • 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 or sacral/lower spine. Patients eligible for this treatment have residual localized tumor without evidence of metastasis.
    • Other Central Nervous System tumors:
        • When located near vital structures; AND
        • When other standard radiation techniques such as IMRT or standard stereotactic modalities would not sufficiently reduce the risk of radiation damage to the critical structure
    • Radiosensitive malignancies in children under the age of 21, which are not amenable to treatment with stereotactic body radiation therapy or IMRT.
    • Locally advanced Sinonasal Cancer when the Tumor involves the base of skull and proton therapy is needed to spare the orbit, optic nerve, optic chiasm, or brainstem
    • Intracranial Arteriovenous Malformation (AVM) when all of the following criteria are met:
        • Adjacent to critical structures such as the optic nerve, brain stem or spinal cord; AND
        • Not amenable to surgical excision or other conventional forms of treatment; AND
        • Not amenable to treatment with stereotactic body radiation therapy or IMRT.
    • Hepatocellular carcinoma and intrahepatic cholangiocarcinoma when the following criteria are met:   
        • For treatment of unresectable, non-metastatic hepatocellular cancer or intrahepatic cholangiocarcinoma; AND
        • Treatment is given with curative intent.
 
Repeat Treatment
    • Proton beam is appropriate for the repeat irradiation of previously treated fields where the dose tolerance of surrounding normal structures would be exceeded with 3D conformal radiation or IMRT or stereotactic radiosurgery.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Other uses of proton beam or helium ion irradiation not addressed in this or other referenced policies does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, any use of proton beam or helium ion irradiation other than that specifically stated as meeting primary coverage criteria, is considered investigational and is not covered.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to July 2021
  
Proton beam or helium ion irradiation meets member benefit certificate primary coverage criteria in the following clinical situations:
 
Initial Treatment
    • Primary therapy for melanoma of the uveal tract (iris, choroid, or ciliary body), with no evidence of metastasis or extrascleral extension.
    • 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 or sacral/lower spine. Patients eligible for this treatment have residual localized tumor without evidence of metastasis.
    • Other Central Nervous System tumors:
        • When located near vital structures; AND
        • When other standard radiation techniques such as IMRT or standard stereotactic modalities would not sufficiently reduce the risk of radiation damage to the critical structure
    • Radiosensitive malignancies in children under the age of 21, which are not amenable to treatment with stereotactic body radiation therapy or IMRT.
    • Locally advanced Sinonasal Cancer when the Tumor involves the base of skull and proton therapy is needed to spare the orbit, optic nerve, optic chiasm, or brainstem
    • Intracranial Arteriovenous Malformation (AVM) when all of the following criteria are met:
        • Adjacent to critical structures such as the optic nerve, brain stem or spinal cord; AND
        • Not amenable to surgical excision or other conventional forms of treatment; AND
        • Not amenable to treatment with stereotactic body radiation therapy or IMRT.  
 
Repeat Treatment
    • Proton beam is appropriate for the repeat irradiation of previously treated fields where the dose tolerance of surrounding normal structures would be exceeded with 3D conformal radiation or IMRT or stereotactic radiosurgery.
 
 Other uses of proton beam or helium ion irradiation not addressed in this or other referenced policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For contracts without Primary Coverage Criteria, any use of proton beam or helium ion irradiation other than that specifically stated as meeting primary coverage criteria, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.
 
Effective Prior to January 2020
Proton beam or helium ion irradiation meets member benefit certificate primary coverage criteria 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.
  • Other Central Nervous System tumors located near vital structures;
  • Radiosensitive malignancies in children under the age of 18, which are not amenable to treatment with stereotactic body radiation therapy or IMRT.
 
Other uses of proton beam or helium ion irradiation not addressed in this or other referenced policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For contracts without Primary Coverage Criteria, any use of proton beam or helium ion irradiation other than that specifically stated as meeting primary coverage criteria, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.
 
Effective prior to April 2013
Proton beam or helium ion irradiation meets member benefit certificate primary coverage criteria 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.  
 
Other uses of proton beam or helium ion irradiation not addressed in this or other referenced policies does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For contracts without Primary Coverage Criteria, any use of proton beam or helium ion irradiation other than that specifically stated as meeting primary coverage criteria, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.

Rationale:
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A RCT, published in 2015 by Mishra and colleagues, compared charged-particle therapy using helium ions and iodine 125 (I-125) plaque therapy in 184 patients with uveal melanoma (Mishra, 2015). 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). OS 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).
 
A 2016 systematic review by Matloob and colleagues evaluated the literature on proton beam therapy for skull-based chordomas (Matloob, 2016). The review included controlled trials and case series with more than 5 patients. Twelve studies met eligibility criteria. The authors did not report study type, but they did not appear to identify only controlled trials, only case series. Sample sizes ranged from 9 to 367 patients. Six studies reported a 5-year survival rates that ranged from 67% to 94%.
 
Leroy and colleageus published a systematic review of the literature on PBT for treatment of pediatric cancers (Leroy, 2016). Their findings on pediatric CNS tumors include the following:
  • Craniopharyngioma: Three studies were identified, 2 retrospective case series and 1 retrospective comparative study of PBT versus IMRT. They concluded that there is very low level evidence that survival outcomes are similar with PBT and IMRT.
  • Ependymoma: One prospective case series and 1 retrospective case series were identified. They concluded that the evidence is insufficient to support or refute the use of PBT for this condition.
  • Medulloblastoma: One prospective case series and 2 retrospective case series were identified. They concluded that the evidence is insufficient to support or refute the use of PBT for this condition.
  • CNS germinoma: One retrospective case series was identified. They concluded that the evidence is insufficient to support or refute the use of PBT for this condition.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2017. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Charged-Particle (Proton Or Helium Ion) Radiotherapy For Uveal Melanomas
 
Lin et al 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 (Lin, 2017). 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).
 
Charged-Particle (Proton Or Helium Ion) RT For Pediatric Central Nervous System Tumors
 
Hug et al reported on proton radiation in the treatment of low-grade gliomas in 27 pediatric patients (Hug, 2002). 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, Fuss et al showed a decrease in radiation dose to the contralateral optic nerve, temporal lobes, pituitary gland, and optic chiasm with the use of protons (Fuss, 1999).
 
 Charged-Particle (Proton Or Helium Ion) RT For Pediatric Non-CNS Tumors
 
Vogel et al published a retrospective case series of proton-based radiotherapy to treat nonhematologic head and neck malignancies in 69 pediatric patients (Vogel, 2018). Thirty-five of the patients had rhabdomyosarcoma and were treated with 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.
 
In summary, 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
 
Kim et al, 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 (Kim, 2013). However, without an alternative intervention, conclusions cannot be drawn about the efficacy and safety of PBT. This Korean study, published by Kim et al, included men with androgen-deprivation therapy-naïve stage T1-T3 prostate cancer. 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.
 
Charged-Particle (Proton Or Helium Ion) RT For Non-Small-Cell Lung Cancer
 
To date, no RCTs comparing health outcomes in patients treated with PBT or with an alternative treatment have been identified.
 
Chang et al 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) (Chang, 2017). Median OS was 26.5 months; at 5 years, the OS rate was 29% (95% CI, 18% to 41%). Median progression-free survival (PFS) was 12.9 months; the 5-year PFS 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 IIIV cancer
(p=0.03), the presence of a tumor in 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 published a retrospective case series of 20 patients with lung cancer treated with PBT at a single center between 2009 and 2015 (Ono, 2017). 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.
 
Final results from a 2017 open-label phase 2 study included 5-year survival rates for patients who had PBT with concurrent chemotherapy.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
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 (NCCN, 2018).”
 
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 (NCCN, 2018).”
 
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 (NCCN, 2018).” 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) updated its model policy on the medical necessity requirements for the use of proton therapy (ASTRO, 2017). ASTRO deemed the following disease sites 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 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 CNS 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.”
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
 
Annual policy review completed with a literature search using the MEDLINE database through May 2021. The key identified literature is summarized below.
 
A single institution retrospective study compared ablative photon vs proton therapy in 78 patients with unresectable hepatocellular carcinoma. The majority of the proton beam patients were treated as part of a phase II single arm clinical trial (NCT 00976898). The primary endpoint was overall survival. Proton therapy was associated with an improved overall survival of 31 months vs 14 months with photons. The proton-treated patients had a significantly lower risk of non-classic radiation induced liver disease (RILD) (OR 0.26, P = .03) and development of RILD at 3 months was significantly associated with worse overall survival. There was no difference in local failure between the two treatment suggesting that the improved survival is related to the decrease in post-treatment liver decompensation.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2021.The key identified literature is summarized below.
 
Hepatocellular Cancer
Hepatocellular carcinomas (HCC) are aggressive primary malignancies of the liver. All patients should be evaluated for potentially curative therapies including resection, transplantation and ablative treatment. Ablative therapies include radiofrequency ablation, microwave therapy, and alcohol injection. Radiation therapy is considered for patients who are not candidates for resection. There is growing evidence for the use of stereotactic body radiation therapy (SBRT). Charged particle therapy such as proton therapy has also been used in the treatment of hepatocellular carcinoma.
 
There are no randomized trials comparing PBT to other forms of external radiation. A systematic review and meta-analysis comparing charged particle therapy to conventional radiation and SBRT has been reported. Overall survival, progression-free survival, and local control were equivalent for particle therapy and SBRT. Both charged particle therapy and SBRT were superior to conventional radiation.
 
A single institution retrospective study compared ablative photon vs proton therapy in patients with unresectable hepatocellular carcinoma. The majority of the proton beam patients were treated as part of a phase II single arm clinical trial (NCT 00976898). The primary endpoint was overall survival. Proton therapy was associated with an improved overall survival of 31 months vs 14 months with photons. The proton-treated patients had a significantly lower risk of non-classic radiation induced liver disease (RILD) (OR 0.26, P = .03) and development of RILD at 3 months was significantly associated with worse overall survival. There was no difference in local failure between the two treatment suggesting that the improved survival is related to the decrease in posttreatment liver decompensation.
 
Proton therapy has been compared to transarterial chemoembolization (TACE) for HCC in a randomized trial. A total of 69 subjects were reported. The primary endpoint was progression-free survival. There was a trend toward improved progression-free survival (48% vs 31%; P = .06) favoring protons but no significant difference in overall survival with a median overall survival of 30 months. Total days of hospitalization within 30 days of treatment was 166 days for the 36 TACE patients and 24 days for the proton patients (P < .001).
 
Another randomized trial compared radiofrequency ablation (RFA) to proton beam therapy for unresectable hepatocellular carcinoma. One hundred forty-four patients were randomly assigned to receive either RFA or PBT. There was significant crossover to the other modality affecting 6 patients assigned to PBT and 19 patients assigned to RFA. For the patients treated per protocol, the two-year local progression-free survival rate was 94.8% in the PBT patients vs 83.9% for RFA (P < .001). The authors concluded that PBT is non-inferior to RFA in this setting.
 
Proton beam therapy is considered medically necessary for the treatment of unresectable HCC with curative intent when there is no evidence of metastatic disease.
 
New References
    • Bahn E, Bauer J, Harrabi S, et al. Late Contrast Enhancing Brain Lesions in Proton-Treated Patients With Low-Grade Glioma: Clinical Evidence for Increased Periventricular Sensitivity and Variable RBE. Int J Radiat Oncol Biol Phys. 2020;107(3):571-8.
    • Bekelman JE, Lu H, Pugh S, et al. Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol. BMJ Open. 2019;9(10):e025556
    • Brown PD, Chung C, Liu DD, et al. A prospective phase II randomized trial of proton radiotherapy vs intensity modulated radiotherapy for patients with newly diagnosed glioblastoma. Neuro Oncol. 2021;23(8):1337-47
    • Cheng JY, Liu CM, Wang YM, et al. Proton versus photon radiotherapy for primary hepatocellular carcinoma: a propensity-matched analysis. Radiat Oncol. 2020;15
    • Hahn C, Eulitz J, Peters N, et al. Impact of range uncertainty on clinical distributions of linear energy transfer and biological effectiveness in proton therapy. Med Phys. 2020;47(12):6151-62.
    • Hallemeier CL, Huguet F, Tait D, et al. Randomized trials for esophageal, liver, pancreas, and rectalcancers. Int J Radiat OncolBiol Phys. 2020;109:305-11.
    • Kim TH, Koh YH, Kim BH, Kim MJ, Lee JH, Park B, Park JW. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: A randomized phase III trial. J Hepatol.2021;74(3):603-12
    • Lin SH, Hobbs, BP, Verma V, et al. Randomized phase IIB trial of proton beam therapy versus intensity-modulated radiation therapy for locally advanced esophageal cancer. J Clin Oncol. 2020;38:1569-79.
    • Liu C, Zheng D, Bradley JA, et al. Incorporation of the LETd-weighted biological dose in the evaluation of breast intensity-modulated proton therapy plans. Acta
    • Manzar GS, Lester SC, Routman DM, et al. Comparative analysis of acute toxicities and patient reportedoutcomes betweenintensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) for the treatment of oropharyngealcancer. Radiother Oncol. 2020;147:64-74.
    • Marteinsdottir M, Wang CC, McNamara A, et al. The impact of variable relative biological effectiveness in proton therapy for left-sided breast cancer when estimating normal tissue complications in the heart and lung. Phys Med Biol. 2021;66(3):035023.
    • Pasalic D, Ludmir EB, Allen PK, et al. Patient-reported outcomes, physician-reported toxicities, and treatment outcomes in a modern cohort of patients with sinonasal cancer treated using proton beam therapy. Radiother Oncol. 2020;148:258-66.
    • Patel S, Nunna RS, Ryoo JS, et al. Outcomes and Patterns of Care in Adult Skull Base Chondrosarcoma Patients in the UnitedStates. World Neurosurg. 2021;150:71-83.
    • Zakeri K, Wang H, Kang JJ, et al. Outcomes and prognostic factors of major salivary gland tumors treated with proton beamradiation therapy. Head Neck. 2021;43(4):1056-62.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Upadhyay et al conducted a systematic review and meta-analysis of secondary malignant neoplasm risk in children treated with proton versus photon radiotherapy for primary CNS tumors (Upadhyay, 2022). 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 published a systematic review of neuropsychological outcomes with proton versus photon radiation therapy in the treatment of pediatric brain tumors (Peterson, 2022). 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.
 
Baliga et al reported on 178 pediatric medulloblastoma patients treated with PBT between 2002 and 2016 (Baliga, 2022). 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 reported on 179 children with nonmetastatic grade II/III intracranial ependymoma who were treated with proton therapy at a single institution (Indelicato, 2018). 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.
 
Liu et al conducted an analysis of the National Cancer Database (NCDB) for cases of localized prostate cancer treated with definitive radiotherapy between 2004 and 2015 (Liu, 2021). 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 1860 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.
 
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 (Grewal, 2019). 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.
 
Liao et al conducted a RCT of PSPT versus IMRT in patients with inoperable NSCLC who were candidates for concurrent chemotherapy (Liao, 2018). 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.
 
Youssef et al 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) (Youssef, 2022). 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.
 
In 2021, PTCOG published consensus guidelines on particle therapy for the management of head and neck cancer (Lin, 2021). 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."
 
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 (Eastham, 2022). 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.
 
Additional 2024 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Young et al conducted a systematic review of clinical outcomes of PBT for medulloblastoma. Thirty-five studies were included, representing an estimated 630 to 654 unique patients treated with PBT (Young, 2023). None of the studies were randomized, 12 were comparative, 9 were prospective, and 22 were retrospective. The average mean/median follow-up was 5.0 years (range, 4 weeks to 12.6 years). OS at 10 years ranged from 85.3% to 86.9% for standard-risk medulloblastoma patients treated with PBT. A cumulative risk of secondary malignancy of 2.1% to 8% was reported in 2 studies. Patients treated with PBT had superior neurocognitive outcomes on the NOS from 3.7 to 5.3 years follow-up over photon RT. Patients in the PBT group had reduced acute toxicities compared to photon RT (grade 3 esophagitis, diarrhea, and weight loss). The authors conclude there is moderate-grade evidence supporting PBT as a preferred treatment for craniospinal RT of medulloblastoma based on equivalent disease control and comparable-to-improved toxicity versus photon RT.
 
Wilson et al conducted a systematic review of the effects of PBT in children and young adults with CNS tumors. Thirty-one studies were included (N=1731 patients) from 10 proton therapy centers (Wilson, 2024). Eleven studies involved children with medulloblastoma or primitive neuroectodermal tumors (n=712), with OS ranging from 68% to 89% for newly diagnosed patients. Five studies investigated ependymoma (n=398), reporting 3-year OS rates from 90% to 97% for patients receiving first-line therapy. Four studies examined atypical teratoid/rhabdoid tumor (n=72), with OS ranging from 53% at 2 years to 90% at 2.3 years. Six studies looked at craniopharyngioma (n=272), with 3-year OS of 94% for PBT and 97% for photon RT in one comparative study, and 5-year OS of 97.7% in another proton therapy study. Three studies investigated low-grade gliomas (n=233), reporting OS rates of 85%, 92%, and 100% at 3.3, 5.0, and 8.0 years follow-up, respectively. One study examined germ cell tumors (n=22), finding 100% OS at 2.3 years. Lastly, one study looked at pineoblastoma (n=22), reporting 90% OS at 3.2 years. Serious adverse events included endocrinopathies (range, 3% to 96%), ototoxicity (range, 0% to 70%), radio-necrosis (range, 0% to 21%), stroke (range, 1.7% to 10%), and brainstem toxicity (range, 0.5% to 15%). The authors conclude that while PBT has been widely implemented for pediatric CNS tumors, improved outcome data, particularly with respect to late effects, is still needed to inform the continued evolution of standard indications for this treatment modality.
 
Lassaletta et al conducted a systematic review and meta-analysis comparing neurocognitive outcomes in pediatric brain tumor patients treated with PBT versus photon RT (Lassaletta, 2023). Ten studies were included (N=630 patients), with an average age ranging from 1 to 20 years. Patients who received PBT achieved significantly higher scores than those treated with photon RT on measures of full-scale intelligence quotient (IQ) (Z-score difference, 0.75; 95% CI, 0.52 to 0.99; p<.001), verbal comprehension (Z-score difference, 0.46; 95% CI, 0.20 to 0.73; p=.001), perceptual reasoning (Z-score difference, 0.69; 95% CI, 0.44 to 0.94; p<.001), working memory (Z-score difference, 0.35; 95% CI, 0.07 to 0.63; p=.016), processing speed (Z-score difference, 0.29; 95% CI, 0.01 to 0.56; p=.046), visual motor integration (Z-score difference, 0.52; 95% CI, 0.15 to 0.88; p=.006), verbal memory (Z-score difference, 0.64; 95% CI, 0.31 to 0.96; p<.001), and focused attention (Z-score difference, 0.29; 95% CI, 0.01 to 0.57; p=.044). Sensitivity analyses confirmed significant differences for IQ, verbal comprehension and perceptual reasoning indices, visual motor integration, and verbal memory. No robust differences were found for nonverbal memory (Z-score difference, 0.43; 95% CI, -0.53 to 1.40; p=.377). The authors conclude that pediatric brain tumor patients who receive PBT achieve significantly higher scores on most neurocognitive outcomes compared to those treated with photon RT, but larger studies with long-term follow-up are needed to confirm these results.
 
Bischoff et al published a retrospective analysis of PBT for pediatric craniopharyngioma in 74 patients from the prospective KiProReg registry study. The median follow-up since diagnosis was 4.3 years (range, 0.8 to 14.7) (Bischoff, 2024). The majority of patients (75.7%) received PBT at the time of disease progression or recurrence, while 24.3% received it as part of their primary therapy. The median total dose was 54 gray (Gy). The estimated 3-year OS, progression-free survival, and cystic failure-free survival rates after PBT were 98.2%, 94.7%, and 76.8%, respectively. All local failures (n=3) occurred in patients receiving PBT at progression or recurrence. Early cystic enlargements after PBT were typically asymptomatic and self-limiting. The most common late toxicities were fatigue, headaches, vision disorders, obesity, and endocrinopathies.
 
Lukez et al conducted a retrospective analysis of 772 patients with localized prostate cancer treated with moderate-intensity IMRT (n=287) or PBT (n=485) between 2002 and 2018 at 4 centers in the United States (Lukez, 2023). The median follow-up was 24 months for IMRT patients and 36 months for PBT patients, with overall outcome reporting rates of 62% and 50% at 1 and 3 years follow-up, respectively. Patients received daily fractions of 250 to 300 Gy to a total dose of 6000 to 7250 Gy. At baseline, treatment groups were not balanced. Patients treated with IMRT were more likely to be in an intermediate National Comprehensive Cancer Network (NCCN) risk group (81.2% vs. 68.2%; p<.001), to be diagnosed at an older age (70 vs. 67 years; p<.001), and to have a lower proportion of Gleason score 6 disease (38.8% vs. 32.1%; p<.001) compared to PBT. In both groups, the rate of toxicity was low through 3 years follow-up. Mean International Prostate Symptom Score (IPSS) at baseline was 7.0 for the IMRT cohort and 7.2 for the PBT cohort, with no significant differences between groups at 12, 24, or 36 months (OR, 1.01; 95% CI, 00.81 to 1.26; p<.01) follow-up. The Expanded Prostate Cancer Index Composite (EPIC) urinary pain score (OR, 6.88; 95% CI, 1.12 to 42.2; p=.037) favored the IMRT group at 1 year but did not differ between groups at 2 or 3 years follow-up. No between-group differences were observed in EPIC genitourinary frequency, problematic genitourinary stream, overall gastrointestinal, bowel pain/urgency, or bowel frequency at 1, 2, or 3 years follow-up.
 
Kubes et al conducted a retrospective analysis of 853 patients with low-, favorable intermediate-, and unfavorable intermediate-risk prostate cancer who received ultra-hypofractionated PBT at a single institution between January 2013 and June 2018 (Kubes, 2023). The study population had a mean age of 64.8 years, with 37.3%, 36.8%, and 25.9% of patients classified as low-, favorable intermediate-, and unfavorable intermediate-risk, respectively. The PBT regimen delivered a total dose of 36.25 Gy in 5 fractions.
 
Additional 2024 Update
 
Head and Neck Cancer
 
Although several trials are underway, there are no published randomized studies comparing proton therapy to IMRT in the treatment of head and neck cancers. In 2010, the Agency for Healthcare Research and Quality (AHRQ) conducted a systematic review of radiation modalities used in the treatment of head and neck malignancies including 2D radiation, 3D conformal radiation, IMRT, and PBT. They concluded that there was insufficient evidence comparing PBT to other modalities. This report was updated in 2014 with the same conclusion. A 2016 single institution report retrospectively compared intensity modulated proton therapy (IMPT) to IMRT in the treatment of oropharyngeal cancer. There was no difference in progression-free survival between the modalities. IMRT-treated patients were more likely to have a gastrostomy tube (G-tube) placed than proton[1]treated patients, but this was not statistically significant. Outcomes meeting statistical significance were patient[1]reported xerostomia at three months, weight loss greater than 20%, and G-tube presence one year after treatment. The authors concluded that prospective multicenter randomized trials are needed to validate these findings.
 
This hypothesis-generating report forms the basis for an NCI-sponsored, phase II/III, randomized clinical trial comparing IMRT and PBT in the treatment of oropharynx cancer (NCT01893307). In a recent review, Leeman et al. concluded that “ultimately, such trials will help establish the clinical usefulness of proton beam therapy and will be necessary to provide sufficient evidence regarding toxicity benefits to support wider adoption.” A recent publication describes the final selection of primary and secondary endpoints to be used for NCT01893307 as this study transitions from phase II to phase III. NRG Oncology, a non-profit research organization formed to conduct clinical research in oncology and to broadly disseminate study results to inform clinical decision-making and health policy, was brought in as a partner and expressed concerns about the proposed endpoints of the study. The initial primary endpoint of physician scored, late onset, grade 3 toxicity was scrapped due to a perceived lack of objectivity in physician ratings using the Common Terminology Criteria for Adverse Events (CTCAE) and insufficient sensitivity to account for other forms of toxicity. The study has now been redesigned as a non-inferiority trial using progression-free survival as the primary endpoint and using an expanded group of toxicity measurements as secondary endpoints. A systematic review and meta-analysis of charged particle therapy vs x-ray-based therapy for treatment of paranasal sinus and nasal cancers was published by Patel et al. There were no head-to-head comparison trials, so their analysis consisted of 41 observational studies. Of these, there were 13 reports for charged particle therapy and 30 cohorts treated with photons. In the meta-analysis of these reports, treatment with charged particle therapy was associated with higher survival at five years. Neurologic toxicity was significantly higher in the charged particle group as well. The studies reviewed included a very heterogeneous group. For photon therapy, treatment techniques included 2D, 3D, IMRT, and brachytherapy. The charged particle cohorts included both protons and carbon ions with most patients being treated with passively scattered protons. A similar proportion of patients in both groups had advanced disease but the photon-treated patients were more likely to have a high-risk histology. The heterogeneity of both the patient populations and treatment techniques as well as the inclusion of inadequate treatment techniques such as 2D and 3D conformal radiotherapy in the photon group make it impossible to draw meaningful conclusions for the entire group. Proton beam therapy may be appropriate to treat certain locally advanced sinonasal cancers involving the base of skull when adjacent critical structures are unable to be adequately spared with IMRT. A systematic review of proton therapy for nasopharyngeal cancer was reported by Lee et al. The authors used PRISMA guidelines and identified 9 relevant studies. They found that oncologic outcomes were similar compared to IMRT treated patients. The main differences noted were lower rates of feeding tubes and lower incidence of mucositis compared to photon-treated patients. No significant differences were found in other acute and late radiation effects. A retrospective series of 68 patients treated with PBT for major salivary gland tumors was recently reported. Proton beam treatment showed favorable short-term local control and survival rates. There was no comparison group reported. Proton beam therapy is considered medically necessary to treat locally advanced sinonasal cancers involving the base of skull. Proton beam therapy is not medically necessary for the treatment of other head and neck cancers.

CPT/HCPCS:
77299Unlisted procedure, therapeutic radiology clinical treatment planning
77399Unlisted procedure, medical radiation physics, dosimetry and treatment devices, and special services
77499Unlisted procedure, therapeutic radiology treatment management
77520Proton treatment delivery; simple, without compensation
77522Proton treatment delivery; simple, with compensation
77523Proton treatment delivery; intermediate
77525Proton treatment delivery; complex
G6017Intra fraction localization and tracking of target or patient motion during delivery of radiation therapy (eg,3d positional tracking, gating, 3d surface tracking), each fraction of treatment

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