National Medical Policy

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1 National Medical Policy Subject: Policy Number: Proton Beam Radiotherapy NMP141 Effective Date*: November 2007 Updated: October 2014 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation X Local Coverage Determination (LCD)* Article (Local)* Other None Proton Beam Therapy: Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Proton Beam Radiotherapy Oct 14 1

2 Current Policy Statement Health Net, Inc. considers proton beam radiotherapy* medically necessary for any of the following: 1. Cordoma or chondrosarcoma arising at the base of the skull or along the axial skeleton without distant metastases; or 2. As primary therapy for melanoma of the uveal tract (iris, choroid, or ciliary body), with no evidence of metastasis or extrascleral extension; or 3. Pituitary Neoplasms; or 4. Intracranial arteriovenous malformations (AVMs) not amenable to surgical excision or other conventional forms of treatment; or 5. Central Nervous System tumors that are adjacent to critical structures such as the optic nerve, base of skull, brain stem or spinal cord. (Lesions include, but are not limited to, CNS primary or metastatic malignancies, retinoblastoma) *NOTE- Proton beam radiotherapy may be used either with or without stereotactic guidance. Stereotactic administration of proton beam radiotherapy is considered medically necessary only for lesions that are located intracranially. Proton beam radiotherapy without stereotactic administration would be considered medically necessary for other lesions that require this type of treatment. Not Medically Necessary Health Net, Inc. considers proton beam radiotherapy not medically necessary for all other indications including the following: 1. Age-related macular degeneration; or 2. Non-uveal melanoma; or 3. As a salvage therapy for locally recurrent prostate cancer, either as adjuvant or as salvage therapy post-radical prostatectomy (NCCN 2012); or 4. Routine treatment of localized prostate cancer (i.e., cancer that is confined to the prostate). At this time, clinical trials have not yet yielded data that demonstrates superiority to, or equivalency of proton beam to conventional external beam radiation therapy. (NCCN Guidelines for Prostate Cancer V4.2013) Health Net, Inc. considers proton beam radiotherapy investigational for the following indications: 1. Treatment of hepatocellular carcinoma. 2. Treatment of lung cancer (including small cell lung cancer and non small cell lung cancer [NSCLC]) Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. Proton Beam Radiotherapy Oct 14 2

3 ICD-9 Codes Malignant neoplasm of main bronchus Malignant neoplasm of upper lobe, bronchus or lung Malignant neoplasm of middle lobe, bronchus or lung Malignant neoplasm of lower lobe, bronchus or lung Malignant neoplasm of other parts of bronchus or lung Malignant neoplasm of bronchus and lung, unspecified Malignant neoplasm of skull and face, except mandible Malignant neoplasm of bone and articular cartilage, site unspecified 185 Malignant neoplasm of prostate Malignant neoplasm of eye Malignant neoplasm of brain and other and unspecified parts of the nervous system Malignant neoplasm of pituitary gland and craniopharyngeal duct Secondary malignant neoplasm of lung Secondary malignant neoplasm of brain and spinal cord Hemangioma of intracranial structures Carcinoma in situ of respiratory system, bronchus and lung Neoplasm of uncertain behavior of trachea, bronchus and lung Neoplasm of pituitary gland and craniopharyngeal duct Neoplasm of uncertain behavior of pineal gland Neoplasm of uncertain behavior of brain and spinal cord Neoplasm of uncertain behavior of meninges Arteriovenous malformations Brainstem vascular malformations, intracranial Arteriovenous malformations ICD-10 Codes C34.ØØ Malignant neoplasm of unspecified main bronchus C34.1Ø Malignant neoplasm of upper lobe, unspecified bronchus or lung C34.2 Malignant neoplasm of middle lobe, bronchus or lung C34.3Ø Malignant neoplasm of lower lobe, unspecified bronchus or lung C34.8Ø Malignant neoplasm of overlapping sites of unspecified bronchus and lung C34.9Ø Malignant neoplasm of unspecified part of unspecified bronchus or lung C41.0 Malignant neoplasm of skull and face C41.9 Malignant neoplasm of bone and articular cartilage, unspecified C61 Malignant neoplasm of prostate C Malignant neoplasm of eye and adnexa C69.92 C70.1 Malignant neoplasm of spinal meninges C71.0 Malignant neoplasm of cerebrum, except lobes and ventricles C71.1 Malignant neoplasm of frontal lobe C71.2 Malignant neoplasm of temporal lobe C71.3 Malignant neoplasm of parietal lobe C71.4 Malignant neoplasm of occipital lobe C71.5 Malignant neoplasm of cerebral ventricle C71.6 Malignant neoplasm of cerebellum C71.7 Malignant neoplasm of brain stem C71.8 Malignant neoplasm of overlapping sites of brain C71.9 Malignant neoplasm of brain, unspecified C72.0 Malignant neoplasm of spinal cord C72.1 Malignant neoplasm of cauda equina C79.31 Secondary malignant neoplasm of brain C79.32 Secondary malignant neoplasm of cerebral meninges Proton Beam Radiotherapy Oct 14 3

4 C79.40 Secondary malignant neoplasm of unspecified part of nervous system C79.49 Secondary malignant neoplasm of other parts of nervous system D07.5 Carcinoma in situ of prostate D38.1 Neoplasm of uncertain behavior of trachea, bronchus and lung D42.0 Neoplasm of uncertain behavior of cerebral meninges D42.1 Neoplasm of uncertain behavior of spinal meninges D42.9 Neoplasm of uncertain behavior of meninges, unspecified D43.0 Neoplasm of uncertain behavior of brain, supratentorial D43.1 Neoplasm of uncertain behavior of brain, infratentorial D43.2 Neoplasm of uncertain behavior of brain, unspecified D43.4 Neoplasm of uncertain behavior of spinal cord D44.3 Neoplasm of uncertain behavior of pituitary gland D44.4 Neoplasm of uncertain behavior of craniopharyngeal duct D44.5 Neoplasm of uncertain behavior of pineal gland D49.6 Neoplasm of unspecified behavior of brain Q28.2 Arteriovenous malformation of cerebral vessels Q28.3 Other malformations of cerebral vessels CPT Codes Stereotactic computer-assisted volumetric (particle beam, gamma ray, or linear accelerator); 1 simple cranial lesion Stereotactic computer-assisted volumetric (particle beam, gamma ray, or linear accelerator); each additional cranial lesion, simple Stereotactic computer-assisted volumetric (particle beam, gamma ray, or linear accelerator); one complex cranial lesion Stereotactic computer-assisted volumetric (particle beam, gamma ray, or linear accelerator); each additional cranial lesion, complex Application of stereotactic headframe for stereotactic radiosurgery Stereotactic computer-assisted volumetric (particle beam, gamma ray, or linear accelerator); 1 spinal lesion Stereotactic computer-assisted volumetric (particle beam, gamma ray, or linear accelerator); each additional spinal lesion Radiation treatment delivery, stereotactic radiosurgery(srs), complete course of treatment of cranial lesions(s) consisting of 1 session; multisource Cobalt 60 based Radiation treatment delivery, stereotactic radiosurgery (SRS), complete course of treatment of cerebral lesion(s) consisting of 1 session, linear accelerator based Stereotactic body radiation therapy, treatment delivery, per fraction to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions Stereotactic radiation treatment management of cerebral lesion(s) (complete course of treatment consisting of one session) Stereotactic body radiation therapy, treatment management, per treatment course, to one or more lesions, including image guidance, entire course not to exceed 5 factions Proton beam delivery; simple, without compensation Proton treatment delivery; simple, with compensation Proton treatment delivery; intermediate Proton treatment delivery; complex HCPCS Codes G0173 Linear accelerator based stereotactic radiosurgery, complete course of therapy in one session (code deleted 12/2014) Proton Beam Radiotherapy Oct 14 4

5 G0251 Linear accelerator based stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, maximum five sessions per course of treatment (code deleted 12/2014) Scientific Rationale Update October 2014 Proton beam therapy (PBT) is a technology for delivering conformal external beam radiation with positively charged atomic particles to a well-defined treatment volume. Per NCCN guidelines on Non-small Cell Lung Cancer (NCCN) regarding general principles of radiation therapy (v4.2014): Determination of the appropriateness of radiation therapy (RT) should be made by a board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice RT has a potential role in all stages of NSCLC, as either definitive or palliative therapy. Radiation oncology input as part of a multidisciplinary evaluation or discussion should be provided for all patients with NSCLC. The critical goals of modern RT are to maximize tumor control and to minimize treatment toxicity. A minimum technologic standard is CT-planned 3D-CRT, More advanced technologies are appropriate when needed to deliver curative RT safely. These technologies include (but are not limited to) 4D-CT and/or PET-CT stimulation, IMRT/VMAT*/IGRT, motion management, and proton therapy. Nonrandomized comparisons of using advanced technologies versus older techniques demonstrate reduced toxicity and improved survival. Centers using advanced technologies should implement and document modalityspecific quality assurance measures. The ideal is external credentialing of both treatment planning and delivery such as required for participation in RTOG clinical trials employing advanced technologies. Volumetric modulated arc therapy (VMAT) is a novel radiation technique, which can achieve highly conformal dose distributions with improved target volume coverage and sparing of normal tissues compared with conventional radiotherapy techniques. Volumetric modulated arc therapy (VMAT) is a novel radiation technique, which can achieve highly conformal dose distributions with improved target volume coverage and sparing of normal tissues compared with conventional radiotherapy techniques. McAvoy et al (2014) reported their experience using proton beam therapy and intensity modulated radiation therapy for reirradiation of intrathoracic recurrence of NSCLC after initial treatment, focusing on patterns of failure, criteria for patient selection, and predictors of toxicity. A total of 102 patients underwent reirradiation for intrathoracic recurrent NSCLC at a single institution. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). All patients had received radiation therapy for NSCLC (median initial dose of 70 EQD2 Gy), with median interval to reirradiation of 17 months and median reirradiation dose of EQD2 Gy. Median follow-up time was 6.5 months (range, 0-72 months). Ninety-nine patients (97%) completed reirradiation. Median local failure-free survival, distant metastasis-free survival (DMFS), and overall survival times were months (range, months), months (range, months), and (range, months), respectively. Toxicity was acceptable, with rates of grade 3 esophageal toxicity of 7% and grade 3 pulmonary toxicity of 10%. Of the patients who developed local failure after reirradiation, 88% had failure in either the original or the reirradiation field. Poor local control was associated with T4 disease, squamous histology, and Eastern Cooperative Oncology Group performance status score >1. Concurrent chemotherapy improved DMFS, but T4 disease was associated with poor DMFS. Higher T status, Eastern Cooperative Oncology Group performance status 1, Proton Beam Radiotherapy Oct 14 5

6 squamous histology, and larger reirradiation target volumes led to worse overall survival; receipt of concurrent chemotherapy and higher EQD2 were associated with improved OS. The authors concluded IMRT and PBT are options for treating recurrent NSCLC. However, rates of locoregional recurrence and distant metastasis are high, and patients should be selected carefully to maximize the benefit of additional aggressive local therapy while minimizing the risk of adverse side effects. Oshiro et al (2014) presented the preliminary results of a Phase II study of highdose (74 Gy RBE) PBT with concurrent chemotherapy for unresectable locally advanced NSCLC. Patients were treated with PBT and chemotherapy with monthly cisplatin (on Day 1) and vinorelbine (on Days 1 and 8). The treatment doses were 74 Gy RBE for the primary site and 66 Gy RBE for the lymph nodes without elective lymph nodes. Adapted planning was made during the treatment. A total of 15 patients with Stage III NSCLC (IIIA: 4, IIIB: 11) were evaluated in this study. The median follow-up period was 21.7 months. None of the patients experienced Grade 4 or 5 non-hematologic toxicities. Acute pneumonitis was observed in three patients (Grade 1 in one, and Grade 3 in two), but Grade 3 pneumonitis was considered to be non-proton-related. Grade 3 acute esophagitis and dermatitis were observed in one and two patients, respectively. Severe ( Grade 3) leukocytopenia, neutropenia and thrombocytopenia were observed in 10 patients, seven patients and one patient, respectively. Late radiation Grades 2 and 3 pneumonitis was observed in one patient each. Six patients (40%) experienced local recurrence at the primary site and were treated with 74 Gy RBE. Disease progression was observed in 11 patients. The mean survival time was 26.7 months. The authors concluded that high-dose PBT with concurrent chemotherapy is safe to use in the treatment of unresectable Stage III NSCLC. According to NCCN guidelines on Head and Neck Cancer (V2.2014), IMRT is preferred over 3-D conformal radiation therapy (RT) for maxillary sinus or paranasal/ethmoid sinus tumors to minimize dose to critical structures. The role of proton therapy is being investigated. Zenda et al (2014) conducted a retrospective analysis to clarify the late toxicity profile of PBT in patients with malignancies of the nasal cavity, para-nasal sinuses, or involving the skull base. Entry to this retrospective study was restricted to patients with malignant tumors of the nasal cavity, para-nasal sinuses, or involving the skull base; definitive or postoperative PBT (>50 GyE) from January 1999 through December 2008; and more than 1 year of follow-up. Late toxicities were graded according to the common terminology criteria for adverse events v4.0 (CTCAE v4.0). From January 1999 through December 2008, 90 patients satisfied all criteria. Median observation period was 57.5 months (range, months), median time to onset of grade 2 or greater late toxicity except cataract was 39.2 months (range, months), and 3 patients had toxicities that occurred more than 5 years after PBT. Grade 3 late toxicities occurred in 17 patients (19 %), with 19 events, and grade 4 late toxicities in 6 patients (7%), with 6 events (encephalomyelitis infection 2, optic nerve disorder 4). Investigators concluded the late toxicity profile of PBT in patients with malignancy involving the nasal cavity, para-nasal sinuses, or skull base malignancy was partly clarified. Because late toxicity can still occur at 5 years after treatment, long-term follow-up is necessary. Fuji et al (2014) evaluated the role of high-dose PBT in patients with sinonasal mucosal melanoma (SMM). The cases of 20 patients with SMM localized to the primary site who were treated by PBT between 2006 and 2012 were retrospectively analyzed. The patterns of overall survival and morbidity were assessed. The median follow-up time was 35 months (range, 6-77 months). The 5-year overall and disease-free survival rates were 51% and 38%, respectively. Four patients showed Proton Beam Radiotherapy Oct 14 6

7 local failure, 2 showed regrowth of the primary tumor, and 2 showed new sinonasal tumors beyond the primary site. The 5-year local control rate after PBT was 62%. Nodal and distant failure was seen in 7 patients. Three grade 4 late toxicities were observed in tumor-involved optic nerve. Reviewers concluded the findings suggested that high-dose PBT is an effective local treatment that is less invasive than surgery but with comparable outcomes. NCCN guidelines on Soft tissue Sarcoma (2.2014) state that when EBRT is used, sophisticated treatment planning with IMRT, tomotherapy and/or proton therapy can be used to improve therapeutic effect. RT is not a substitute for definitive surgical resection with negative margins, and re-resection to negative margins is preferable. If the patient has not previously received RT, one could attempt to control microscopic residual disease with postoperative RT, if re-resection is not feasible. The guidelines note further that newer techniques such as IMRT and 3D conformal RT using protons or photons may allow tumor target coverage and acceptable clinical outcomes within normal tissue dose constraints to adjacent organs at risk. However, the safety and efficacy of adjuvant RT techniques is yet to be evaluated in multicenter randomized controlled studies. NCCN guidelines on Hepatobiliary Cancer (2.2014) states that EBRT allows focal administration of high-dose radiation to liver tumors while sparing surrounding liver tissue, thereby limiting the risk of radiation-induced liver damage in patients with unresectable or inoperable HCC. Stereotactic body radiation therapy (SBRT) is an advanced technique of EBRT that deliver large ablative doses of radiation. There is growing evidence (primarily from non-randomized clinical trials) supporting the usefulness of SBRT for patients with unresectable locally advanced or recurrent HCC. All tumors irrespective of the location may be amenable to EBRT, (SBRT or 3-D conformal radiation therapy). The guidelines do not mention proton beam therapy in the guidelines. Hong et al (2014) evaluated the feasibility of a respiratory-gated PBTfor liver tumors. Fifteen patients were enrolled in a prospective institutional review board-approved protocol. Eligibility criteria included Childs-Pugh A/B cirrhosis, unresectable biopsyproven hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), or metastatic disease (solid tumors only), 1-3 lesions, and tumor size of 6 cm. Patients received 15 fractions to a total dose of GyE [gray equivalent] using respiratory-gated proton beam therapy. Gating was performed with an external respiratory position monitoring based system. Of the 15 patients enrolled in this clinical trial, 11 had HCC, 3 had ICC, and 1 had metastasis from another primary. Ten patients had a single lesion, 3 patients had 2 lesions, and 2 patients had 3 lesions. Toxicities were grade 3 bilirubinemia-2, grade 3 gastrointestinal bleed-1, and grade 5 stomach perforation-1. One patient had a marginal recurrence, 3 had hepatic recurrences elsewhere in the liver, and 2 had extrahepatic recurrence. With a median follow-up for survivors of 69 months, 1-, 2-, and 3-year overall survivals are 53%, 40%, and 33%, respectively. Progression-free survivals are 40%, 33%, and 27% at 1, 2, and 3 years, respectively. Investigators concluded respiratory-gated PBT for liver tumors is feasible. Phase 2 studies for primary liver tumors and metastatic tumors are underway. Lee et al (2014) evaluated the clinical effectiveness and safety of PBT in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Twenty-seven HCC patients with PVTT underwent PBT, including 22 patients with modified International Union Against Cancer (muicc) stage IVA,five patients with stage IVB primary tumors, and 16 with main PVTT. A median dose of 55 GyE (range, GyE) in fractions was delivered to a target volume encompassing both the PVTT and primary tumor. Overall, treatment was well tolerated, with no toxicity Proton Beam Radiotherapy Oct 14 7

8 of grade 3. Median overall survival (OS) times in all patients and in stage IVA patients were 13.2 months and 16 months, respectively. Assessments of PVTT response showed complete response in 0 of 27 (0%) patients, partial response in 15 (55.6%), stable disease in 10 (37%), and progressive disease in 2 (7.4%) patients, with an objective response rate of 55.6%. PVTT responders showed significantly higher actuarial 1-year local progression-free survival (LPFS; 85.6% vs. 51.3%), relapse-free survival (RFS; 20% vs. 0%) and OS (80% vs. 25%) rates than nonresponders (p<0.05 each). Multivariate analysis showed that PVTT response and muicc stage were independent prognostic factors for OS. The authors concluded the data suggest that PBT could improve LPFS, RFS, and OS in advanced HCC patients with PVTT and it is feasible and safe for these patients. Dionisi et al (2014) reviewed the literature concerning the use of PBT systematically in the treatment of HCC, focusing on clinical results and technical issues. The literature search was conducted according to a specific protocol in the Medline and Scopus databases by two independent researchers covering the period of Both clinical and technical studies referring to a population of patients actually treated with protons were included. The PRISMA guidelines for reporting systematic reviews were followed. A final set of 16 studies from seven proton therapy institutions worldwide were selected from an initial dataset of 324 reports. Seven clinical studies, five reports on technical issues, three studies on treatment related toxicity and one paper reporting both clinical results and toxicity analysis were retrieved. Four studies were not published as full papers. Passive scattering was the most adopted delivery technique. More than 900 patients with heterogeneous stages of disease were treated with various fractionation schedules. Only one prospective full paper was found. Local control was approximately 80% at 3-5years, average overall survival at 5years was 32%, with data comparable to surgery in the most favorable groups. Toxicity was low (mainly gastrointestinal). Normal liver V0Gy<30%volume and V30Gy<18-25%volume were suggested as cut-off values for hepatic toxicity. The good clinical results of the selected papers are counterbalanced by a low level of evidence. However, the rationale to enroll patients in prospective studies appears to be strong. NCCN guidelines on Prostate Cancer (2.2014) state that proton beams can be used and an alternative radiation source. They note, Two comparisons between men with proton beam therapy (PBT) and EBRT show similar toxicity rates. A single center report of prospectively collected quality of life data 3 months, 12 months, and >2 years after treatment revealed significant problems with incontinence, bowel dysfunction, and impotence. Perhaps more concerning is that only 29% of men with normal erectile function maintained normal erectile function after therapy NCCN echoed the following 2012 ASTRO statement in its review of PBT: Prostate cancer has the most patients treated with conformal proton therapy of any other disease site. The outcome is similar to IMRT therapy, however, with no clear advantage from clinical data for either technique in disease control or prevention of late toxicity. This is a site where further head-to-head clinical trials are needed to determine the role of proton beam therapy. In addition, careful attention must be paid to the role of dosimetric issues including corection for organ motion in this disease. Based on the current data, proton therapy is an option for prostate cancer, but no clear benefit over the existing therapy of IMRT photons has been demonstrated. The American Urologic Association (AUA) guidelines on the management of clinically localized prostate cancer (last updated 2011) briefly mention proton therapy in the guidleines, however, they do not make a recommendation for or against it. Per the guidelines, The results of RCTs have guided the use of dose escalation and Proton Beam Radiotherapy Oct 14 8

9 neoadjuvant or adjuvant hormonal therapy. As a result, hormonal therapy often is prescribed for men with Gleason score 7 cancer or higher or a PSA level in excess of 10 ng/ml in conjunction with standard-dose external beam radiotherapy (~70 Gy). Alternatively, dose escalation can be performed safely to 78 to 79 Gy using a 3- dimensional conformal radiation technique and at least four fields with a margin of no more than 10 mm at the prostatic rectal interface. Such techniques include a CT scan for treatment planning and either a multileaf collimator, IMRT, or proton radiotherapy using a high-energy (6 mv or higher) photon beam. For low-risk patients, the RCTs suggest a benefit of dose escalation. For patients in the intermediate-risk category, RCTs have shown either short-course hormonal therapy (~ 6 months) and standard-dose external beam radiotherapy or dose escalation (78 to 79 Gy) should be considered standard. In May 2014, the American Society for Radiation Oncology (ASTRO) approved a new Model Policy for proton beam therapy (PBT) that details which cancer diagnoses meet ASTRO s evidence-based standards. The Model Policy recommends two coverage groups for PBT: Patients with specific diagnoses for which PBT has been proven to be effective; and patients with cancer diagnoses where evidence of effectiveness of PBT is still emerging, and therefore coverage with evidence development is recommended for patients if they are enrolled in clinical trials or a multi-institutional registry to collect data and inform consensus on the role of proton therapy. ASTRO also encourages coverage of PBT for cancer patients with difficult-totreat, rare or highly complex cases for which the characteristics of PBT offers advantages over other forms of treatment. Per the ASTRO document: Disease sites that frequently support the use of PBT include the following: 1. Ocular tumors,including intraocular melanomas, 2. Tumors that approach or are located at the base of the skull (e.g. chordoma, chondrosarcomas), 3. Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where spinal cord has previously been irradiated, 4. Hepatocellular carcinoma treated in a hypofractionated regimens, 5. Primary or benign tumors in children treated with curative intent and occasional palliative treatment of tumors when at least one of the four criteria is met: The target volume is in close proximity to one or more critical structures and a steep dose gradient outside the target must be achieved to avoid exceeding the tolerance dose to the critical structure(s) A decrease in the amount of dose inhomogeneity in a large treatment volume is required to avoid an excessive dose hotspot within the treated volume to lessen the risk of excessive early or late normal tissue toxicity. A photon-base technique would increase the probability of clinically meaningful normal tissue toxicity by exceeding an integral dose-based metric associated with toxicity The same or an immediately adjacent areas has been previously irradiated, and the dose distribution within the patient must be sculpted to avoid exceeding the cumulative tolerance dose of nearby normal tissue, 6. Patients with genetic syndromes making total volume of radiation minimization crucial such as, but not limited to NF-1 patients and retinoblastoma patients. ASTRO noted there is a need for continued clinical evidence development and comparative effectiveness analyses for the appropriate use of PBT for various disease sites. The noted that all other sites not noted above (1-6) would be appropriate in the context of a either an IRB-approved clinical trial or in multi-institutional registries Proton Beam Radiotherapy Oct 14 9

10 adhering to Medicare requirements for CED. This would include various systems, such as, but not limited to the following: 1. Head and neck malignancies 2. Thoracic malignancies 3. Abdominal malignancies 4. Pelvic malignancies, including genitourinary, gynecologic and gastrointestinal carcinomas ASTRO notes further, In the treatment of prostate cancer, the use of PBT is evolving as the comparative efficacy evidence is still being developed. In order for an informed consensus on the role of PBT for prostate cancer to be reached, 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. PBT for primary treatment of prostate cancer should only be performed within the context of a prospective clinical trial or registry. Mouw et al (2014) investigated long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with PBT in a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PBT between 1986 and The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-pbt enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). Post-PBT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-prt event requiring intervention, with cataracts the most common (4 eyes). No patients developed an in-field second malignancy. The reviewers concluded long-term followup of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed. Sethi et al (2014) reported that the leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT. A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P =.015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P =.120). Investigators concluded retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on Proton Beam Radiotherapy Oct 14 10

11 studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy. Bishop et al (2014) compared PBT with IMRT for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity. The authors reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity. At 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742; nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and.04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and.024, respectively) dysfunction. The authors concluded survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function. Greenberger et al (2014) reported their experience with 32 pediatric patients with primary low-grade gliomas are treated with PBT. Thirty-two pediatric patients with low-grade gliomas of the brain or spinal cord were treated with PBT from 1995 to Sixteen patients received at least 1 regimen of chemotherapy before definitive RT. The median radiation dose was 52.2 GyRBE ( GyRBE). The median age at treatment was 11.0 years (range, years), with a median follow-up time of 7.6 years (range, years). The 6-year and 8-year rates of progression-free survival were 89.7% and 82.8%, respectively, with an 8-year overall survival of 100%. For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (P=.80), with a median neurocognitive testing interval of 4.5 years (range, years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (<7 years) and those with significant dose to the left temporal lobe/hippocampus. The incidence of endocrinopathy correlated with a mean dose of 40 GyRBE to the hypothalamus, pituitary, or optic chiasm. Stabilization or improvement of visual acuity was achieved in 83.3% of patients at risk for radiation-induced injury to the optic pathways. The authors concluded the report of late effects in children with low-grade gliomas after PBT is encouraging. PBT appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis. Zhang et al (2014) compared the risks of radiogenic second cancers and cardiac mortality in 17 pediatric medulloblastoma patients treated with passively scattered proton or field-in-field photon craniospinal irradiation (CSI). Standard of care photon or proton CSI treatment plans were created for all 17 patients in a commercial treatment planning system (TPS) (Eclipse version 8.9; Varian Medical Systems, Palo Proton Beam Radiotherapy Oct 14 11

12 Alto, CA) and prescription dose was 23.4 or 23.4Gy (RBE) to the age specific target volume at 1.8Gy/fraction. The therapeutic doses from proton and photon CSI plans were estimated from TPS. Stray radiation doses were determined from Monte Carlo simulations for proton CSI and from measurements and TPS for photon CSI. The Biological Effects of Ionization Radiation VII report and a linear model based on childhood cancer survivor data were used for risk predictions of second cancer and cardiac mortality, respectively. The ratios of lifetime attributable risk (RLARs) (proton/photon) ranged from 0.10 to 0.22 for second cancer incidence and ranged from 0.20 to 0.53 for second cancer mortality, respectively. The ratio of relative risk (RRR) (proton/photon) of cardiac mortality ranged from 0.12 to The RLARs of both cancer incidence and mortality decreased with patient's age at exposure (e), while the RRRs of cardiac mortality increased with e. Girls had a significantly higher RLAR of cancer mortality than boys. The authors concluded passively scattered proton CSI provides superior predicted outcomes by conferring lower predicted risks of second cancer and cardiac mortality than field-in-field photon CSI for all medulloblastoma patients in a large clinically representative sample in the United States, but the magnitude of superiority depends strongly on the patients' anatomical development status. Watson et al (2014) evaluated the efficacy and toxicity of proton therapy for functional pituitary adenomas (FPAs). The authors analyzed 165 patients with FPAs who were treated at a single institution with proton therapy between 1992 and 2012 and had at least 6 months of follow-up. All but 3 patients underwent prior resection, and 14 received prior photon irradiation. Proton stereotactic radiosurgery was used for 92% of patients, with a median dose of 20 Gy (RBE). The remainder received fractionated stereotactic proton therapy. Time to biochemical complete response (CR, defined as 3 months of normal laboratory values with no medical treatment), local control, and adverse effects are reported. With a median follow-up time of 4.3 years (range, years) for 144 evaluable patients, the actuarial 3-year CR rate and the median time to CR were 54% and 32 months among 74 patients with Cushing disease (CD), 63% and 27 months among 8 patients with Nelson syndrome (NS), 26% and 62 months among 50 patients with acromegaly, and 22% and 60 months among 9 patients with prolactinomas, respectively. One of 3 patients with thyroid stimulating hormone-secreting tumors achieved CR. Actuarial time to CR was significantly shorter for corticotroph FPAs (CD/NS) compared with other subtypes (P=.001). At a median imaging follow-up time of 43 months, tumor control was 98% among 140 patients. The actuarial 3-year and 5-year rates of development of new hypopituitarism were 45% and 62%, and the median time to deficiency was 40 months. Larger radiosurgery target volume as a continuous variable was a significant predictor of hypopituitarism (adjusted hazard ratio 1.3, P=.004). Four patients had new-onset postradiosurgery seizures suspected to be related to generously defined target volumes. There were no radiation-induced tumors. The authors concluded proton irradiation is an effective treatment for FPAs, and hypopituitarism remains the primary adverse effect. At this time, numerous clinical trials investigating proton beam therapy was identified at clinical trials.gov. PBT is being investigated for numerous cancers including but not limited to prostate, head and neck, esophageal, soft tissue sarcoma, NSCLC, rectal, pancreas, CNS tumors, retinoblastoma, HCC, pediatric, breast, chordomas and chondrosarcomas. Scientific Rationale Update October 2013 The NCCN 2013 Guidelines on Prostate Cancer also notes that per a study by Cohen et al. (2012), a single center report of prospectively collected quality of life data. QOL questionnaires were sent at specified intervals to 95 men who received proton Proton Beam Radiotherapy Oct 14 12

13 beam radiation for localized prostate cancer. Of these, 87 men reported 3 and/or 12 month outcomes, whereas 73 also reported long-term outcomes (minimum 2 years). The long-term results revealed significant problems with incontinence, bowel dysfunction and impotence. Only 28% of men with normal erectile function maintained erectile function after this therapy. As noted in the Scientific Rationale Update for February 2013, NCCN states that proton therapy is not recommended for routine use at this time, since clinical trials have not yet yielded data that demonstrates superiority to, or equivalence of, proton beam and conventional external beam for treatment of prostate cancer. Proton beam radiotherapy (PBRT) is an emerging treatment for prostate cancer despite limited knowledge of clinical benefit or potential harms compared with other types of radiotherapy. The authors therefore compared patterns of PBRT use, cost, and early toxicity among Medicare beneficiaries with prostate cancer with those of intensity-modulated radiotherapy (IMRT). Yu et al. (2013) completed a retrospective study of all Medicare beneficiaries aged greater than or equal to 66 years who received PBRT or IMRT for prostate cancer during 2008 and/or We used multivariable logistic regression to identify factors associated with receipt of PRT. To assess toxicity, each PRT patient was matched with two IMRT patients with similar clinical and socio-demographic characteristics. The main outcome measures were receipt of BPRT or IMRT, Medicare reimbursement for each treatment, and early genitourinary, gastrointestinal, and other toxicity. All statistical tests were two-sided. 27,647 men were identified; 553 (2%) received PBRT and 27,094 (98%) received IMRT. Patients receiving PBRT were younger, healthier, and from more affluent areas than patients receiving IMRT. Median Medicare reimbursement was $32,428 for PBRT and $18,575 for IMRT. Although PRT was associated with a statistically significant reduction in genitourinary toxicity at 6 months compared with IMRT (5.9% vs 9.5%; odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38 to 0.96, P =.03), at 12 months post-treatment there was no difference in genitourinary toxicity (18.8% vs 17.5%; OR = 1.08, 95% CI = 0.76 to 1.54, P =.66). There was no statistically significant difference in gastrointestinal or other toxicity at 6 months or 12 months post-treatment. Although PBRT is substantially more costly than IMRT, there was no difference in toxicity in a comprehensive cohort of Medicare beneficiaries with prostate cancer at 12 months post-treatment. The NCCN 2013 Guidelines on Prostate Cancer also notes that there is evidence post prostatectomy that supports offering adjuvant/salvage radiation therapy (RT) in all men with adverse pathologic features or detectable PSA and no evidence of disseminated disease. There is specific criteria noted within the NCCN guidelines for salvage radiation therapy but there is no mention of using proton beam radiation therapy in this situation. Gray et al. (2012, ASTRO) Quality of Life (QOL) data for 153 patients treated with IMRT monotherapy and collected by the PROST-QA consortium using the Expanded Prostate Cancer Index Composite (EPIC) were compared to data for 94 patients treated at the Massachusetts General Hospital with proton beam therapy (PBT) monotherapy and 123 patients treated at Harvard-affiliated hospitals with 3DCRT monotherapy and followed using the Prostate Cancer Symptoms Index (PCSI) instrument. PCSI scores were inverted for comparison to EPIC. Mean scores at baseline, at first follow-up (2-3 months) and at 24 months were compared using a paired t test. To maintain the overall type 1 error at 0.05 after multiple comparisons, a p value of.006 was considered significant. Clinically meaningful differences in QOL scores were defined as those exceeding half the baseline standard deviation. Distribution of Gleason score, T-stage and baseline PSA were similar in the PBT and IMRT cohorts but the 3DCRT cohort had higher baseline PSA and more patients with T3 disease. Median patient age was 69 for IMRT, 70 for 3DCRT and 64 for PBT (p < Proton Beam Radiotherapy Oct 14 13

14 0.0001). Treatment dose range was Gy for IMRT, Gy RBE for PBT and Gy for 3DCRT. At the first survey post-treatment 3DCRT and IMRT but not PBT were associated with significant and clinically meaningful lower mean bowel QOL scores; all groups had significant decreases in bowel QOL scores at 24 months. Significantly lower scores in the urinary irritation domain were also seen at first follow-up for all 3 groups but this was clinically meaningful only in patients receiving IMRT. Sexual function domain scores were all lower but not clinically meaningful at 24 months. In this nonrandomized comparison using 2 validated QOL instruments, PBT appears to be associated with better early gastrointestinal QOL compared to 3DCRT and IMRT with similar mild effects at later time points. While subject to selection bias, these preliminary data suggest transient differences in PRO between IMRT and PBT underscoring the rationale for a randomized controlled trial. Ohri et al. (2012) completed a meta-analysis of published series that report late gastrointestinal (GI) and genitourinary (GU) toxicity rates following definitive radiation therapy (RT) for prostate cancer using the RTOG Late Radiation Morbidity Scoring Schema. Univariate analyses were performed to test RT technique, RT dose, pelvic irradiation, and androgen deprivation therapy (ADT) as predictors of moderate (grade >= 2) and severe (grade >= 3) GI and GU toxicity. To isolate the effect of radiotherapy dose on late toxicity, we also performed a meta-analysis restricted to randomized trials that tested RT dose escalation. Statistical analyses were repeated using the subset of studies that utilized escalated RT doses. Twenty published reports detailing the treatment techniques and toxicity outcomes of 35 patient series including a total of 11,835 patients were included in this analysis. Median rates of moderate late toxicity were 15% (GI) and 17% (GU). For severe effects, these values were 2% (GI) and 3% (GU). Meta-analysis of five randomized trials revealed that an 8-10 Gy increase in RT dose increases the rate of both moderate (OR = 1.63, 95% CI: [1.44 to 1.82], p < 0.001) and severe (OR = 2.03, 95% CI: [1.64 to 2.42], p < 0.001) late GI toxicity. Among 17 series where doses of at least 74 Gy were utilized, use of intensity-modulated radiotherapy (IMRT) or proton beam radiotherapy (PBRT) was associated with a significant decrease in the reported rate of severe GI toxicity compared to 3-D RT. Meta-analysis of randomized dose escalation trials demonstrates that late toxicity rates increase with RT dose. Series where dose escalated RT is delivered using IMRT or PBRT have relatively short follow up but report lower late GI toxicity rates than those employing 3-D RT. There continues to be no mention of proton beam radiotherapy in the NCCN Guidelines on Melanoma (Version ), the NCCN Guidelines on Small Cell Lung Cancer (Version ), or in the NCCN Guidelines on Hepatobilary Cancer, which includes hepatocellular cancer (Version ). The 2013 NCCN Guidelines on Non-Small Cell Lung Cancer notes that advanced technologies such as 4D-conformal RT simulation, IMRT/volumetric modulated arc therapy (VMAT) image guided RT, motion management strategies and proton therapy have been shown to reduce toxicity and increase survival in nonrandomized trials. However, this is the only mention of PBT in guidelines. There is no mention of proton beam therapy for age related macular degeneration in the 2013 UpToDate article on Age-related macular degeneration: Treatment and prevention. Scientific Rationale Update February 2013 Proton-beam RT uses charged particles, or protons, to deliver high doses of RT to the target volume while limiting the scatter dose received by surrounding tissues. Although proton beam therapy is being more widely used in men with localized prostate cancer as new treatment facilities become available, studies have not Proton Beam Radiotherapy Oct 14 14

15 established whether proton beam therapy (either alone or in combination with photon therapy) is either more effective or less toxic than photon therapy alone, especially IMRT, or brachytherapy. The 2013 NCCN Guidelines on Prostate Cancer note the following: Proton beams can be used as an alternative radiation source. Theoretically, protons may reach deeply-located tumors with less damage to surrounding tissues. However, proton therapy is not recommended for routine use at this time, since clinical trials have not yet yielded data that demonstrates superiority to, or equivalence of, proton beam and conventional external beam for treatment of prostate cancer. The California Technology Assessment Forum (CTAF, October 17, 2012), has guidelines on Proton Therapy for Prostate Cancer. The goal of this assessment is to evaluate the evidence for the use of proton beam therapy in the treatment of localized prostate cancer. CTAF summarized proton beam therapy for the treatment of prostate cancer as follows: In summary, proton beam therapy has been widely used for the treatment of localized prostate cancer. In nonrandomized studies, rates of disease free progression appear to be favorable and although side effects are common, rates of significant toxicity are relatively low. However, there is limited evidence of comparative efficacy with other prostate cancer treatments. The main recent RCT evaluating proton beam therapy actually compared low dose with high dose proton beam therapy and did not include a group that did not receive proton beam therapy. The comparisons with other treatments (brachytherapy, IMRT) have been limited by being retrospective case matched analyses and have included patients treated during different time periods. Thus the role of proton beam therapy for localized prostate cancer within the current list of treatment options remains unclear. It is recommended that proton beam therapy for localized prostate cancer does not meet CTAF criteria 4 or 5 for safety, efficacy and improvement in health outcomes. Per Blue Cross Blue Shield Association Technology Evaluation Center (TEC) completed a study on Proton Beam Therapy for Prostate Cancer, in June Based on their findings, the following recommendations were made: Whether proton beam therapy improves outcomes in any setting in prostate cancer has not yet been established. Based on the above, proton beam therapy as a boost to x-ray external-beam radiotherapy and proton beam therapy without x-ray external-beam radiotherapy in the treatment of prostate cancer does not meet the TEC criteria. The Agency for Healthcare Research and Quality (AHRQ) Technology Assessment Program published the technology assessment in August 2010: Comparative evaluation of radiation treatments for clinically localized prostate cancer: an update. The technology assessment noted that current review did not identify any comparative studies evaluating the role of particle radiation therapy (e.g.,proton beam) in the treatment of prostate cancer. Proton Beam Radiotherapy Oct 14 15

16 The American Cancer Society (ACS) website shows the following information about proton beam therapy: Proton beam therapy is related to 3D-CRT and uses a similar approach. But instead of using x-rays, this technique focuses proton beams on the cancer. Protons are positive parts of atoms. Unlike x-rays, which release energy both before and after they hit their target, protons cause little damage to tissues they pass through and then release their energy after traveling a certain distance. This means that proton beam radiation may be able to deliver more radiation to the prostate and do less damage to nearby normal tissues. Although early results are promising, studies are needed to determine if proton beam therapy is better in the long-term than other types of external beam radiation. There is an interventional randomized phase III Clinical Trial currently recruiting participants on Hypo-fractionated Proton Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Prostate Cancer. The ClinicalTrials.gov Identifier number is NCT This was last verified on November The purpose of this study is to compare the effects, good and/or bad of two treatment methods on subjects and their cancer. Proton beam radiation therapy is one of the treatments for men with prostate cancer who have localized disease. The benefit of the combination with androgen suppression is not completely understood. This study will compare the use of hypofraction proton therapy (28 treatments) alone to proton therapy with androgen suppression therapy. The estimated primary completion date is December Per Meyer et al. (2012) In men with prostate cancer, modeling studies have shown that three-dimensional conformal therapy using protons spares normal tissues better than IMRT in the low-to-mid dose range, although IMRT may offer a slight benefit in the high-dose range. To date, clinical studies have shown only limited improvement, if any, in toxicity profiles, although comparisons between nonrandomized series are inherently difficult. No randomized trials are currently underway. Intensity modulated proton therapy (IMPT) using scanned proton beams will have dose conformality similar to IMRT with substantially lower integral radiation dose to the pelvis, but IMPT is not currently employed at most proton centers and will require very careful control of the proton range with techniques such as a rectal dosimeter. Protons may have benefits in treating prostate cancer for the two following reasons. First, there is the expected reduction in normal tissue integral dose, which may be important in preventing radiation-induced second malignancies, particularly in younger men. Secondly, escalation of dose to focal lesions within the prostate may be more feasible with protons compared with x-ray therapy. The role of particle therapy in treating other sites, such as prostate cancer, remains more controversial, and has been the subject of intense scrutiny in the oncology community. Townsend et al. (2012) Patients with localized prostate cancer may select radiation therapy, such as external beam therapy (XRT) or permanent or temporary brachytherapy. Other forms of treatment that can be considered for local treatment of prostate cancer include cryotherapy and proton beam therapy, although long-term results for these modalities are still being reported. Nihei et al. (2011) Proton beam therapy (PBT) is theoretically an excellent modality for external beam radiotherapy, providing an ideal dose distribution. However, it is not clear whether PBT for prostate cancer can clinically control toxicities. The purpose of the present study was to estimate prospectively the incidence of late rectal toxicities after PBT for organ-confined prostate cancer. The major eligibility criteria included clinical Stage T1-T2N0M0; initial prostate-specific antigen level of Proton Beam Radiotherapy Oct 14 16

17 â 20 ng/ml and Gleason score â 7; no hormonal therapy or hormonal therapy within 12 months before registration; and written informed consent. The primary endpoint was the incidence of late Grade 2 or greater rectal toxicity at 2 years. Three institutions in Japan participated in the present study after institutional review board approval from each. PBT was delivered to a total dose of 74 GyE in 37 fractions. The patients were prospectively followed up to collect the data on toxicities using the National Cancer Institute-Common Toxicity Criteria, version 2.0. Between 2004 and 2007, 151 patients were enrolled in the present study. Of the 151 patients, 75, 49, 9, 17, and 1 had Stage T1c, T2a, T2b, T2c, and T3a, respectively. The Gleason score was 4, 5, 6, and 7 in 5, 15, 80 and 51 patients, respectively. The initial prostatespecific antigen level was <10 or ng/ml in 102 and 49 patients, respectively, and 42 patients had received hormonal therapy and 109 had not. The median followup period was 43.4 months. Acute Grade 2 rectal and bladder toxicity temporarily developed in 0.7% and 12%, respectively. Of the 147 patients who had been followed up for >2 years, the incidence of late Grade 2 or greater rectal and bladder toxicity was 2.0% (95% confidence interval, 0-4.3%) and 4.1% (95% confidence interval, %) at 2 years, respectively. The results of the present prospective study have revealed a valuable piece of evidence that PBT for localized prostate cancer can achieve a low incidence of late Grade 2 or greater rectal toxicities. Wein et al. (2011) External beam radiotherapy involves the use of beams of gamma radiation, usually photons, directed at the prostate and surrounding tissues through multiple fields. To minimize radiation injury to the bladder and rectum, threedimensional conformal radiotherapy (3D-CRT), in which a computer alters the radiation beams to focus the radiation dose to the region of the prostate gland, was developed. The most sophisticated form of 3D-CRT, called intensity-modulated radiation therapy (IMRT), can provide localization of the radiation dose to geometrically complex fields. Heavy-particle therapy that uses beams of high-energy protons or neutrons has also been used to treat patients with prostate cancer. Heavy-particle therapy is another form of 3D-CRT in which the radiation beam can be virtually stopped within the tissue, allowing high doses of radiation to be delivered to a localized region. However, proton beam therapy is extremely expensive, and limited long-term results have been reported. High-dose proton or neutron beam therapy has been advocated as a more effective method of conformal radiotherapy, but there is no convincing evidence that treatment results are superior to those achieved with photons. Scientific Rationale Update November 2012 Approximately 40% of men with newly diagnosed prostate cancer undergo radical prostatectomy (RP) as their primary treatment. Following RP, men who experience a biochemical recurrence or biochemical failure, fall into two groups: 1. Those whose prostate specific antigen (PSA) fails to fall to undetectable levels after surgery, or 2. Those who achieve an undetectable PSA after surgery with a subsequent detectable PSA level that increases on two or more laboratory determinations (NCCN, 2012). Salvage therapy is treatment that is usually given after cancer has not responded to other treatments. Salvage therapy is started for recurrent prostate cancer, when first line therapy fails to eliminate the cancer. Most prostate cancer treatments can be used for both salvage therapy and first line therapy. Chemotherapy, on the other hand, is usually used only as a salvage treatment for prostate cancer. When prostatectomy is used as a first line treatment, the patient is no longer eligible for cryotherapy or brachytherapy due to insufficient tissue. Cryotherapy is becoming Proton Beam Radiotherapy Oct 14 17

18 more commonly used after radiation therapy fails because cryotherapy uses freezing temperatures rather than more radiation and is also minimally invasive. NCCN Clinical Practice Guidelines in Oncology on Prostate Cancer (2012), note the following: Proton beams can be used as an alternative radiation source. Protons may reach deeply-located tumors with less damage to surrounding tissues. However, proton therapy is not recommended for routine use at this time since clinical trials have not yet yielded data that demonstrates superiority to, or equivalence of, proton beam and conventional external beam for treatment of prostate cancer. (This is the only reference to proton beam therapy for prostate cancer on the NCCN site) Evidence from randomized trials supports offering adjuvant / salvage external beam RT, usually within 6 months after radical prostatectomy in all men with detectable PSA, adverse laboratory or pathologic features including positive margin, seminal vesicle invasion, and / or extracapsular extension, and NO evidence of disseminated disease. Positive surgical margins are especially unfavorable if diffuse (>10mm margin involvement or > 3 sites of positivity, or associated with persistent serum levels of PSA. If adjuvant RT is considered, it should be given before the PSA exceeds 1.5ng/mL. Optimal treatment of prostate cancer requires assessment of risk: How likely is a given cancer to be confined to the prostate or to spread to the regional lymph nodes? How likely is the cancer to progress or metastasize after treatment? How likely is salvage by adjuvant radiation after an unsuccessful radical prostatectomy? Prostate cancers are best characterized by clinical (TNM) stage determined by digital rectal examination (DRE), Gleason score in the biopsy specimen, and serum PSA level. Imaging studies (ultrasound, MRI) have been investigated intensively but have yet to be accepted as essential adjuncts to staging. Nomograms can be used to inform treatment decision-making for men contemplating active surveillance, radical prostatectomy, neurovascular bundle preservation, or omission of pelvic lymph node dissection during radical prostatectomy, brachytherapy or external beam radiation therapy (EBRT). Potential success of adjuvant or salvage radiation therapy after unsuccessful radical prostatectomy can be assessed using a nomogram. Most patients who have had a radical prostatectomy are cured of prostate cancer. However, some suffer pathologic or biochemical failure. Per UpToDate (2012) "For men with a recurrence following radical prostatectomy, salvage external beam RT can provide long-term disease control if the recurrence is encompassed within the treatment field and a sufficient radiation dose can be delivered to eradicate the residual/recurrent cancer. The success of salvage RT depends upon dose and treatment volume (ie, prostate bed with or without pelvis), in addition to the localization of all clonogenic cells to the treatment field". Per ASTRO (2009) In hepatocellular carcinoma and prostate cancer, there is evidence of the efficacy of proton beam therapy (PBT) but no suggestion that it is superior to photon based approaches. Further clinical research is needed and should be encouraged. There is no mention of salvage treatment for prostate cancer using proton beam therapy on this site. Proton Beam Radiotherapy Oct 14 18

19 Stephenson et al. (2007) completed a study and developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence. The authors constructed a model to predict the probability of disease progression after salvage radiation therapy (SRT) in a multi-institutional cohort of 1,540 patients. The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/ml or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P <.001), prostatectomy Gleason grade (P <.001), PSA doubling time (P <.001), surgical margins (P <.001), androgen-deprivation therapy before or during SRT (P <.001), and lymph node metastasis (P =.019). The resultant nomogram was internally validated and had a concordance index of Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level. There is no mention of proton beam salvage radiation therapy for recurrent prostate cancer. In summary, a search of the peer-review medical literature failed to identify studies, clinical trials, comparative studies or case series where proton beam radiation therapy (PBRT) has been investigated as salvage therapy for locally recurrent prostate cancer. In addition, the NCCN practice guideline for prostate cancer (2012) does not recommend routine use of PBRT as salvage therapy for locally recurrent prostate cancer, either as adjuvant or salvage therapy post-rp. There is a lack of clinical trial data demonstrating "superiority or equivalence" of PBRT compared to conventional external beam for the treatment of prostate cancer at any stage of the disease. Some men will experience pathologic or biochemical failure (bf) after RP. In these instances, selecting men appropriate for adjuvant or salvage external beam radiation "is difficult" (NCCN, 2012). Scientific Rationale Update September 2012 There is no mention of proton beam radiotherapy in the 2012 NCCN Guidelines on Central Nervous System Cancers. Oligodendrogliomas are noted on this site, however, proton beam radiotherapy was not listed as a treatment for this type of cancer. Proton and heavy ion therapy are alternatives to conventional x-ray-based radiation therapy. Rational incorporation of technologies that have been used to improve modern x-ray therapy, such as use of image guidance, will bolster the strengths of proton therapy in the upcoming years. For certain tumor sites, such as large uveal melanomas, select skull base tumors, and select pediatric malignancies, particle therapy is largely accepted as standard of care treatment. The role of particle therapy in treating other sites, such as prostate cancer, remains more controversial. However, there is minimal information noted on proton beam radiotherapy for nonuveal melanoma. Age Related Macular Degeneration HAYES report on Proton Beam Therapy for Ocular Tumors, Hemangiomas, and Macular Degeneration, updated June 12, 2009, notes the lack of peer-reviewed information in the scientific literature regarding proton beam radiotherapy for age related macular degeneration. Hepatocellular Cancer Proton Beam Radiotherapy Oct 14 19

20 The 2012 NCCN guidelines on Hepatobiliary Cancer do not mention proton beam radiotherapy for this type of cancer. Surgical intervention is the treatment of choice for hepatocellular cancer (HCC). In patients who are poor operative candidates, there are a number of ablative treatment options. Radiation has traditionally held a minor role in treating HCC, as the liver is a highly radiosensitive structure. However, small volumes can be treated to high doses so long as there is reasonable sparing of the remaining parenchyma. As a result, there has been interest in using the normal-tissue sparing properties of charged particle irradiation to deliver high doses of radiation to hepatocellular cancers (particularly in the setting of portal vein thrombus) as well as tumors metastatic to the liver. However, additional peer-reviewed studies are necessary. ASTRO 2012 Guidelines Allen et al. (2012) Proton beam therapy (PBT) is a novel method for treating malignant disease with radiotherapy. The purpose of this work was to evaluate the state of the science of PBT and arrive at a recommendation for the use of PBT. The emerging technology committee of the American Society of Radiation Oncology (ASTRO) routinely evaluates new modalities in radiotherapy and assesses the published evidence to determine recommendations for the society as a whole. In 2007, a Proton Task Force was assembled to evaluate the state of the art of PBT. This report reflects evidence collected up to November Data was reviewed for PBT in central nervous system tumors, gastrointestinal malignancies, lung, head and neck, prostate, and pediatric tumors. Current data do not provide sufficient evidence to recommend PBT in lung cancer, head and neck cancer, GI malignancies, 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 PBT appears superior to photon approaches but more data is needed. In large ocular melanomas and chordomas, the authors believe that there is evidence for a benefit of PBT over photon approaches. PBT is an important new technology in radiotherapy. Current evidence provides a limited indication for PBT. More robust prospective clinical trials are needed to determine the appropriate clinical setting for PBT. Lung Cancer Professional Society Statements The National Comprehensive Cancer Network (NCCN, 2012) GUIDELINES on NSCLC note the following: Use of more advanced technologies is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints. Such technologies include (but are not limited to) 4DCT simulation, IMRT/VMAT, stereotactic ablative radiotherapy (SABR), IGRT, motion management strategies, and proton therapy. In nonrandomized retrospective comparisons in patients with locally advanced NSCLC treated with concurrent chemotherapy, 4DCT planned IMRT significantly reduced rates of high grade pneumonitis and higher overall survival compared to 3CRT; and proton therapy reduced esophagitis and pneumonitis despite higher doses compared to 3DCRT or IMRT, while a prospective clinical trial demonstrated favorable outcomes compared to historical results. The National Comprehensive Cancer Network (NCCN, 2013) does not mention proton beam radiotherapy in the treatment of small cell lung cancer. The Agency for Healthcare Research and Quality (AHRQ, 2009) on Particle Beam Radiation Therapies for Cancer notes: Proton Beam Radiotherapy Oct 14 20