| Coverage Policy Manual | |
| Policy #: | 2008012 |
| Category: | Radiology |
| Initiated: | September 2008 |
| Last Review: | January 2024 |
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| Radiation Therapy, Proton Beam or Helium Ion Irradiation | |
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| 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:
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.
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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:
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:
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
Repeat Treatment
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
Repeat Treatment
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:
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:
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.
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| Rationale: |
Charged-particle beam radiation therapy has been most extensively studied in uveal melanomas, where the focus has been to provide adequate local control while still preserving vision. Pooling data from 3 centers, Suit and Urie (1992) reported local control in 96% and 5-year survival of 80%, results considered equivalent to enucleation. A recent summary of results from the United Kingdom reports 5-year actuarial rates of 3.5% for local tumor recurrence, 9.4% for enucleation, 61.1% for conservation of vision of 20/200 or better, and 10.0% death from metastasis. (Damato, 2005) The available evidence also suggested that charged-particle beam irradiation is at least as effective as, and may be superior to, alternative therapies including conventional radiation or resection to treat chordomas or chondrosarcoma of the skull base or cervical spine. A Technology Evaluation Center (TEC) Assessment completed in 1996 reached the same conclusions.
There are a number of case series reported that describe initial results using proton beam therapy in hepatocellular cancer, non-small cell lung cancer, metastatic tumors of the choroid, and recurrent uveal melanoma. However, without controlled studies, it is not possible to determine if proton beam therapy offers any advantage over conventional treatments for these conditions.
Recent publications describe initial, preliminary results of using proton beam radiotherapy in malignancies such as breast cancer. In addition, the combination of proton beam radiotherapy with transpupillary thermotherapy in the treatment of ocular melanoma is being studied. (Desjardins, 2006)
Brada et. al. concluded the clinical implementation of high-energy proton therapy is fueled by the combination of apparent advantage of dose distribution, early results, and the availability of equipment supported by commercial interest. The lack of available evidence in favor of protons should be a stimulus for more research, particularly in the form of appropriately designed and powered prospective studies. "However, prospective outcome data from appropriately designed studies in children should be available before protons become an accepted alternative to conventional therapy in pediatric tumors."
Terasawa and colleagues, 2009, published an article based on a technical brief produced by the Tufts Medical Center Evidence-based Practice Center for the Agency for Healthcare Research and Quality. They found that published evidence about safety and efficacy of charged-particle radiation therapy came from mostly small, single-group, retrospective studies. Of the few studies comparing treatments with or without charged particles there was no statistically significant differences in overall or cancer-specific survival. They recommended comparative studies and randomized trials to document the theoretical advantages of charged-particle radiation therapy in specific clinical situations. No information was identified that would support the use of proton beam therapy for additional indications not currently covered in this policy.
2013 Update
Pediatric Central Nervous System Tumors
Radiation therapy is an integral component of the treatment of many pediatric central nervous system (CNS) tumors including high-grade gliomas, primitive neuroectodermal tumors (PNETs), medulloblastomas, ependymomas, germ cell tumors, some craniopharyngiomas and subtotally resected low-grade astrocytomas (Hoffman, 2009). Children who are cured of their tumor experience long-term sequelae of radiation treatment, which may include developmental, neurocognitive, neuroendocrine, and hearing late effects. Radiation to the cochlea may lead to loss of hearing at doses greater than 35-45 Gy in the absence of chemotherapy, and the risk of ototoxicity is increased in children who receive ototoxic platinum-based chemotherapy regimens (Cotter, 2012). Craniospinal irradiation, most commonly used in the treatment of medulloblastoma, has been reported to lead to thyroid dysfunction, and damage to the lungs, heart and intestinal tract (Cotter, 2012). In addition, patients who receive radiation at a young age are at an increased risk of developing radiation-induced second tumors compared to their adult counterparts (Cotter, 2012).
The development of more conformal radiation techniques has decreased inadvertent radiation to normal tissues; however, while intensity-modulated radiation therapy (IMRT) decreases high doses to nearby normal tissues, it delivers a larger volume of low- and intermediate-dose radiation. Proton beam radiotherapy eliminates the exit dose to normal tissues, and may eliminate ~50% of radiation to normal tissue.
A 2012 5-year update of a systematic review (Lodge, 2007) drew similar conclusions to the original review, that except for rare indications such as childhood cancer, the gain from proton RT in clinical practice remains controversial (De Ruysscher, 2012).
A 2012 review of the literature on the use of proton radiotherapy for solid tumors of childhood, the most common of which are CNS tumors, offered the following summaries of studies and conclusions (Cotter, 2012).
Moeller and colleagues reported on 23 children who were enrolled in a prospective observational study and treated with proton beam therapy for medulloblastoma between the years 2006-2009 (Moeller, 2011). As hearing loss is common following chemoradiotherapy for children with medulloblastoma, the authors sought to compare whether proton radiotherapy led to a clinical benefit in audiometric outcomes (since, compared to photons, protons reduce radiation dose to the cochlea for these patients). The children underwent pre- and 1-year post-radiotherapy pure-tone audiometric testing. Ears with moderate-to-severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis. The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (p<0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies; the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was 5%. The authors compared this to a rate of grade 3-4 toxicity following IMRT of 18% in a separate case series. The authors concluded that preservation of hearing in the audible speech range, as observed in their study, may improve both quality of life and cognitive functioning for these patients.
Merchant and colleagues (Merchant, 2008) sought to determine whether proton radiotherapy has clinical advantages over photon radiotherapy in childhood brain tumors. Three-dimensional imaging and treatment-planning data, which included targeted tumor and normal tissues contours, were acquired for 40 patients. Histologic subtypes in the 40 patients were 10 each with optic pathway glioma, craniopharyngioma, infratentorial ependymoma, or medulloblastoma. Dose-volume data were collected for the entire brain, temporal lobes, cochlea, and hypothalamus, and the data were averaged and compared based on treatment modality (protons vs. photons) using dose-cognitive effects models. Clinical outcomes were estimated over 5 years. With protons (compared to photons), relatively small critical normal tissue volumes (e.g. cochlea and hypothalamus) were spared from radiation exposure when not adjacent to the primary tumor volume. Larger normal tissue volumes (e.g. supratentorial brain or temporal lobes) received less of the intermediate and low doses. When these results were applied to longitudinal models of radiation dose-cognitive effects, the differences resulted in clinically significant higher IQ scores for patients with medulloblastoma and craniopharyngioma and academic reading scores in patients with optic pathway glioma. There were extreme differences between proton and photon dose distributions for the patients with ependymoma, which precluded meaningful comparison of the effects of protons versus photons. The authors concluded that the differences in the overall dose distributions, as evidenced by modeling changes in cognitive function, showed that these reductions in the lower-dose volumes or mean dose would result in long-term, improved clinical outcomes for children with medulloblastoma, craniopharyngioma, and glioma of the optic pathway.
Practice Guidelines and Position Statements
Non-Small Cell Lung Cancer: NCCN guidelines for Non-Small Cell Lung Cancer (V3.2012) states that “use of more advanced technologies is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints.” These technologies include proton beam therapy in addition to others. “A non-randomized retrospective comparison study in patients with locally advanced NSCLC showed that PBT reduced esophagitis and pneumonitis despite higher doses compared to 3DCRT or IMRT and a prospective study reported favorable outcomes compared to historical results” (Moeller, 2011).
Bone Cancer: NCCN guidelines for Bone Cancer (V2.2012) states that “proton and/or photon beam RT may be useful for patients with chondrosarcomas of the skull base and axial skeleton with tumors in unfavorable location not amenable to resection” (NCCN, V2.2012).
American Society for Radiation Oncology (ASTRO):
The Emerging Technology Committee of ASTRO published 2012 evidence-based recommendations declaring a lack of evidence for proton beam therapy (PBT) for malignancies outside of large ocular melanomas and chordomas:
“Current data do not provide sufficient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, GI malignancies (with the exception of hepatocellular) and pediatric non-CNS malignancies. In hepatocellular carcinoma and prostate cancer there is evidence for the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies there is a suggestion from the literature that PBT is superior to photon approaches but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patient’s protons appear to offer a dosimetric benefit over photons but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical trials are needed and should be encouraged” (Allen, 2012).
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Uveal Melanomas and Skull-Based Tumors
In 2013, Wang et al published a systematic review on charged-particle (proton, helium or carbon ion) radiation therapy for uveal melanoma (Wang, 2013) The review included 27 controlled and uncontrolled studies that reported health outcomes eg, mortality, local recurrence. Three of the studies were randomized controlled trials (RCTs). One of the RCTs compared helium ion therapy with an alternative treatment (in this case, brachytherapy). The other 2 RCTs compared different proton beam protocols 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-naïve patients (all but one of the identified studies). In a pooled analysis of data from 9 studies, there was not a statistically significant difference in mortality with charged-particle therapy compared with brachytherapy (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.01 to 1.63). However, there was a significantly lower rate of local control with charged-particle therapy compared with brachytherapy in a pooled analysis of 14 studies (OR=0.22; 95% CI, 0.21 to 0.23). There were significantly lower rates of radiation retinopathy and cataract formation in patients treated with charged-particle therapy compared with brachytherapy (pooled rates of 0.28 vs 0.42 and 0.23 vs 0.68, respectively). According to this review, there is low-quality evidence that charged-particle therapy is at least as effective as alternative therapies as primary treatment of uveal melanoma and is better at preserving vision.
Non-Small-Cell Lung Cancer
As of February 2014, no RCTs or non-RCTs reporting health outcomes in patients treated with PBT versus an alternative treatment have been published. In 2013, Bush et al published data on a relatively large series of patients (n=111) treated at 1 U.S. facility over 12 years (Bush, 2013). Patients had NSCLC that was inoperable (or refused surgery) and were treated with high-dose hypofractionated PBT to the primary tumor. Most patients (64%) had stage II disease and the remainder had stage 1 disease. The 4-year actuarial OS rate was 51% and the CSS rate was 74%. The subgroup of patients with peripheral stage I tumors treated with either 60 or 70 Gy had an OS of 60% at 4 years. In terms of adverse events, 4 patients had rib fractures determined to be related to treatment; in all cases, this occurred in patients with tumors adjacent to the chest wall. The authors noted that a 70-Gy regimen is now used to treat stage I patients at their institution. A limitation of the study was a lack of comparison group.
American Society for Radiation Oncology
ASTRO published a position statement in February 2013 which states the following: “At the present time, ASTRO believes the comparative efficacy evidence of proton beam therapy with other prostate cancer treatments is still being developed, and thus the role of proton beam therapy for localized prostate cancer within the current availability of treatment options remains unclear” (ASTRO, 2013)
In September 2013, as part of its national “Choosing Wisely” initiative, ASTRO listed PBT for prostate cancer as one of 5 radiation oncology practices that should not be routinely used because they are not supported by evidence (ASTRO, 2014)
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Craniopharyngiomas are benign lesions, which occur most commonly in children in the late first and second decades of life. MD Anderson Cancer Center and Methodist Hospital in Houston reported on 52 children treated at 2 centers in Texas; 21 received PBT and 31 received IMRT (Bishop, 2014). Patients received a median dose of 50.4 Gy. At 3 years, OS 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. Seventeen patients (33%) were found on imaging to have 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.
Head and Neck Tumors, Other Than Skull-Based
A 2014 systematic review evaluated the literature on charged particle therapy versus photon therapy for the treatment of paranasal sinus and nasal cavity malignant disease (Patel, 2014). The authors identified 41 observational studies that included 13 cohorts treated with charged particle therapy (total N=286 patients) and 30 cohorts treated with photon therapy (total N=1186 patients). There were no head-to-head trials. In a meta-analysis, the pooled event rate of OS was significantly higher with charged particle therapy than photon therapy at the longest duration of follow-up (RR=1.27; 95% CI, 1.01 to 1.59). Findings were similar for the outcome survival at 5 years (RR=1.51; 95% CI, 1.14 to 1.99). Findings were mixed for the outcomes locoregional control and disease-free survival; photon therapy was significantly better for only 1 of the 2 timeframes (longest follow-up or 5-year follow-up). In terms of adverse effects, there were significantly more neurologic toxic effects with charged particle therapy compared with photon therapy (p<0.001) but other toxic adverse event rates eg, eye, nasal and hematologic did not differ significantly between groups. The authors noted that the charged particle studies were heterogeneous, eg, type of charged particles (carbon ion, proton), and delivery techniques. It should also be noted that comparisons were indirect, and none of the studies included in the review actually compared the 2 types of treatment in the same patient sample.
Also in 2014, Zenda and colleagues reported on late toxicity in 90 patients after PBT for nasal cavity, paranasal sinuses, or skull base malignancies (Zenda, 2014). 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 patients (19%) and grade 4 occurred in 6 patients (7%). Five patients developed cataracts, and 5 had optic nerve disorders. Late toxicities (other than cataracts) developed a median of 39.2 months after PBT.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
(NCT01993810) Comparing Photon Therapy To Proton Therapy To Treat Patients With Lung Cancer; planned enrollment 560; completion date December 2020.
In June 2014, ASTRO published a model policy on use of PBT (ASTRO. 2015). The document stated that ASTRO supports PBT for the treatment of the following conditions:
The model policy stated the following regarding PBT for treating prostate cancer:
“…It is essential to collect further data, especially to understand how the effectiveness of proton therapy compares to other radiation therapy modalities such as IMRT and brachytherapy. There is a need for more well-designed registries and studies with sizable comparator cohorts to help accelerate data collection. Proton beam therapy for primary treatment of prostate cancer should only be performed within the context of a prospective clinical trial or registry.”
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:
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:
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
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:
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.
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Youssef I, Yoon J, Mohamed N, et al.(2022) Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Oropharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy. JAMA Netw Open. Nov 01 2022; 5(11): e2241538. PMID 36367724 Zenda S, Kawashima M, Arahira S, et al.(2014) 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. Aug 20 2014. PMID 25135461 |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
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