20, 2012 Health Technology Assessment Proton Beam Therapy Final Evidence Report March 28, 2014 Health Technology Assessment Program (HTA) Washington State Health Care Authority PO Box 42712 Olympia, WA 98504-2712 (360) 725-5126 hta.hca.wa.gov shtap@hca.wa.go FINAL APPRAISAL DOCUMENT PROTON BEAM THERAPY March 28, 2014 Daniel A. Ollendorf, MPH, ARM Chief Review Officer Jennifer A. Colby, PharmD Sr. Research Associate Steven D. Pearson, MD, MSc President WA – Health Technology Assessment March 28, 2014 Table of Contents About ICER .................................................................................................................................................... ii Acknowledgements ..................................................................................................................................... iii Executive Summary.................................................................................................................................. ES-1 Appraisal Report ........................................................................................................................................... 1 Final Scope ................................................................................................................................................ 1 1. Background .......................................................................................................................................... 3 2. Proton Beam Therapy: What Patients Can Expect .............................................................................. 7 3. Clinical Guidelines and Training Standards ........................................................................................ 11 4. Medicare and Representative Private Insurer Coverage Policies ...................................................... 14 5. Previous Health Technology Assessments ......................................................................................... 17 6. Ongoing Clinical Studies ..................................................................................................................... 20 7. Methods ............................................................................................................................................. 23 8. Results ................................................................................................................................................ 33 9. Summary and Recommendations for Future Research ..................................................................... 64 References .................................................................................................................................................. 66 Appendix A .................................................................................................................................................. 38 Appendix B .................................................................................................................................................. 84 Appendix C .................................................................................................................................................. 91 Appendix D ................................................................................................................................................ 146 Appendix E ................................................................................................................................................ 152 Appendix F ................................................................................................................................................ 162 Proton Beam Therapy: Final Evidence Report Page i WA – Health Technology Assessment March 28, 2014 About ICER The Institute for Clinical and Economic Review (ICER) is an independent non-profit health care research organization dedicated to improving the interpretation and application of evidence in the health care system. There are several features of ICER’s focus and methodology that distinguish it from other health care research organizations:  Commitment to aiding patients, clinicians, and insurers in the application and use of comparative effectiveness information through various implementation avenues, including its flagship initiatives, the New England Comparative Effectiveness Public Advisory Council (CEPAC; cepac.icer-review.org) and the California Technology Assessment Forum (CTAF; www.ctaf.org).  Focus on implementation and evaluation of ICER research to create innovative decision support tools, insurance benefit designs, and clinical/payment policy.  Deep engagement throughout the process with all stakeholders including patients, clinicians, manufacturers, purchasers, and payers.  Inclusion of economic modeling in our research, and use of an integrated rating system for comparative clinical effectiveness and comparative value to guide health care decisions. ICER’s independent mission is funded through a diverse combination of sources; funding is not accepted from manufacturers or private insurers to perform reviews of specific technologies. A full list of funders, as well more information on ICER’s mission and policies, can be found at www.icer-review.org. Proton Beam Therapy: Final Evidence Report Page ii WA – Health Technology Assessment March 28, 2014 Acknowledgements ICER would like to thank the following individuals for their expert opinion as well as peer review of draft documents: Justin E. Bekelman, MD Assistant Professor of Radiation Oncology, Medical Ethics and Health Policy University of Pennsylvania Perelman School of Medicine Senior Fellow, Leonard Davis Institute for Health Economics Radiation Oncologist, Department of Radiation Oncology Abramson Cancer Center University of Pennsylvania Thomas F. DeLaney, MD Andres Soriano Professor of Radiation Oncology, Harvard Medical School Radiation Oncologist, Department of Radiation Oncology Medical Director- Francis H. Burr Proton Therapy Center Co-Director, Center for Sarcoma and Connective Tissue Oncology Massachusetts General Hospital Lia M. Halasz, MD Assistant Professor, Department of Radiation Oncology Joint Assistant Professor, Department of Neurological Surgery University of Washington Radiation Oncologist, University of Washington Medicine and Seattle Cancer Care Alliance Proton Therapy Center, a ProCure Center Proton Beam Therapy: Final Evidence Report Page iii WA – Health Technology Assessment March 28, 2014 Executive Summary Introduction Protons are positively-charged subatomic particles that have been in clinical use as a form of external beam radiotherapy for over 60 years. Compared to the photon X-ray energy used in conventional radiotherapy, proton beams have physical attributes that are potentially appealing. Specifically, protons deposit radiation energy at or around the target, at the end of the range of beam penetration, a phenomenon known as the Bragg peak (Larsson, 1958). In contrast, photons deliver radiation across tissue depths on the way toward the target tumor and beyond, as depicted in Figure ES1 below. The total radiation dose for proton therapy is delivered in the “spread out Bragg peak” (SOBP) region from multiple proton beams; proton radiation is delivered to the target tumor as well as to shallow tissue depths before the target, but not to deeper tissue depths beyond the target (Levin, 2005). Figure ES1. Dose distribution by tissue depth for proton and photon radiation. Source: Adapted from Levin WP, Kooy H, Loeffler, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849-854. The goal of any external beam radiotherapy is to deliver sufficient radiation to the target tumor while mitigating the effects on adjacent normal tissue. As Figure ES1 demonstrates, this has been a challenge for conventional photon therapy due to the amount of radiation deposited both before and after the Proton Beam Therapy: Final Evidence Report ES-1 WA – Health Technology Assessment March 28, 2014 target is reached. While the amount of photon radiation at entry into the body is much higher than at exit, photon beams typically “scatter” to normal tissues after leaving the target. This so-called “exit” dose is absent for protons, as tissue beyond the point of peak energy deposition receives little to no radiation (Kjellberg, 1962). Initial use of proton beam therapy (PBT) focused on conditions where sparing very sensitive adjacent normal tissues was felt to be of utmost importance, such as cancers or noncancerous malformations of the brain stem, eye, or spinal cord. In addition, proton beam therapy was advocated for many pediatric tumors because even lower-dose irradiation of normal tissue in pediatric patients can result in pronounced acute and long-term toxicity (Thorp, 2010). There are also long-standing concerns regarding radiation’s potential to cause secondary malignancy later in life, particularly in those receiving radiation at younger ages. Finally, radiation may produce more nuanced effects in children, such as neurocognitive impairment in pediatric patients treated with radiotherapy for brain cancers (Yock, 2004). The construction of cyclotrons at the heart of proton beam facilities is very expensive ($150-$200 million for a multiple gantry facility); accordingly, as recently as 10 years ago there were fewer than 5 proton beam facilities in the United States (Jarosek, 2012). More recently, however, the use of PBT has been expanded in many settings to treat more common cancers such as those of the prostate, breast, liver, and lung. With the growth in potential patient numbers and reimbursement, the construction of proton centers has grown substantially. As depicted in Figure ES2 below, there are now 14 operating proton centers in the U.S., including one in Seattle that came online in March 2013. Eleven additional centers are under construction or in the planning stages, and many more are proposed (not shown) (Particle Therapy Co-Operative Group, 2014). Figure ES2. Map of proton beam therapy centers in the United States. Source: The National Association for Proton Therapy. http://www.proton-therapy.org/map.htm; Particle Therapy Co-Operative Group. http://www.ptcog.ch/ Proton Beam Therapy: Final Evidence Report ES-2 WA – Health Technology Assessment March 28, 2014 As with pediatric and rare tumors, clinical interest in the use of PBT for more common cancers is focused on sparing adjacent tissues from excess radiation. Some of these considerations are specific to tumor type and location. For example, interest in minimizing radiation exposure in hepatocellular carcinoma stems from concerns that excess radiation to liver tissue that is uninvolved with the tumor but nonetheless cirrhotic may result in radioembolization or other serious hepatic injury (Maor, 2013). However, while enthusiasm for expanded use of PBT has grown in recent years, there remain uncertainties regarding its use in more common conditions and even for cancer types for which its deployment has been relatively well-accepted. Some concerns have been raised about the hypothetical advantages of the radiation deposition for proton beams. The dose range is relatively certain for tumors that are close to the skin, but there is more uncertainty around the end of the dose range when deep- seated tumors such as prostate cancer are considered (Goitein, 2008). In addition, a penumbra (i.e., lateral spread or blurring of the beam as it reaches the target) develops at the end of the beam line, which can result in more scatter of the beam to adjacent normal tissue than originally estimated, particularly at deeper tissue depths (Rana, 2013). Protons are also very sensitive to tissue heterogeneity, and the precision of the beam may be disturbed as it passes through different types of tissue (Unkelbach, 2007). Another concern is the effects of neutrons, which are produced by passively-scattered proton beams and result in additional radiation dose to the patient. The location of neutron production in a PBT patient and its biologic significance is currently a topic of significant debate (Hashimoto, 2012; Jarlskog, 2008). In addition, while it is assumed that the biologic effects of protons are equivalent to photons, specific relative biological effectiveness (RBE) values of protons in relation to photons are not known with absolute certainty for all types of tissues and fractionation schemes (Paganetti, 2002). It is also the case that, while PBT treatment planning and delivery have evolved, so too have other approaches to radiotherapy. For example, intensity-modulated radiation therapy (IMRT) uses sophisticated treatment planning and multiple beam angles to confirm radiation delivery to the target, and has become the de facto standard of care for photon radiotherapy in the U.S. (Esiashvili, 2004). The potential for comparison of PBT and IMRT in clinical trial settings has been the subject of numerous editorials, commentaries, and bioethics exercises in recent years (Efstathiou, 2013; Nguyen, 2007; Zietman, 2007; Goitein, 2008; Combs, 2013; Glimelius, 2007; Glatstein, 2008; Hofmann, 2009; Bekelman, 2013; Bekelman, 2012). The intensity of this debate has created opportunities for the development of randomized trials, several of which are well underway (see Section 6 on page 22). Appraisal Scope This appraisal focuses on the use of one form of external beam radiation, proton beam therapy (PBT), to treat patients with multiple types of cancer as well as those with selected noncancerous conditions. Within each condition type, two general populations were specified as of interest for this evaluation, as noted on the following page: Proton Beam Therapy: Final Evidence Report ES-3 WA – Health Technology Assessment March 28, 2014  Patients receiving PBT as primary treatment for their condition (i.e., curative intent)  Patients receiving PBT for recurrent disease or for failure of initial therapy (i.e., salvage) All forms of PBT were considered for this evaluation, including monotherapy, use of PBT as a “boost” mechanism to conventional radiation therapy, and combination therapy with other modalities such as chemotherapy and surgery. All PBT studies that met entry criteria for this review were included, regardless of manufacturer, treatment protocol, location, or other such concerns. Key questions of interest for the appraisal can be found below. Key Questions 1) What is the comparative impact of proton beam therapy treatment with curative intent on survival, disease progression, health-related quality of life, and other patient outcomes versus radiation therapy alternatives and other cancer-specific treatment options (e.g., surgery, chemotherapy) for the following conditions: a. Cancers I. Bone tumors II. Brain, spinal, and paraspinal tumors III. Breast cancer IV. Esophageal cancer V. Gastrointestinal cancers VI. Gynecologic cancers VII. Head and neck cancers (including skull base tumors) VIII. Liver cancer IX. Lung cancer X. Lymphomas XI. Ocular tumors XII. Pediatric cancers (e.g., medulloblastoma, retinoblastoma, Ewing’s sarcoma) XIII. Prostate cancer XIV. Soft tissue sarcomas XV. Seminoma XVI. Thymoma b. Noncancerous Conditions i. Arteriovenous malformations ii. Hemangiomas iii. Other benign tumors (e.g., acoustic neuromas, pituitary adenomas) Proton Beam Therapy: Final Evidence Report ES-4 WA – Health Technology Assessment March 28, 2014 2) What is the comparative impact of salvage treatment (including treatment for recurrent disease) with proton beam therapy versus major alternatives on survival, disease progression, health-related quality of life, and other patient outcomes versus radiation therapy alternatives and other cancer- specific treatment options (e.g., surgery, chemotherapy) for the condition types listed in key question 1? 3) What are the comparative harms associated with the use of proton beam therapy relative to its major alternatives, including acute (i.e., within the first 90 days after treatment) and late (>90 days) toxicities, systemic effects such as fatigue and erythema, toxicities specific to each cancer type (e.g., bladder/bowel incontinence in prostate cancer, pneumonitis in lung or breast cancer), risks of secondary malignancy, and radiation dose? 4) What is the differential effectiveness and safety of proton beam therapy according to factors such as age, sex, race/ethnicity, disability, presence of comorbidities, tumor characteristics (e.g., tumor volume and location, proliferative status, genetic variation) and treatment protocol (e.g., dose, duration, timing of intervention, use of concomitant therapy)? 5) What are the costs and cost-effectiveness of proton beam therapy relative to radiation therapy alternatives and other cancer-specific treatment options (e.g., surgery, chemotherapy)? We focused primary attention on randomized controlled trials and comparative cohort studies that involved explicit comparisons of PBT to one or more treatment alternatives and measures of clinical effectiveness and/or harm. For the purposes of this review, we distinguished between comparative cohort studies that drew patients from a common pool of subjects and those that involved comparisons of non-contemporaneous case series (i.e., comparison of a current series to a series from another published study or historical control group), given the increased likelihood of selection and/or measurement biases with the latter design. Case series of PBT alone were abstracted and summarized in evidence tables, but were not the primary focus of evaluation for each key question. Importantly, studies that involved comparisons of treatment planning algorithms or modeled simulations of outcomes were not explicitly abstracted. As noted in the Background section to this document, there are significant uncertainties that remain with the delivery of proton beams for a variety of tumor types and locations, including physical uncertainty at the end of the beam range and penumbra effects, as well as concerns regarding the effects of neutron radiation produced by PBT and a lack of precise understanding of PBT’s relative biological effectiveness for all tumor types and tissue depths. Because of these concerns, we felt that any estimation of the clinical significance of PBT therapy must come from studies in which actual patient outcomes were measured. We do recognize and make explicit mention, however, of clinical areas in which simulation studies are likely to remain the cornerstone of evidence, given logistical and ethical challenges posed by conducting clinical trials in these areas (e.g., pediatric tumors, very rare cancers). One notable exception to this rule was the use of Proton Beam Therapy: Final Evidence Report ES-5 WA – Health Technology Assessment March 28, 2014 modeling to answer questions of cost and/or cost-effectiveness, as clinical outcomes in these studies were typically derived from actual clinical outcome data from other published studies. Uses of PBT and relevant comparators are described in detail in the sections that follow. Of note, while PBT is considered part of a “family” of heavy ion therapies that includes carbon-ion, neon-ion, and other approaches, it is the only heavy ion therapy currently in active use in the U.S. Studies that focused on these other heavy-ion therapies were therefore excluded (unless they involved comparisons to PBT). While all potential harms of PBT and its comparators were recorded, the primary focus was on adverse effects requiring medical attention (where such designations were available). Radiation-related toxicities may have also been labeled “early” (i.e., typically occurring within 90 days of treatment) or “late” (occurring >90 days after treatment or lasting longer than 90 days). In addition, because the risk of secondary malignancy is felt to be of great interest because of its link to radiation of normal tissues, these outcomes were abstracted when reported. Finally, published studies of the economic impact of PBT are summarized in response to Key Question 5 regarding the costs and cost-effectiveness of PBT. In addition, a straightforward budget impact analysis is included that employs data from the HCA to estimate the effects of replacing existing radiation treatments with PBT for certain conditions. Analytic Framework The analytic framework for this review is shown in the Figure below. Note that the figure is intended to convey the conceptual links involved in evaluating outcomes of PBT and its alternatives, and is not intended to depict a clinical pathway through which all patients would flow. Analytic Framework: Proton Beam Therapy Quality of Life Patients with Local Tumor Treatment with Control Metastatic a condition Proton Beam Disease Mortality of focus Therapy Tumor Recurrence Local Tumor Symptoms Potential Harms: Acute Toxicity Quality of Life Late Toxicity Treatment Risks Mortality Radiation of Normal Tissue The available literature varies with respect to how directly the impact of PBT is measured. Some studies are randomized or observational comparisons focused directly on survival, tumor control, health-related quality of life, and long-term harms, while in other studies a series of conceptual links must be made Proton Beam Therapy: Final Evidence Report ES-6 WA – Health Technology Assessment March 28, 2014 between intermediate effectiveness measures (e.g., biochemical recurrence in prostate cancer) or measures of harm (e.g., early toxicity) and longer-term outcomes. Study Quality We used criteria published by the U.S. Preventive Services Task Force to assess the quality of RCTs and comparative cohort studies, using the categories “good”, “fair”, or “poor”. Guidance for quality rating using these criteria is presented on the following page (AHRQ, 2008).  Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention to confounders in analysis. In addition, for RCTs, intention to treat analysis is used.  Fair: Studies will be graded "fair" if any or all of the following problems occur, without the fatal flaws noted in the "poor" category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow- up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for. Intention to treat analysis is done for RCTs.  Poor: Studies will be graded "poor" if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied at all equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention to treat analysis is lacking. Data from all retrieved studies were included in evidence tables regardless of study quality. However, the focus of attention in presentation of results was primarily on good- or fair-quality studies. Study quality was not assessed for single-arm case series, as the focus of quality ratings was on the level of bias in assessing the comparative impact of PBT versus alternatives on measures of effectiveness and harm. The overall strength of evidence for PBT use to treat each condition type was determined primarily on the number of good- or fair-quality comparative studies available for each condition type and key question, although the totality of evidence (including case series) was considered in situations where future comparative study was unlikely (e.g., pediatrics, rare cancers). We followed the methods of the U.S. Agency for Healthcare Research and Quality (AHRQ) in assigning strength of evidence as follows: Low, Moderate, High, and No Evidence (AHRQ, 2014). A “no evidence” rating is made when no studies Proton Beam Therapy: Final Evidence Report ES-7 WA – Health Technology Assessment March 28, 2014 meeting entry criteria for the review are identified. While the remaining ratings are based on an overall value judgment, this is informed by assessment of the evidence across several domains, as listed below:  Risk of bias: aspects of study design and conduct, control for confounding, etc.  Consistency: direction and magnitude of findings, use of uniform outcome measures, etc.  Directness: focus on most important clinical outcomes and/or comparisons to most relevant alternatives  Precision: degree of certainty around estimates of treatment effect Net Health Benefit Because of the large number of conditions and comparators under study, a standardized system was used to describe our judgment of the overall net health benefit (that is, taking into account both clinical effectiveness and potential harms) of PBT in comparison to its major treatment alternatives. The five categories of net health benefit were derived from ICER’s rating matrix for clinical effectiveness (Ollendorf, 2010), and are listed below:  Superior: Evidence suggests a moderate-to-large net health benefit vs. comparator(s)  Incremental: Evidence suggests a small net health benefit vs. comparators(s)  Comparable: Evidence suggest that, while there may be tradeoffs in effectiveness or harms, overall net health benefit is comparable vs. comparator(s)  Inferior: Evidence suggests a negative net health benefit vs. comparator(s)  Insufficient: Evidence is insufficient to determine the presence and magnitude of a potential net health benefit vs. comparators(s) When the net health benefit was rated superior, incremental, comparable, or inferior, we have provided additional information on the specific comparisons of both clinical benefits and harms. For example, if we have given an overall rating of an incremental net health benefit, we give information on whether that rating was based on evidence demonstrating small increases in effectiveness with no difference in harms, or on evidence demonstrating equivalent effectiveness and a small reduction in harms. Results Evidence Quality & Overall Results Our summary of the net health benefit of PBT vs. alternative treatments and the strength of available evidence on net health benefit, as well as an evaluation of consistency of these findings with clinical guideline statements and public/private coverage policy, can be found in Table ES2 on page ES-11. Detailed descriptions of the evidence base for each key question can be found in the sections that follow. The level of comparative evidence was extremely limited for certain conditions and entirely Proton Beam Therapy: Final Evidence Report ES-8 WA – Health Technology Assessment March 28, 2014 absent for others. We identified a total of six RCTs and 37 nonrandomized comparative studies across all 19 condition types. A detailed listing of RCTs can be found in Table ES1 on the following page. Importantly, five of the six RCTs involved different treatment protocols for PBT and had no other comparison groups; while these are included for completeness, primary attention was paid to studies (RCTs and otherwise) that compared PBT to an alternative form of treatment. Most of the comparative studies identified also had major quality concerns. For example, nearly all non- randomized comparative studies were retrospective in nature, and many involved comparisons of a PBT cohort to a non-contemporaneous group receiving alternative therapy. Major differences in patient demographics and baseline clinical characteristics as well as duration of follow-up were often noted between groups. Of the 6 RCTs identified, 1, 4, and 1 were judged to be of good, fair, and poor quality respectively. Corresponding figures for non-randomized comparative studies were 1, 20, and 16. We also examined the possibility of publication bias by cross-referencing the results of our literature search with a list of completed randomized controlled trials of PBT available on the U.S. National Institutes of Health’s clinicaltrials.gov website. A single RCT was identified on clinicaltrials.gov (NCT00388804) that has not been published, a study comparing multiple radiation modalities (including PBT) with short-course androgen suppression therapy vs. PBT alone in men with intermediate-risk prostate cancer. The study was terminated due to slower-than-expected patient accrual. As noted on Table ES2, we judged PBT to have superior net health benefit for ocular tumors, and incremental net health benefit for adult brain/spinal tumors and pediatric cancers. We felt PBT to be comparable to alternative treatment options for patients with liver, lung, and prostate cancer as well as one noncancerous condition (hemangiomas). Importantly, however, the strength of evidence was low for all of these conditions. We determined the evidence base for all other condition types to be insufficient to determine net health benefit, including two of the four most prevalent cancers in the U.S.: breast and gastrointestinal (lung and prostate are the other two). Current authoritative guideline statements and coverage policies relevant to Washington State reflect these uncertainties through coverage restrictions or limitations on recommendations for use. The lack of comparative data for rare and childhood cancers is not surprising, and in fact is considered appropriate by many (Macbeth, 2008). Because information from dosimetry, planning, and simulation studies indicates that the radiation dose from PBT would be consistently lower than other radiation modalities in children, and because of the increased sensitivity of children to any level of ionizing radiation in comparison to adults, many in the clinical community feel that there is not sufficient equipoise to ethically justify comparative study of PBT in pediatric populations (Efstathiou, 2013; Macbeth, 2008). It should be noted, however, that this opinion is not universal, and other commentators have noted that the clinical data accrued to date on PBT in pediatric cancers is lacking critical information on measures of long-term effectiveness and harm (De Ruysscher, 2012). Proton Beam Therapy: Final Evidence Report ES-9 WA – Health Technology Assessment March 28, 2014 The situation is more complex with adult cancers, particularly those that are more prevalent. As mentioned in the Introduction, significant uncertainties remain regarding proton physics and the relative biological effectiveness of PBT in all tissues (Rana, 2013; Paganetti, 2002; Goitien, 2008). It is because of these unknowns that we opted in this review not to abstract information from dosimetry, planning, and simulation studies, as evidence on the clinical impact of these uncertainties can only be obtained by measuring patient outcomes. Table ES1. Randomized controlled trials of proton beam therapy. Cancer Type Measurement of Measurement Comparison N (Author, Year) Clinical Outcomes of Harms Prostate Dose/fractionation 82 Yes Yes (Kim, 2011) comparison Prostate Dose/fractionation 391 Yes Yes (Zietman, 2010) comparison Uveal melanoma Dose/fractionation 188 Yes Yes (Gragoudas, 2000) comparison Skull-base chordoma Dose/fractionation 96 No Yes and chondrosarcoma comparison (Santoni, 1998) Uveal melanoma PBT vs. PBT + TTT 151 No Yes (Desjardins, 2006) Prostate PBT + photon vs. 202 Yes Yes (Shipley, 1995) Photon PBT: proton beam therapy; TTT: transpupillary thermotherapy Proton Beam Therapy: Final Evidence Report ES-10 WA – Health Technology Assessment March 28, 2014 Table ES2. Summary table assessing strength of evidence, direction of benefit, and consistency with relevant guideline statements and coverage policy. Net Health Incidence Type of Net Strength of Guideline Condition Benefit vs. Coverage Policies (per 100,000) Health Benefit Evidence Recommendations Comparators Cancer Bone 1.3 Insufficient --- + M M Brain/spinal 9.6 Incremental B: = H: ↓ + U U Breast 97.7 Insufficient --- o NM NR/NC Esophageal 7.5 Insufficient --- o NM NR/NC GI 100.6 Insufficient --- o NM NR/NC Gynecologic 38.2 Insufficient --- o NM NR/NC Head/neck 17.2 Insufficient --- + NM M Liver 12.8 Comparable B: = H: = + NM M Lung 95.0 Comparable B: = H: = + M M Lymphomas 32.9 Insufficient --- o NR/NC NR/NC Ocular 1.2 Superior B: ↑ H: ↓ ++ U U Pediatric 9.1 Incremental B: = H: ↓ + U U Prostate 99.4 Comparable B: = H: = + M M Sarcomas 4.8 Insufficient --- o NM M Seminoma 4.0 Insufficient --- o NM NM Thymoma 0.2 Insufficient --- o NM NM Noncancerous AVMs 1.0 Insufficient --- o NM M Hemangiomas 2.0 Comparable B: = H: = + NM NM Other 2.0 Insufficient --- o NM M B: Benefits; H: Harms Strength of Evidence: Low=+; Moderate=++; High=+++; No evidence=o Legend: U = Universally recommended or covered; M=Mixed recommendations or coverage policies; NM=Not mentioned in guidelines or coverage policies; NR/NC=Not recommended or not covered Proton Beam Therapy: Final Evidence Report ES-11 WA – Health Technology Assessment March 28, 2014 Evidence on the effects of PBT with curative intent (i.e., as a primary therapeutic option) are summarized by condition in the sections that follow. As with all of the key questions, the primary focus was on active comparisons of PBT to one or more therapeutic alternatives. Note that, while the detailed report summarizes the evidence base for all conditions (including case series data), the focus of this executive summary is restricted to conditions with one or more comparative studies available. Impact of Proton Beam Therapy with Curative Intent on Patient Outcomes for Multiple Cancers and Noncancerous Conditions (KQ1) Cancers Bone Cancer We identified a single poor-quality retrospective comparative cohort study that evaluated PBT for primary and recurrent sacral chordomas in 27 patients. Among these patients 21 were treated with surgery and combination PBT /photon therapy (mean radiation dose: 72.8 Gray Equivalents [GyE]), in comparison to six patients who received PBT/photons alone (mean dose: 70.6 GyE) (Park, 2006). Two- thirds of patients in each group were male, but groups differed substantially in terms of age (mean of 68 years in the radiation-only group vs. 54 years in the radiation+surgery group) and duration of follow-up (mean of 5 and 8 years in the two groups). For patients with primary tumors, Kaplan-Meier estimates of local control, disease-free survival and overall survival exceeded 90% among those treated by surgery and radiation (n=14). Only two of the six patients with primary tumors received radiation alone, one of whom had local failure at four years, distant metastases at five years, and died at 5.5 years. (NOTE: see KQ2 on page ES-17 for discussion of results specific to recurrent cancers.) Brain, Spinal, and Paraspinal Tumors We identified two poor-quality retrospective comparative cohort studies of primary PBT for brain, spinal, and paraspinal tumors. One was an evaluation of PBT (mean dose: 54.6 GyE) vs. photon therapy (mean dose: 52.9 Gy) in 40 adults (mean age: 32 years; 65% male) who received surgical and radiation treatment of medulloblastoma at MD Anderson Cancer Center (Brown, 2013). PBT patients were followed for a median of 2.2 years, while photon patients were followed for a median of nearly five years. No statistical differences between radiation modalities were seen in Kaplan-Meier assessment of either overall or progression-free survival at two years. A numeric difference was seen in the rate of local or regional failure (5% for PBT vs. 14% for photon), but this was not assessed statistically. The second study involved 32 patients treated for intramedullary gliomas at Massachusetts General Hospital (Kahn, 2011) with either PBT (n=10) or IMRT (n=22). While explicit comparisons were made between groups, the PBT population was primarily pediatric (mean age: 14 years), while the IMRT population was adult (mean age: 44 years). Patients in both groups were followed for a median of 24 months; dose was >50 GyE or Gy in approximately 75% of patients. While the crude mortality rate was Proton Beam Therapy: Final Evidence Report ES-12 WA – Health Technology Assessment March 28, 2014 lower in the PBT group (20% vs. 32% for IMRT, not tested), in multivariate analyses controlling for age, tumor pathology, and treatment modality, PBT was associated with significantly increased mortality risk (Hazard Ratio [HR]: 40.0, p=0.02). The rate of brain metastasis was numerically higher in the PBT group (10% vs. 5% for IMRT), but this was not statistically tested. Rates of local or regional recurrence did not differ between groups. Head and Neck Cancers We identified two poor-quality retrospective comparative cohorts of primary PBT in head and neck cancer. One was an evaluation of 33 patients treated with either PBT alone or PBT+photon therapy to a target dose of 76 Gy for a variety of head and neck malignancies in Japan (Tokuuye, 2004). Treatment groups differed substantially in terms of age (mean: 67 vs. 54 years for PBT and PBT+photon respectively), gender (82% vs. 44% male), and duration of follow-up (mean: 5.9 vs. 3.1 years). Numeric differences in favor of PBT+photon therapy were seen for local control, recurrence, and mortality, but these were not statistically tested, nor were multivariate adjustments made for differences between groups. The other study was a very small (n=6) comparison of endoscopic resection followed by either PBT or IMRT as well as endoscopy alone in patients with malignant clival tumors (Solares, 2005). Limited description of the study suggests that PBT was used only in cases of residual disease, while it is unclear whether IMRT was also used in this manner or as an adjuvant modality. One of the IMRT patients died of causes unrelated to disease; no other deaths were reported. Liver Cancer We identified two fair-quality prospective comparative cohort studies from Japan with evidence of the clinical effectiveness of primary use of PBT in liver cancer. One was an evaluation of 35 patients with unresectable hepatocellular carcinoma (HCC) who were treated with PBT (mean dose: 76.5 GyE) either alone or in combination with chemotherapy and were followed for up to 4 years (Matsuzaki, 1995). While statistical testing was not performed, rates of local tumor control and the proportion of patients experiencing reductions in tumor volume were nearly identical between groups. The other study was also prospective but compared PBT to another heavy-ion modality not in circulation in the U.S. (carbon ion). In this study, a fair-quality comparison of 350 patients (75% male; age ≥70: 50%) with HCC who received PBT (53-84 GyE) or carbon-ion (53-76 GyE) therapy and were followed for a median of 2.5 years (Komatsu, 2011), no statistically-significant differences were observed in 5-year Kaplan-Meier estimates of local control, no biological evidence of disease, or overall survival between treated groups. Lung Cancer We identified three fair-quality comparative cohort studies examining the clinical effectiveness of PBT in lung cancer. Two studies retrospectively compared outcomes with PBT to those with IMRT or older three-dimensional conformal radiotherapy (3D-CRT) at MD Anderson Cancer Center (Lopez Guerra, Proton Beam Therapy: Final Evidence Report ES-13 WA – Health Technology Assessment March 28, 2014 2012; Sejpal, 2011). The Lopez Guerra study involved 250 patients with non-small-cell lung cancer (NSCLC) (median age 71.5 years, 57% male) who were treated with 66 Gy of photons or 74 GyE of protons and followed for up to one year to assess a key measure of lung function known as diffusing capacity of lung for carbon monoxide (DLCO). While this measure did not differ between PBT and IMRT at 5-8 months after treatment, DLCO declined significantly more in the 3D-CRT group as compared to PBT after adjustment for pretreatment characteristics and other lung function measures (p=0.009). The study by Sejpal and colleagues focused on survival in 202 patients (median age 64 years, 55% male) with locally-advanced, unresectable NSCLC who were followed for a median of 1.5 years and treated with 74 GyE of PBT or 63 Gy of either IMRT or 3D-CRT (Sejpal, 2011). Actuarial estimates of median overall survival were 24.4, 17.6, and 17.7 months for PBT, IMRT, and 3D-CRT respectively, although these differences were not statistically significant (p=0.1061). A third study was a prospectively-measured cohort but, as with the study of liver cancer mentioned above, compared PBT to carbon ion therapy, evaluating 111 Japanese NSCLC patients (median age 76 years, 67% male) over a median of 3.5 years (Fujii, 2013). No statistically-significant differences between groups were observed in three-year actuarial estimates of local control, progression-free survival, or overall survival. Ocular Tumors In comparison to other cancer types, the evidence base for ocular tumors was relatively substantial. A total of seven comparative studies were identified of the clinical benefits of primary PBT in such cancers—a single RCT, four retrospective cohort studies, a comparison of a recent case series to the treatment groups from the RCT, and a comparison of noncontemporaneous case series. The RCT compared PBT alone to a combination of PBT and transpupillary thermotherapy (TTT) in 151 patients (mean age: 58 years; 52% male) treated for uveal melanoma and followed for a median of 3 years in France (Desjardins, 2006). Combination therapy was associated with a statistically-significantly (p=0.02) reduced likelihood of secondary enucleation; no other outcomes differed significantly between groups. In a separate, poor-quality comparison of these findings to a separate series of patients undergoing PBT with endoresection of the scar (Cassoux, 2013), rates of secondary enucleation did not differ between groups, but rates of neovascular glaucoma were significantly lower in the PBT+endoresection group vs. the groups from the RCT (7% vs. 58% and 49% for PBT alone and PBT+TTT respectively, p<0.0001). Of note, however, median follow-up was less than two years in the PBT+endoresection series vs. 9 years in the RCT. Three of the cohort studies were all fair-quality and involved comparisons to surgical enucleation in patients with uveal melanoma at single centers (Mosci, 2012; Bellman, 2010; Seddon, 1990). PBT was associated with statistically-significant improvements in overall survival rates relative to enucleation at 2-5 years in two of these studies (Bellman, 2010; Seddon, 1990). Rates of metastasis-related and all cancer-related death were statistically-significantly lower among PBT patients through two years of follow-up in the Seddon study (n=1,051), but were nonsignificant at later timepoints (Seddon, 1990). Proton Beam Therapy: Final Evidence Report ES-14 WA – Health Technology Assessment March 28, 2014 The 5-year metastasis-free survival rate in the Bellman study (n=67) was 50% higher among PBT patients in a Cox regression model controlling for baseline characteristics (59.0% vs. 39.4% for enucleation, p=0.02). In the third study, Kaplan-Meier curves for all-cause mortality, melanoma-related mortality and metastasis-free survival did not statistically differ for 132 patients treated with PBT and enucleation (Mosci, 2012). Metastasis-free survival also did not differ in Cox regression adjusting for age, sex, and tumor thickness. Another fair-quality study assessed the impact of PBT + chemotherapy vs. PBT alone in 88 patients with uveal melanoma (aged primarily between 20-55 years; 63% male) who were followed for 5-8 years (Voelter, 2008). Five-year overall survival rates did not statistically differ between groups on either an unadjusted or Cox regression-adjusted basis. Finally, a poor-quality comparison of noncontemporaneous case series evaluated treatment with PBT + laser photocoagulation or PBT alone in 56 patients with choroidal melanoma (Char, 2003). At one year, there were no differences in visual acuity between groups. Prostate Cancer The largest evidence base available was for prostate cancer (10 studies). However, only 6 of these studies reported clinical outcomes and compared PBT to alternative treatments. These included an RCT, a prospective comparative cohort, and four comparisons of noncontemporaneous case series. (NOTE: comparisons of different dose levels of PBT are reported as part of the evidence base for Key Question 4 on patient subgroups.) The included RCT was a fair-quality comparison of 202 patients (median age 69 years) with advanced (stages T3-T4) prostate cancer who were randomized to receive either photon therapy with a proton boost (total dose: 75.2 GyE) or photons alone (67.2 Gy) and were followed for a median of five years (Shipley, 1995). Kaplan-Meier estimates of local tumor control, disease-specific survival, and overall survival were similar at both 5- and 8-year timepoints among the entire intent-to-treat population as well as those completing the trial (n=189). However, in patients with poorly-differentiated tumors (Gleason grades 4 or 5), local control at 8 years was significantly better in patients receiving PBT+photons (85% vs. 40% for photons alone, p=0.0014). The prospective cohort study was a fair-quality comparison of patient-reported health-related QoL at multiple timepoints among 185 men (mean age: 69 years) with localized prostate cancer who were treated with PBT, PBT+photons, photons alone, surgery, or watchful waiting (Galbraith, 2001). Overall QoL, general health status, and treatment-related symptom scales were employed. No differences in overall QoL or general health status were observed at 18 months of follow-up, although men treated with PBT monotherapy reported better physical function in comparison to surgery (p=0.01) or photon radiation (p=0.02), and better emotional functioning in relation to photon radiation (p<0.001). Men receiving PBT+photons also reported significantly fewer urinary symptoms at 18 months in comparison to watchful waiting (p<0.01). Proton Beam Therapy: Final Evidence Report ES-15 WA – Health Technology Assessment March 28, 2014 Outcomes were also assessed in three comparisons of noncontemporaneous case series. One was a fair-quality evaluation of high-dose PBT+photons (79.2 GyE) in 141 patients enrolled in a clinical trial at MGH and Loma Linda University who were matched on clinical and demographic criteria to 141 patients treated with brachytherapy at MGH (Coen, 2012). Patients were followed for a median of eight years. Eight-year actuarial estimates of overall survival, freedom from metastasis, and biochemical failure did not statistically differ between groups. The proportion of patients achieving a nadir PSA level of ≤0.5 ng/mL as of their final measurement was significantly higher in the brachytherapy group (92% vs. 74% for PBT, p=0.0003). Two additional studies were deemed to be of poor quality due to a lack of control for confounding between study populations. One was a comparison of a cohort of 206 brachytherapy patients treated at the University of California San Francisco compared with same MGH/Loma Linda PBT+photon group described above (Jabbari, 2010). The difference in the percentage of patients achieving nadir PSA after a median of 5.4 years of follow-up was similar to that reported in the Coen study above (91% vs. 59%), although statistical results were not reported. Five-year estimates of disease-free survival (using biochemical failure definitions) did not statistically differ between groups. The other study involved comparisons of bowel- and urinary-related QoL in three distinct cohorts receiving PBT (n=95; 74-82 GyE), IMRT (n=153; 76-79 Gy), or 3D-CRT (n=123; 66-79 Gy) (Gray, 2013). Statistical changes were assessed within (but not between) each cohort immediately following treatment as well as at 12 and 24 months of follow-up, and were also assessed for whether the change was considered “clinically meaningful” (>0.5 SD of baseline values). Some differences in QoL decrements were seen at earlier timepoints. However, at 24 months, all groups experienced statistically and clinically significant decrements in bowel QoL, and none of the groups had significant declines in urinary QoL. A fourth, poor-quality comparison of case series (Hoppe, 2013) involved an evaluation of patient- reported outcomes on the Expanded Prostate Cancer Index Composite (EPIC) questionnaire among a cohort of 1,243 patients receiving PBT for prostate cancer at the University of Florida and a group of 204 patients receiving IMRT from a previous multicenter study (Sandler, 2010). Statistically-significant differences between treatment groups were observed for many baseline characteristics, only some of which were adjusted for in multivariate analyses. No differences were observed in summary scores for bowel, urinary, and sexual QoL at two years, although more IMRT patients reported specific bowel frequency (10% vs. 4% for PBT, p=0.05) and urgency (15% vs. 7%, p=0.02) problems at two years. Noncancerous Conditions Hemangiomas We identified a single comparative study of PBT’s clinical effectiveness in hemangiomas, a poor-quality retrospective cohort study of 44 patients (mean age 41 years, gender unreported) with diffuse or circumscribed choroidal hemangiomas who were treated with either PBT (20-23 GyE) or photon therapy Proton Beam Therapy: Final Evidence Report ES-16 WA – Health Technology Assessment March 28, 2014 (16-20 Gy) and followed for an average of 2.5 years (Höcht, 2006). Unadjusted outcomes were reported for the entire cohort only; reduction in tumor thickness, resolution of retinal detachment, and stabilization of visual acuity were observed in >90% of the overall sample. In Kaplan-Meier analysis of outcomes adjusting for differential follow-up between treatment groups, therapeutic modality had no statistically-significant effects on stabilization of visual acuity (p=0.43). Other Benign Tumors We identified two comparative studies of PBT’s clinical effectiveness in other benign tumors, both of poor quality. One was a retrospective cohort of consisting of 20 patients with giant-cell bone tumors (mean age: 40 years; 35% male) who were treated with PBT+photon therapy (mean: 59 GyE) or photons alone (mean: 52 Gy) and followed for median of 9 years (Chakravati, 1999). Patients could also have received partial tumor resection. Of note, however, the PBT population consisted entirely of young adults (mean age: 23 years), while the photon-only population was much older (mean: 46 years); no attempt was made to control for differences between treatment groups. Rates of disease progression, progression-free survival, and distant metastases were numerically similar between groups, although these rates were not statistically tested. The other study was a small cohort study comparing PBT alone, photon therapy alone, or PBT + photons in 25 patients with optic nerve sheath meningioma (ONSM) (Arvold, 2009). On an overall basis, visual acuity improved in most patients. Rates did not numerically differ between treatment groups, although these were not tested statistically. NO COMPARATIVE STUDIES IDENTIFIED FOR KEY QUESTION 1: breast, esophageal, gastrointestinal, gynecologic, and pediatric cancers; lymphomas, sarcomas, seminomas, and thymomas; arteriovenous malformations. Impact of Proton Beam Therapy on Outcomes in Patients with Recurrent Cancer or Noncancerous Conditions (KQ2) Cancers Bone Cancer In a previously-described study of 27 patients with sacral chordomas who were treated with PBT/photon radiation alone or in combination with surgery (Park, 2006), seven radiation/surgery patients and four radiation-only patients had recurrent disease. Among patients in the radiation/surgery group, four patients died of disease 4-10 years after treatment; the remainder was alive with disease at last follow- Proton Beam Therapy: Final Evidence Report ES-17 WA – Health Technology Assessment March 28, 2014 up. In the radiation-only group, two of four patients died of disease at 4-5 years of follow-up; the other two were alive with disease at last follow-up. Head and Neck Cancers In a previously-described study comparing PBT with or without photon radiation in 33 patients with a variety of head and neck cancers (Tokuuye, 2004), four patients were identified as having recurrent disease, three of whom received PBT alone. Two of the three PBT-only patients were alive with local tumor control at last follow-up (5 and 17 years respectively); one patient had their cancer recur three months after PBT and died in month 7 of follow-up. The one PBT+photon patient died at 2.5 years of follow-up, but was described as having local tumor control. Liver Cancer Two studies were identified with information on recurrent disease. One was a poor-quality comparison of PBT to conventional photon radiation in eight patients with recurrent HCC after hepatectomy (Otsuka, 2003). Five patients were treated with PBT (68.8-84.5 GyE), and three with photons (60-70 Gy). Seven of eight patients died of liver failure or lung metastasis a median of 1.5 years after radiation; the one patient alive at the end of follow-up was a photon patient. The rate of local tumor control was 78%, and did not differ between treatment groups. The other study was a previously-described prospective comparison of PBT to carbon-ion therapy in 350 patients with primary or recurrent HCC (Komatsu, 2011). No subgroup analyses were performed, but prior treatment history for HCC was found not to have a statistically-significant impact on local tumor control (p=0.73). Prior treatment was not examined as a risk factor for overall survival, however. Lung Cancer In a previously-described study of patients with locally-advanced, unresectable NSCLC who were treated with PBT, IMRT, or 3D-CRT (Sejpal, 2011), 22% of the study sample was identified as having a prior malignancy of any type. The effects of prior malignancy on overall survival were not reported, however. Ocular Tumors We identified a single comparative study of PBT in recurrent ocular cancer. In this fair-quality, comparative cohort study, a total of 73 patients with uveal melanoma had recurrence of disease following an initial course of PBT at Massachusetts General Hospital (Marucci, 2011). Patients (mean age: 58 years) were treated with either a second course of PBT (70 GyE) in five fractions or surgical enucleation and followed for 5-7 years. The likelihood of overall survival at five years was significantly (p=0.04) longer in the PBT group (63% vs. 36% for enucleation), as was the probability of being free of metastasis at this timepoint (66% vs. 31% respectively, p=0.028). Findings were similar after Cox proportional hazards regression adjusting for tumor volume and year of retreatment as well as patient age. The likelihood of local tumor recurrence at five years was 31% in the PBT group. No local Proton Beam Therapy: Final Evidence Report ES-18 WA – Health Technology Assessment March 28, 2014 recurrences were found in the enucleation group, which is not surprising given the nature of the treatment. Noncancerous Conditions Other Benign Tumors In a previously-described retrospective cohort of consisting of 20 patients with giant-cell bone tumors who were treated with PBT+photon therapy or photons alone (Chakravati, 1999), five of 20 were identified as having recurrent disease. Two of the five were treated with PBT+photon therapy, one of whom had progression of disease at eight months but no further progression after retreatment at five years of follow-up. The other patient was free of local progression and metastases as of 9 years of follow-up. In the three photon patients, one had local progression at 12 months but no further progression as of year 19 of follow-up, one patient was free of progression and metastases as of five years of follow-up, and one patient had unknown status. NO COMPARATIVE STUDIES IDENTIFIED FOR KEY QUESTION 2: brain/spinal/paraspinal, breast, esophageal, gastrointestinal, gynecologic, pediatric, and prostate cancers; lymphomas, sarcomas, seminomas, and thymomas; arteriovenous malformations and hemangiomas. Comparative Harms of Proton Beam Therapy in Patients with Multiple Cancers or Noncancerous Conditions (KQ3) As with information on clinical effectiveness, data on potential harms of PBT come from RCTs, comparative cohort studies, and case series, although comparative harms data are still lacking for many condition types. Across all condition types, a total of 25 studies reported comparative information on treatment-related harms; differences in the types of harms relevant to each condition, as well as variability in harms classification even within conditions, precludes any attempt to summarily present harms data across all 19 condition categories. However, summary statements regarding our overall impression of the effects of PBT on patient harms are provided within each condition type in the sections that follow. Secondary Malignancy Of note, observational data on secondary malignancy with PBT are generally lacking. Two studies were identified with comparative information. One was a fair-quality matched retrospective cohort study comparing 1,116 patients in a linked Medicare-SEER database who received either PBT or photon Proton Beam Therapy: Final Evidence Report ES-19 WA – Health Technology Assessment March 28, 2014 radiation for a variety of cancers and were followed for a median of 6.4 years (Chung, 2013). On an unadjusted basis, the incidence rates of any secondary malignancy and malignancies occurring in the prior radiation field were numerically lower for PBT, but not statistically-significantly so. After adjustment for age, sex, primary tumor site, duration of follow-up, and year of diagnosis, PBT was associated with a risk of secondary malignancy approximately one-half that of photon therapy (HR=0.52; 95% CI: 0.32, 0.85; p=0.009). There are challenges with these findings, however. First and foremost, the lower rate of secondary malignancy with PBT appeared to be manifested almost entirely in the first five years after radiotherapy, a time period in which a second cancer event is not typically attributed to prior radiation (Bekelman, 2013). In addition, patients were accrued over a very long time period (1973- 2001), only the very end of which included highly conformal photon techniques like IMRT. The second study was a poor-quality retrospective cohort study comparing PBT to photon radiotherapy in 86 infants who were treated for retinoblastoma and followed for a median of 7 years (PBT) or 13 years (photon radiotherapy) (Sethi, 2013). Therapy was received at two different centers (PBT at MGH and photon radiotherapy at Children’s Hospital Boston). Kaplan-Meier analyses were conducted to control for differential follow-up but no adjustments were made for other differences between groups. Ten-year estimates of the cumulative incidence of secondary malignancy were numerically lower for PBT, but not statistically-significantly so (5% vs. 14% for photon, p=0.12). However, when malignancies were restricted to those occurring in-field or thought to be radiation-induced, a significant difference in favor of PBT was observed (0% vs. 14%, p=0.015). In addition, significant differences in favor of PBT in both cumulative incidence and radiotherapy-related malignancy were observed for the subgroup of patients with hereditary disease. Other harms are presented in detail for each condition type in the sections that follow. Cancers Bone Cancer Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with bone cancer. In a previously-described study of 27 patients with sacral chordomas who were treated with PBT/photon radiation alone or in combination with surgery (Park, 2006), multiple descriptive harms were reported. Patients receiving radiation alone reported numerically lower rates of abnormal bowel or bladder function as well as difficulty ambulating in comparison to those receiving combination therapy, but rates were not statistically tested. PBT patients also reported higher rates of return to work, although this was also not tested statistically. Brain, Spinal, and Paraspinal Tumors Limited, low-quality evidence suggests that PBT is associated with reductions in acute radiation- related toxicity relative to photon radiation in patients with brain and spinal tumors. Proton Beam Therapy: Final Evidence Report ES-20 WA – Health Technology Assessment March 28, 2014 In a previously-described study comparing PBT to photon therapy in 40 adult patients treated for medulloblastoma (Brown, 2013), PBT was associated with statistically-significantly lower rates of weight loss (median % of baseline: -1.2% vs. 5.8% for photon, p=0.004) as well as requirements for medical management of esophagitis (5% vs. 57% respectively, p<0.001). PBT patients also experienced less RTOG grade 2 or greater nausea and vomiting (26% vs. 71%, p=0.004). In a second poor-quality study comparing primarily 10 pediatric patients (mean age: 14 years) receiving PBT for spinal cord gliomas to 22 adults receiving IMRT for the same condition (mean age: 44 years) (Kahn, 2011), no cases of long-term toxicity or myelopathy were reported in either group. Minor side- effect rates were reported for the overall cohort only. Esophageal Cancer Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with esophageal cancer, particularly in comparison to IMRT. Two studies were identified that examined comparative harms in patients treated with PBT for esophageal cancer. One was a relatively large, fair-quality, retrospective comparative cohort study of 444 patients (median age: 61 years; 91% male) who were treated with chemotherapy and radiation (PBT, IMRT, or 3D-CRT) followed by surgical resection (Wang, 2013). Patients were followed for up to 60 days after hospital discharge. After adjustment for patient characteristics and clinical variables, 3D-CRT was associated with a significantly greater risk of postoperative pulmonary complications vs. PBT (Odds Ratio [OR]: 9.13, 95% CI: 1.83, 45.42). No significant differences were observed between PBT and IMRT, however. No differences in the rate of gastrointestinal complications were observed for any treatment comparison. In addition, a fair-quality comparative study was identified that examined early impact on lung inflammation and irritation in 75 patients receiving PBT, IMRT, or 3D-CRT for esophageal cancer (McCurdy, 2013); patients were followed for up to 75 days following radiation. Nearly all outcome and toxicity measures were reported for the entire cohort only. However, the rate of pneumonitis was found to be significantly higher among PBT patients (33% vs. 15% for IMRT/3D-CRT, p=0.04). Head and Neck Cancers Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with head and neck cancer. In a previously-described study comparing PBT with versus without photon radiation in 33 patients with a variety of head and neck cancers (Tokuuye, 2004), rates of tongue ulceration, osteonecrosis, and esophageal stenosis differed somewhat between treatment groups, but were not statistically tested. Overall toxicity rates were estimated to be 22.8% at both three and five years, but were not stratified by treatment modality. In a separate, fair-quality study comparing rates of vision loss from radiation-induced optic neuropathy in 75 patients treated with PBT or carbon-ion therapy for head and neck or skull base tumors (Demizu, 2009), unadjusted rates of vision loss were similar between modalities (8% and 6% for PBT and carbon- Proton Beam Therapy: Final Evidence Report ES-21 WA – Health Technology Assessment March 28, 2014 ion respectively, not statistically tested). In multivariate analyses controlling for demographic and clinical characteristics, treatment modality had no effect on rates of vision loss (p=0.42). Another comparison of PBT and carbon-ion therapy in 59 patients with head and neck or skull base tumors (Miyawaki, 2009) was of poor quality (due to no control for differences between patient groups) and focused on the incidence of radiation-induced brain changes. The incidence of CTCAE brain injury of any grade was significantly (p=0.002) lower in the PBT group. MRI-based assessment of brain changes showed a lower rate in the PBT group (17% vs. 64% for carbon-ion), although this was not tested statistically. Liver Cancer Limited, low-quality evidence suggests that PBT is associated with comparable rates of toxicity to other radiation modalities in patients with liver cancer. Two comparative studies were identified with comparative information on radiation-related harms. In a previously-described study of eight patients with recurrent HCC after hepatectomy (Otsuka, 2003), there were no instances of bone marrow depression or gastrointestinal complications in either group. Serum aspartate aminotransferase (AST) level s increased in the three photon patients and 4/5 PBT patients, although this was not tested statistically. In the other study, a previously-described comparison of PBT to carbon-ion therapy in 350 patients with primary or recurrent HCC (Komatsu, 2011), rates of toxicities as graded by the Common Terminology Criteria for Adverse Events (CTCAE) framework were comparable between groups, including dermatitis, GI ulcer, pneumonitis, and rib fracture. The rate of grade 3 or higher toxicities was similar between groups (3% vs. 4% for PBT and carbon-ion respectively), although this was not statistically tested. Lung Cancer Moderate evidence suggests that rates of treatment-related toxicities with PBT are comparable to those seen with other radiation modalities in patients with lung cancer. A total of three comparative studies assessed harms in patients with lung cancer. One was a study of severe radiation-induced esophagitis (within six months of treatment) among 652 patients treated for NSCLC with PBT, IMRT, or 3D-CRT at MD Anderson Cancer Center (Gomez, 2012). Rates of grade 3 or higher esophagitis were 6%, 8%, and 28% for PBT, 3D-CRT, and IMRT respectively (p<.05 for PBT and 3D- CRT vs. IMRT). In a previously-described noncontemporaneous case series comparison of patients with locally- advanced, unresectable NSCLC who were treated with PBT, IMRT, or 3D-CRT (Sejpal, 2011), hematologic toxicity rates did not differ by radiation modality. Significant differences in favor of PBT were seen in rates of grade 3 or higher esophagitis (5%, 39%, and 18% for PBT, IMRT, and 3D-CRT respectively, p<0.001) as well as pneumonitis (2%, 6%, and 30%, p<0.001), while rates of grade 3 or higher dermatitis were significantly greater in the PBT group (24% vs. 17% and 7% for IMRT and 3D-CRT, p<0.001). Proton Beam Therapy: Final Evidence Report ES-22 WA – Health Technology Assessment March 28, 2014 Finally, in a previously-described comparison of PBT to carbon-ion therapy in 111 patients in Japan (Fujii, 2013), rates of pneumonitis, dermatitis, and rib fracture did not differ statistically between radiation modalities across all toxicity grades. Ocular Tumors Limited, low-quality evidence suggests comparable rates of harm for PBT relative to treatment alternatives in patients with ocular tumors. We identified two comparative studies assessing the harms of PBT for ocular cancers. In the previously- described Desjardins RCT comparing PBT with thermotherapy to PBT alone in 151 patients with uveal melanoma (Desjardins, 2006), no statistically-significant differences were observed between groups in rates of cataracts, maculopathy, pappilopathy, glaucoma, or intraocular pressure. The combination therapy group had a significantly lower rate of secondary enucleation (p=0.02), although actual figures were not reported. In a previously-described comparison of PBT to enucleation in 132 patients treated for unilateral choroidal tumors (Mosci, 2012), rates of eye loss in the PBT arm were assessed and estimated to be 26% at five years of follow-up. Pediatric Cancers PBT’s theoretical potential to lower radiation-induced toxicity in children serves as the comparative evidence base. Comparative studies are lacking, most likely due to a lack of clinical equipoise. Other than the study of secondary malignancy described above, we identified no comparative studies of the potential harms of PBT in patients with pediatric cancers. Prostate Cancer Moderate evidence suggests that rates of major harms are comparable between PBT and photon radiation treatments, particularly IMRT. We identified four comparative studies of the harms associated with PBT and alternative treatments in patients with prostate cancer. The previously-described RCT of PBT+photon therapy vs. photons alone (Shipley, 1995) examined rates of rectal bleeding, urethral stricture, hematuria, incontinence, and loss of full potency; no patients in either arm had grade 3 or higher toxicity during radiation therapy. Actuarial estimates of rectal bleeding at eight years were significantly higher in the PBT+photon arm (32% vs. 12% for photons alone, p=0.002), although this was primarily grade 2 or lower toxicity. Rates of urethral stricture, hematuria, incontinence, and loss of potency did not differ between groups. Three additional studies involved retrospective comparisons using available databases. The most recent was a matched comparison of 314 PBT and 628 IMRT patients treated for early-stage prostate cancer using the linked Chronic Condition Warehouse-Medicare database with a focus on complications occurring within 12 months of treatment (Yu, 2013). At six months, rates of genitourinary toxicity were significantly lower in the PBT arm (5.9% vs. 9.5%, p=0.03). This difference was not apparent after 12 Proton Beam Therapy: Final Evidence Report ES-23 WA – Health Technology Assessment March 28, 2014 months of follow-up, however (18.8% vs. 17.5%, p=0.66). Rates of gastrointestinal and other (e.g., infection, nerve damage) complications did not statistically differ at either timepoint. Another recent study compared matched cohorts of men with prostate cancer in the linked Medicare- SEER database who were treated with PBT or IMRT (684 patients in each arm) and followed for a median of four years (Sheets, 2012). IMRT patients had a statistically-significantly lower rate of gastrointestinal morbidity (12.2 vs. 17.8 per 100 person-years, p<0.05). No other statistical differences were noted in genitourinary morbidity, erectile dysfunction, hip fracture, or use of additional cancer therapy. Finally, Kim and colleagues conducted an analysis of nearly 30,000 men in the Medicare-SEER database who were treated with PBT, IMRT, 3D-CRT, brachytherapy, or conservative management (observation alone) and evaluated for gastrointestinal toxicity (Kim, 2011). All forms of radiation had higher rates of GI morbidity than conservative management. In pairwise comparisons using Cox proportional hazards regression, PBT was associated with higher rates of GI morbidity than conservative management (HR: 13.7; 95% CI: 9.1, 20.8), 3D-CRT (HR: 2.1; 95% CI: 1.5, 3.1), and IMRT (HR: 3.3; 95% CI: 2.1, 5.2). Noncancerous Conditions Hemangiomas Limited evidence suggests comparable rates of harm for PBT relative to treatment alternatives in patients with hemangiomas. A single, previously-described retrospective comparative cohort study assessed outcomes in patients with circumscribed or diffuse hemangiomas treated with PBT or photon radiation (Höcht, 2006). Small differences in unadjusted rates of optic nerve/disc atrophy, lacrimation (formation of tears) and ocular pressure as well as effects on the retina, lens, and iris were observed between groups, but most side effects were grade 1 or 2. The rate of retinopathy was substantially higher in PBT patients (40% vs. 16% for photons). However, in Cox proportional hazards regression adjusting for between-group differences, no effect of radiation modality on outcomes was observed, including retinopathy (p=0.12). Other Benign Tumors Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with other benign tumors. The previously-described Arvold study comparing PBT, PBT+photon, and photon therapy alone in 25 patients treated for optic nerve sheath meningiomas (Arvold, 2009) showed numerically lower rates of acute orbital pain and headache for both PBT groups compared to photon therapy, and numerically higher rates of late asymptomatic retinopathy. None of these comparisons were tested statistically, however. Proton Beam Therapy: Final Evidence Report ES-24 WA – Health Technology Assessment March 28, 2014 NO COMPARATIVE STUDIES IDENTIFIED FOR KEY QUESTION 3: gastrointestinal and gynecologic cancers; lymphomas, sarcomas, seminomas, and thymomas; arteriovenous malformations. Differential Effectiveness and Safety of Proton Beam Therapy in Key Patient Subgroups (KQ4) The sections below summarize available information on how the effectiveness and safety of PBT differs relative to treatment alternatives in specific patient subgroups as delineated in Key Question 4. Because the focus of this question is on differential effects of PBT in key subgroups, the focus of this section is on comparative studies only. Patient Demographics Limited comparative subgroup data are available on the differential impact of PBT according to patient demographics. In a retrospective comparison of PBT and surgical enucleation in uveal melanoma, the rate of death due to metastatic disease through two years of follow-up increased with older age in the surgical group but not in the PBT group (Seddon, 1990). In a retrospective analysis of secondary malignancy with PBT vs. photon radiation in multiple cancer types (Chung, 2013), reductions in malignancy rates with PBT of 5% were seen with each year of increasing age (mean age was 59 years in both groups). In other comparative studies, patient demographics had no impact on the effect of treatment (Tokuuye, 2004; Marucci, 2011). Clinical Characteristics In a comparison of secondary malignancy rates in 86 infants with retinoblastoma treated with PBT or photon radiation (Sethi, 2013), statistically-significant reductions in the estimated incidence of secondary malignancy at 10 years were observed in favor of PBT for the subset of patients with hereditary disease (0% vs. 22% for photons, p=0.005). No significant differences were observed in the overall cohort, however. In other comparative studies, clinical characteristics, including prior therapy received, had no effect on treatment outcomes (Brown, 2013; Tokuuye, 2004). Tumor Characteristics The impact of tumor characteristics on estimates of treatment effect was measured in six comparative studies. In one study comparing PBT to carbon-ion therapy in liver cancer (Komatsu, 2011), larger tumor Proton Beam Therapy: Final Evidence Report ES-25 WA – Health Technology Assessment March 28, 2014 sizes were associated with a greater risk of cancer recurrence in PBT patients but not in those receiving carbon-ion therapy. In the Shipley RCT comparing PBT+photon therapy to photons alone in men with prostate cancer (Shipley, 1995), the 8-year estimate of local control was significantly higher in patients receiving PBT among those with poorly-differentiated tumors (85% vs. 40% for photons, p=0.0014). No differences were observed among those with well- or moderately-differentiated tumors. In the other studies, tumor characteristics (e.g., volume, thickness, level of prostate cancer risk) had no differential impact on outcomes (Tokuuye, 2004; Sejpal, 2011; Mosci, 2012; Coen, 2012). Treatment Protocol Four RCTs were identified that involved comparisons of different dosing regimens for PBT. Two of these were in men with prostate cancer (Kim, 2013; Zietman, 2010). In the more recent study, five different fractionation schemes were compared in 82 men with stage T1-T3 prostate cancer, with total doses ranging from 35-60 GyE (Kim, 2013); patients were followed for a median of approximately 3.5 years. Rates of biochemical failure using two different definitions did not differ statistically between treatment groups. Similarly, no significant differences were observed in rates of acute and late skin, gastrointestinal, or genitourinary toxicity between arms. In another RCT conducted at MGH and Loma Linda University, 395 men with stage T1b-T2b prostate cancer were randomized to receive a conventional dose of combination PBT+photon therapy (70.2 GyE total dose) or a “high dose” of combination therapy (79.2 GyE) (Zietman, 2010). Patients were followed for a median of 9 years. Significant differences in favor of the high-dose group were seen for disease control as measured by a PSA nadir value <0.5 ng/mL (59.8% vs. 44.7% for high and conventional dose respectively, p=0.003) and 10-year estimates of biochemical failure (16.7% vs. 32.3%, p=0.0001). Survival and mortality rates did not differ. Acute GI toxicity was significantly more frequent in the high- dose group (63% vs. 44% for conventional, p=0.0006); no differences were observed in other measures of toxicity. A quality-of-life subset analysis of this RCT found no differences between groups in patient- reported measures of urinary obstruction and irritation, urinary incontinence, bowel problems, or sexual dysfunction (Talcott, 2010). Gragoudas and colleagues examined the impact of two different total doses of PBT (50 vs. 70 GyE) on clinical outcomes and potential harms in 188 patients with melanoma of the choroid or ciliary body (Gragoudas, 2006). Patients were followed for up to five years. No statistical differences were observed in any measure of effectiveness (visual acuity, vision preservation, local recurrence, death from metastases) or harm (hemorrhage, subretinal exudation, glaucoma, uveitis, secondary enucleation). The fourth RCT involved 96 patients with chordomas and skull base tumors who received combination PBT and photon therapy at total doses of either 66.6 or 72 GyE (Santoni, 1998). Patients were followed for a median of 3.5 years. This RCT focused on harms alone. No significant differences were observed in Proton Beam Therapy: Final Evidence Report ES-26 WA – Health Technology Assessment March 28, 2014 the rate of temporal lobe damage between groups or in grade 1, 2, or 3 clinical symptoms such as headache and motor function. Finally, in a previously-described comparative cohort study assessing outcomes for both PBT and carbon-ion therapy (Fujii, 2013), no differences were observed in estimates of local control, progression- free survival, or overall survival when stratified by number of fractions received or total radiation dose. Costs and Cost-Effectiveness of Proton Beam Therapy in Patients with Multiple Cancers and Noncancerous Conditions (KQ5) A total of 16 studies were identified that examined the costs and cost-effectiveness of PBT in a variety of settings and perspectives (see Appendix E for study details). Studies are organized by cancer type in the sections that follow. Five of the 16 studies focused attention on the operating costs, reimbursement, and/or viability of proton treatment centers for multiple types of cancer, and are summarized at the end of this section. Breast Cancer Three studies modeled the costs and cost-effectiveness of PBT in breast cancer. One U.S.-based study examined reimbursement for treatment with 3D-conformal partial breast irradiation using protons or photons vs. traditional whole breast irradiation (Taghian, 2004). Payments included those of treatment planning and delivery as well as patient time and transport. Total per-patient costs were substantially higher for PBT vs. photon partial irradiation ($13,200 vs. $5,300) but only modestly increased relative to traditional whole breast irradiation ($10,600), as the latter incurred higher professional service fees and involved a greater amount of patient time. Two additional studies from the same group assessed the cost-effectiveness of PBT vs. photon radiation among women with left-sided breast cancer in Sweden (Lundkvist, 2005a and 2005c). In the first of these, photon radiation was assumed to increase the risk of ischemic and other cardiovascular disease as well as pneumonitis relative to PBT (Lundkvist, 2005a); clinical effectiveness was assumed to be identical. Reductions in adverse events led to a gain in quality-adjusted life years (QALYs) equivalent to approximately one month (12.35 vs. 12.25 for photon). Costs of PBT were nearly triple those of photon therapy, however ($11,124 vs. $4,950), leading to an incremental cost-effectiveness ratio (ICER) of $65,875 per QALY gained. The other study used essentially the same model but focused attention only on women at high risk of cardiac disease (43% higher than general population) (Lundkvist, 2005c). In this instance, a lower ICER was observed ($33,913 per QALY gained). Head and Neck Cancer Two studies modeled the cost-effectiveness of PBT in head and neck cancers. In one study, Ramaekers and colleagues used a Markov model to assess the cost-effectiveness of intensity-modulated PBT (IMPT) or IMRT therapy among patients with locally-advanced, Stage III-IV head and neck cancers in the Netherlands (Ramaekers, 2013). IMPT and IMRT were assumed to result in equivalent rates of disease Proton Beam Therapy: Final Evidence Report ES-27 WA – Health Technology Assessment March 28, 2014 progression and survival, but IMPT was assumed to result in lower rates of significant dysphagia (difficulty swallowing) and xerostomia (dry mouth syndrome). IMPT was found to result in one additional month of quality-adjusted survival (6.62 vs. 6.52 QALYs for IMRT), but treatment costs were estimated to be 24% higher. The resulting ICER was estimated to be $159,421 per QALY gained vs. IMRT. Use of IMPT only in patients at high risk of radiation toxicity (and IMRT in all others) resulted in an ICER that was approximately half of the base case ($75,106 per QALY gained). Head and neck cancer was also evaluated in the above-mentioned Swedish model (Lundkvist, 2005c). The base case involved a 65 year-old cohort with head and neck cancers of all stages. PBT was assumed not only to reduce the risk of xerostomia and acute mucositis (ulceration of mucous membranes), but also to reduce overall mortality at 8 years by 25% based on modeled delivery of a higher curative dose. As a result, PBT generated an additional 1.02 QALYs over photon radiation at an additional cost of approximately $4,000, resulting in an ICER of $3,769 per QALY gained. Lung Cancer Two studies from the same center estimated the economic impact of PBT in lung cancers among patients in the Netherlands (Grutters, 2011; Grutters, 2010). One was a Markov model comparing PBT to carbon-ion therapy, stereotactic radiation therapy, and conventional radiation in patients with stage 1 non-small-cell lung cancer (NSCLC) over a 5-year time horizon (Grutters, 2010). Effects of therapy included both overall and disease-related mortality as well as adverse events such as pneumonitis and esophagitis. For inoperable NSCLC, PBT was found to be both more expensive and less effective than either carbon-ion or stereotactic radiation and was therefore not included in subsequent analyses focusing on inoperable disease. While not reported in the paper, PBT’s derived cost-effectiveness relative to conventional radiation (based on approximately $5,000 in additional costs and 0.35 additional QALYs) was approximately $18,800 per QALY gained. The second study was a value of information analysis that examined the implications of adopting PBT for Stage I NSCLC in three scenarios: (a) without further research; (b) along with the conduct of a clinical trial; and (c) delay of adoption while a clinical trial is conducted (Grutters, 2011). Costs included those of treatment (currently abroad, as the Netherlands has no proton facilities), the clinical trial vs. conventional radiation, and adverse events due to suboptimal care. These were calculated and compared to the expected value of sampling information (reduced uncertainty), obtained through simulation modeling of uncertainty in estimates both before and after the trial. The analysis found that adoption of PBT along with conduct of a clinical trial produced a net gain of approximately $1.9 million for any trial with a sample size <950, while the “delay and trial” strategy produced a net loss of ~$900,000. Results were sensitive to a number of parameters, including treatment costs abroad and costs of suboptimal treatment. Pediatric Cancers Three decision analyses were available in pediatric cancers, all of which focused on a lifetime time horizon in children with medulloblastoma who were treated at 5 years of age (Mailhot Vega, 2013; Proton Beam Therapy: Final Evidence Report ES-28 WA – Health Technology Assessment March 28, 2014 Lundkvist, 2005b; Lundkvist, 2005c). In a US-based model that incorporated costs and patient preference (utility) values of treatment as well as management of adverse events such as growth hormone deficiency, cardiovascular disease, hypothyroidism, and secondary malignancy (Maillhot Vega, 2013), PBT was found to generate lower lifetime costs ($80,000 vs. $112,000 per patient for conventional radiation) and a greater number of QALYs (17.37 vs. 13.91). Reduced risks for PBT were estimated based on data from dosimetric and modeling studies. Sensitivity analyses on the risk of certain adverse events changed the magnitude of PBT’s cost-effectiveness, but it remained less costly and more effective in all scenarios. The same Swedish group that examined breast and head/neck cancer also assessed medulloblastoma in two modeling studies (Lundkvist, 2005b; Lundkvist, 2005c). As with the analysis above, PBT was assumed to reduce both mortality and nonfatal adverse events relative to conventional photon therapy. On a per-patient basis, PBT was assumed to reduce lifetime costs by approximately $24,000 per patient and increase quality-adjusted life expectancy by nearly nine months (12.8 vs. 12.1 QALYs) (Lundkvist, 2005b). On a population basis, 25 medulloblastoma patients treated by PBT would have lifetime costs reduced by $600,000 and generate an additional 17.1 QALYs relative to conventional photon radiation (Lundkvist, 2005c). Prostate Cancer We identified four studies examining the costs and cost-effectiveness of PBT for prostate cancer. The analysis of the 2008-2009 Chronic Condition Warehouse previously reported under KQ 3 (harms) also examined treatment costs for matched Medicare beneficiaries with prostate cancer who received PBT or IMRT (Yu, 2013). Median Medicare reimbursements were $32,428 and $18,575 for PBT and IMRT respectively (not statistically tested). A relatively recent Markov decision analysis estimated the lifetime costs and effectiveness of PBT, IMRT, and stereotactic body radiation therapy (SBRT) for localized prostate cancer (Parthan, 2012). Clinical effectiveness and impact on mortality were assumed to be equivalent across all three groups. SBRT was found to have the lowest treatment costs and shortest time in treatment of the three modalities, and produced slightly more QALYs (8.11 vs. 8.05 and 8.06 for IMRT and PBT respectively) based on an expected rate of sexual dysfunction approximately half that of IMRT or PBT. SBRT was cost-saving or cost-effective vs. PBT in 94% of probabilistic simulations. An earlier decision analysis estimated the potential cost-effectiveness of a hypothetically-escalated PBT dose (91.8 GyE) vs. 81 Gy delivered with IMRT over a 15-year time horizon (Konski, 2007). The model focused on mortality and disease progression alone (i.e., toxicities were assumed to be similar between groups), and assumed a 10% reduction in disease progression from PBT’s higher dose. This translated into QALY increases of 0.42 and 0.46 years in 70- and 60-year-old men with intermediate-risk disease respectively. Costs of PBT were $25,000-$27,000 higher in these men. ICERs for PBT vs. IMRT were $63,578 and $55,726 per QALY for 70- and 60-year-old men respectively. Proton Beam Therapy: Final Evidence Report ES-29 WA – Health Technology Assessment March 28, 2014 Finally, the Lundkvist model also evaluated costs and outcomes for a hypothetical cohort of 300 65 year- old men with prostate cancer (Lundkvist, 2005, e30). PBT was assumed to result in a 20% reduction in cancer recurrence relative to conventional radiation as well as lower rates of urinary and gastrointestinal toxicities. PBT was estimated to be approximately $8,000 more expensive than conventional radiation over a lifetime but result in a QALY gain of nearly 4 months (0.297). The resulting cost-effectiveness ratio was $26,481 per QALY gained. Facility-based Analyses Two recent U.S.-based studies modeled the case distribution necessary to service the debt incurred from the construction of new proton facilities (Elnahal, 2013; Johnstone, 2012). The more recent of these examined the impact of accountable care organization (ACO) Medicare reimbursement scenarios on debt servicing, by assessing the potential mix of complex or pediatric cases along with noncomplex and prostate cases that could be delivered with session times <30 minutes (Elnahal, 2013). Overall, replacing fee-for-service reimbursement with ACO payments would be expected to reduce daily revenue by 32%. Approximately one-quarter of complex cases would need to be replaced by noncomplex cases simply to cover debt, and PBT facilities would need to operate 18 hours per day. The earlier study assessed the fee-for-service case distribution required to service debt in PBT facilities of various sizes (Johnstone, 2012). A single-room facility would be able to cover debt while treating only complex and pediatric cases if 85% of treatment slots were filled, but could also achieve this by treating four hours of noncomplex (30 minutes per session) and prostate (24 minutes) cases. Three- and four- room facilities could not service debt by treating complex and pediatric cases alone; an estimated 33- Proton Beam Therapy: Final Evidence Report ES-30 WA – Health Technology Assessment March 28, 2014 50% of volume would need to be represented by simple/prostate cases to service debt in larger facilities. An additional U.S. study examined the potential impact on reimbursement of replacing 2007 radiation therapy volume at Rhode Island Hospital (i.e., IMRT, stereotactic radiation, GammaKnife®) with PBT in all instances, based on Medicare reimbursement rates (Dvorak, 2010). No impact on capital expenditures was assumed. A total of 1,042 patients were treated with other radiation modalities, receiving nearly 20,000 treatment fractions. Estimated Medicare reimbursement was approximately $6 million at baseline. Replacing all of these fractions with PBT would increase reimbursement to approximately $7.3 million, representing a 22% increase. It was further estimated that 1.4 PBT gantries would be necessary to treat this patient volume. Two additional studies modeled the costs of new construction of proton facilities in Europe (Peeters, 2010; Goitien, 2003). Both assumed a 30-year facility lifetime and 13-14 hours of daily operation. Taking into account both construction and daily operating costs, the total institutional costs to deliver PBT was estimated to be 2.4-3.2 times higher than that of conventional photon radiation in these studies. The Peeters study also estimated the costs to operate a combined proton-carbon ion facility, and estimated these costs at approximately 5 times higher than that of a photon-only facility (Peeters, 2010). NO ECONOMIC STUDIES IDENTIFIED FOR KEY QUESTION 5: Bone, brain/spinal/paraspinal, esophageal, gastrointestinal, gynecologic, and liver cancers; lymphomas, sarcomas, seminomas, and thymomas; arteriovenous malformations, hemangiomas, and other benign tumors. Budget Impact Analysis: Prostate and Lung Cancer To provide additional context for an understanding of the economics of PBT, we performed a simple budget impact analysis based on 2012 radiation therapy volume within the Public Employees Benefits Board (PEBB) at the HCA. We focused on prostate and lung cancer as two common cancers for which treatment with PBT would be considered. In 2012, 110 prostate cancer patients received treatment with IMRT or brachytherapy. Considering only the costs of treatment delivery (i.e., not of planning or follow-up), allowed payments averaged $19,143 and $10,704 for IMRT and brachytherapy respectively, and totaled approximately $1.8 million for the population. A single PEBB prostate cancer patient was referred for PBT; in this patient, allowed payments totaled $27,741 for 21 treatment encounters ($1,321 per encounter). Applying this payment level to all 110 patients would result in a total of approximately $3.1 million, or a 73% increase. Comparisons of weighted average payments per patient can be found in Figure ES3 below. Proton Beam Therapy: Final Evidence Report ES-31 WA – Health Technology Assessment March 28, 2014 Figure ES3. Comparisons of average per-patient payments in PEBB plan based on current radiation therapy volume and expected payments for proton beam therapy. $30,000 $25,000 $20,000 $15,000 Std Rx $27,741 PBT $10,000 $16,105 $13,210 $5,000 $7,138 $0 Prostate Lung NOTE: “Std Rx” refers to the current mix of radiation treatments used in each population (IMRT and brachytherapy for prostate cancer, IMRT and radiosurgery for lung cancer) In 2012, 33 PEBB patients received radiation treatment for lung cancer. Allowed payments for treatment delivery averaged $15,963 and $4,792 for IMRT and radiosurgery respectively, and totaled approximately $240,000 for the population. Because PEBB had no lung cancer referrals for PBT, we assumed that treatment with 10 fractions would cost the same per fraction as for prostate cancer ($1,321), summing to a total cost of $13,210. Based on these assumptions, converting all 33 patients to PBT would raise total payment to approximately $440,000 annually, or an 84% increase. Because volume of radiation treatments in the PEBB plan for these cancers was relatively low, and a single case was referred out of state for PBT, these payment estimates might be considered too variable for comparison. We conducted an additional analysis for prostate cancer patients using national Medicare payment estimates from a publicly-available analysis of changes in Hospital Outpatient Prospective Payment System (HOPPS) rates conducted by Revenue Cycle, Inc. for Varian Medical Systems (Varian, Inc., 2014). We used 2013 payment estimates for HDR brachytherapy, IMRT, and PBT. We assumed 40 fractions were delivered each for IMRT and PBT. Payment estimates, including simulation, planning, and treatment, were $8,548, $21,884, and $30,270 for brachytherapy, IMRT, and PBT respectively. Based on the 2012 mix of treatments in the PEBB plan (70 IMRT, 40 brachytherapy), expected Medicare HOPPS payments would total approximately $1.9 million. If all 110 patients were treated instead with PBT, expected payments would be approximately $3.3 million. This represents a 78% increase, which is similar in magnitude to that estimated using actual PEBB payments. Proton Beam Therapy: Final Evidence Report ES-32 WA – Health Technology Assessment March 28, 2014 There are clear limitations to this analysis in that we do not know whether patients treated by PBT would have the same severity mix as the existing population, or whether some of these patients would not even be candidates for PBT. We also did not estimate total costs of care for these patients, so any potential cost-offsets are not represented here. Nevertheless, this analysis represents a reasonable estimate of the treatment expenditures the PEBB plan could expect to incur if current radiation treatment approaches were replaced by PBT. Summary and Recommendations for Future Research Proton beam therapy (PBT) has been used for clinical purposes for over 50 years and has been delivered to tens of thousands of patients with a variety of cancers and noncancerous conditions. Despite this, evidence of PBT’s comparative clinical effectiveness and comparative value is lacking for nearly all conditions under study in this review. As mentioned previously, it is unlikely that significant comparative study will be forthcoming for childhood cancers despite uncertainty over long-term outcomes, as the potential benefits of PBT over alternative forms of radiation appear to be generally accepted in the clinical and payer communities. In addition, patient recruitment for potential studies may be untenable in very rare conditions (e.g., thymoma, arteriovenous malformations). In other areas, however, including common cancers such as breast and prostate, the poor evidence base and residual uncertainty around the effects of PBT is highly problematic. We rated the net health benefit of PBT relative to alternative treatments to be “Superior” (moderate- large net health benefit) in ocular tumors and “Incremental” (small net health benefit) in adult brain/spinal and pediatric cancers. We judged the net health benefit to be “Comparable” (equivalent net health benefit) in several other cancers, including liver, lung, and prostate cancer, as well as hemangiomas. It should be noted, however, that we made judgments of comparability based on a limited evidence base that provides relatively low certainty that PBT is roughly equivalent to alternative therapies. While further study may reduce uncertainty and clarify differences between treatments, it is currently the case that PBT is far more expensive than its major alternatives, and evidence of its short or long-term relative cost-effectiveness is lacking for many of these conditions. It should also be noted that we examined evidence for 11 cancers and noncancerous conditions not listed above, and determined that there was insufficient evidence to obtain even a basic understanding of PBT’s comparative clinical effectiveness and comparative value. For relatively common cancers, the ideal evidence of PBT’s clinical impact would come from randomized clinical trials such as those currently ongoing in liver, lung, and prostate cancer. To allay concerns regarding the expense and duration of trials designed to detect survival differences, new RCTs can focus on validated intermediate endpoints such as tumor progression or recurrence, biochemical evidence of disease, development of metastases, and near-term side effects or toxicities. In any event, overall and disease-free survival should be included as secondary measures of interest. Proton Beam Therapy: Final Evidence Report ES-33 WA – Health Technology Assessment March 28, 2014 In addition, the availability of large, retrospective databases that integrate clinical and economic information should allow for the development of robust observational studies even as RCTs are being conceived of and designed. Advanced statistical techniques and sampling methods have been used to create observational datasets of patients treated with PBT and alternative therapies using national databases like the Medicare-SEER database and Chronic Conditions Warehouse used in some of the studies summarized in this review. These studies will never produce evidence as persuasive as randomized comparisons because of concerns regarding selection and other biases, and administrative databases lack the clinical detail necessary to create rigorously-designed observational datasets. The continued growth of electronic health records from integrated health systems may allow for the creation of more detailed clinical and economic comparisons in large, well-matched patient groups receiving alternative radiation modalities. Use of clinical records-based registries and other observational datasets may therefore yield substantial information on PBT’s benefits and harms under typical-practice conditions, as well as an indication of whether RCTs should be considered in the first place. Use of available clinical and administrative datasets also represents an opportunity for the payer and clinical communities to collaborate in setting standards for study design, identifying the outcomes of most interest, and sharing resources so that evidence can be generated in the most efficient manner possible. Proton Beam Therapy: Final Evidence Report ES-34 WA – Health Technology Assessment March 28, 2014 Appraisal Report Final Scope It is estimated that nearly 14 million Americans are cancer survivors and that 1.7 million new cases will be diagnosed in 2013 (American Cancer Society, 2013). Among the treatment options for cancer, radiation therapy is commonly employed; an estimated 50% of patients receive radiation therapy at some point during the course of their illness (Delaney, 2005). This appraisal focuses on the use of one form of external beam radiation, proton beam therapy (PBT), to treat patients with multiple types of cancer as well as those with selected noncancerous conditions. The final scope of the appraisal, described using the Populations, Interventions, Comparators, Outcomes, Timeframe, and Study Designs (PICOTS) format (Counsell, 1997) is described in detail in the sections that follow. Within each condition type, two general populations were specified as of interest for this evaluation:  Patients receiving PBT as primary treatment for their condition (i.e., curative intent)  Patients receiving PBT for recurrent disease or for failure of initial therapy (i.e., salvage) All forms of PBT were considered for this evaluation, including monotherapy, use of PBT as a “boost” mechanism to conventional radiation therapy, and combination therapy with other modalities such as chemotherapy and surgery. All PBT studies that met entry criteria for this review were included, regardless of manufacturer, treatment protocol, location, or other such concerns. Objectives and Methods The objective of this review was to appraise the comparative clinical effectiveness and comparative value of proton beam therapy in a variety of cancers and noncancerous conditions. To support this appraisal we report the results of a systematic review of published randomized controlled trials, comparative observational studies, and case series on clinical effectiveness and potential harms, as well as any published studies examining the costs and/or cost-effectiveness of proton beam therapy. Key Questions 1) What is the comparative impact of proton beam therapy treatment with curative intent on survival, disease progression, health-related quality of life, and other patient outcomes versus radiation therapy alternatives and other cancer-specific treatment options (e.g., surgery, chemotherapy) for the following conditions: a. Cancers Proton Beam Therapy: Final Evidence Report Page 1 WA – Health Technology Assessment March 28, 2014 i. Bone tumors ii. Brain, spinal, and paraspinal tumors iii. Breast cancer iv. Esophageal cancer v. Gastrointestinal cancers vi. Gynecologic cancers vii. Head and neck cancers (including skull base tumors) viii. Liver cancer ix. Lung cancer x. Lymphomas xi. Ocular tumors xii. Pediatric cancers (e.g., medulloblastoma, retinoblastoma, Ewing’s sarcoma) xiii. Prostate cancer xiv. Soft tissue sarcomas xv. Seminoma xvi. Thymoma b. Noncancerous Conditions i. Arteriovenous malformations ii. Hemangiomas iii. Other benign tumors (e.g., acoustic neuromas, pituitary adenomas) 2) What is the comparative impact of salvage treatment (including treatment for recurrent disease) with proton beam therapy versus major alternatives on survival, disease progression, health- related quality of life, and other patient outcomes versus radiation therapy alternatives and other cancer-specific treatment options (e.g., surgery, chemotherapy) for the condition types listed in key question 1? 3) What are the comparative harms associated with the use of proton beam therapy relative to its major alternatives, including acute (i.e., within the first 90 days after treatment) and late (>90 days) toxicities, systemic effects such as fatigue and erythema, toxicities specific to each cancer type (e.g., bladder/bowel incontinence in prostate cancer, pneumonitis in lung or breast cancer), risks of secondary malignancy, and radiation dose? 4) What is the differential effectiveness and safety of proton beam therapy according to factors such as age, sex, race/ethnicity, disability, presence of comorbidities, tumor characteristics (e.g., tumor volume and location, proliferative status, genetic variation) and treatment protocol (e.g., dose, duration, timing of intervention, use of concomitant therapy)? 5) What are the costs and cost-effectiveness of proton beam therapy relative to radiation therapy alternatives and other cancer-specific treatment options (e.g., surgery, chemotherapy)? Proton Beam Therapy: Final Evidence Report Page 2 WA – Health Technology Assessment March 28, 2014 1. Background Protons are positively-charged subatomic particles that have been in clinical use as a form of external beam radiotherapy for over 60 years. Compared to the photon X-ray energy used in conventional radiotherapy, proton beams have physical attributes that are potentially appealing. Specifically, protons deposit radiation energy at or around the target, at the end of the range of beam penetration, a phenomenon known as the Bragg peak (Larsson, 1958). In contrast, photons deliver radiation across tissue depths on the way toward the target tumor and beyond, as depicted in Figure 1 below. The total radiation dose for proton therapy is delivered in the “spread out Bragg peak” (SOBP) region from multiple proton beams; proton radiation is delivered to the target tumor as well as to shallow tissue depths before the target, but not to deeper tissue depths beyond the target (Levin, 2005). Figure 1. Dose distribution by tissue depth for proton and photon radiation. Source: Adapted from Levin WP, Kooy H, Loeffler, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849-854. The goal of any external beam radiotherapy is to deliver sufficient radiation to the target tumor while mitigating the effects on adjacent normal tissue. As Figure 1 demonstrates, this has been a challenge for Proton Beam Therapy: Final Evidence Report Page 3 WA – Health Technology Assessment March 28, 2014 conventional photon therapy due to the amount of radiation deposited both before and after the target is reached. While the amount of photon radiation at entry into the body is much higher than at exit, photon beams typically “scatter” to normal tissues after leaving the target. This so-called “exit” dose is absent for protons, as tissue beyond the point of peak energy deposition receives little to no radiation (Kjellberg, 1962). Initial use of proton beam therapy (PBT) focused on conditions where sparing very sensitive adjacent normal tissues was felt to be of utmost importance, such as cancers or noncancerous malformations of the brain stem, eye, or spinal cord. In addition, proton beam therapy was advocated for many pediatric tumors because even lower-dose irradiation of normal tissue in pediatric patients can result in pronounced acute and long-term toxicity (Thorp, 2010). There are also long-standing concerns regarding radiation’s potential to cause secondary malignancy later in life, particularly in those receiving radiation at younger ages. Finally, radiation may produce more nuanced effects in children, such as neurocognitive impairment in pediatric patients treated with radiotherapy for brain cancers (Yock, 2004). The construction of cyclotrons at the heart of proton beam facilities is very expensive ($150-$200 million for a multiple gantry facility); accordingly, as recently as 10 years ago there were fewer than 5 proton beam facilities in the United States (Jarosek, 2012). More recently, however, the use of PBT has been expanded in many settings to treat more common cancers such as those of the prostate, breast, liver, and lung. With the growth in potential patient numbers and reimbursement, the construction of proton centers has grown substantially. As depicted in Figure 2 below, there are now 14 operating proton centers in the U.S., including one in Seattle that came online in March 2013. Eleven additional centers are under construction or in the planning stages, and many more are proposed (not shown) (Particle Therapy Co-Operative Group, 2014). Figure 2. Map of proton beam therapy centers in the United States. Source: The National Association for Proton Therapy. http://www.proton-therapy.org/map.htm; Particle Therapy Co-Operative Group. http://www.ptcog.ch/ Proton Beam Therapy: Final Evidence Report Page 4 WA – Health Technology Assessment March 28, 2014 Several approaches to reduce the costs of delivering PBT are being explored. One is the use of “hypofractionation”, a process of delivering higher-dose fractions of radiation that has the potential to reduce the frequency of radiation delivery and shorten the overall treatment course (Nguyen, 2007). Another is the construction of compact, single-gantry proton facilities that have been estimated to cut the construction cost of a proton facility to the range of $15-$25 million. Some commentators believe that lower construction costs will reduce the debt incurred by medical institutions and therefore lead to the ability to reduce the price charged to payers for each treatment course (Smith, 2009). As with pediatric and rare tumors, clinical interest in the use of PBT for more common cancers is focused on sparing adjacent tissues from excess radiation. Some of these considerations are specific to tumor type and location. For example, interest in minimizing radiation exposure in hepatocellular carcinoma stems from concerns that excess radiation to liver tissue that is uninvolved with the tumor but nonetheless cirrhotic may result in radioembolization or other serious hepatic injury (Maor, 2013). However, while enthusiasm for expanded use of PBT has grown in recent years, there remain uncertainties regarding its use in more common conditions and even for cancer types for which its deployment has been relatively well-accepted. Some concerns have been raised about the hypothetical advantages of the radiation deposition for proton beams. The dose range is relatively certain for tumors that are close to the skin, but there is more uncertainty around the end of the dose range when deep- seated tumors such as prostate cancer are considered (Goitein, 2008). In addition, a penumbra (i.e., lateral spread or blurring of the beam as it reaches the target) develops at the end of the beam line, which can result in more scatter of the beam to adjacent normal tissue than originally estimated, particularly at deeper tissue depths (Rana, 2013). Protons are also very sensitive to tissue heterogeneity, and the precision of the beam may be disturbed as it passes through different types of tissue (Unkelbach, 2007). Another concern is the effects of neutrons, which are produced by passively-scattered proton beams and result in additional radiation dose to the patient. The location of neutron production in a PBT patient and its biologic significance is currently a topic of significant debate (Hashimoto, 2012; Jarlskog, 2008). In addition, while it is assumed that the biologic effects of protons are equivalent to photons, specific relative effectiveness (RBE) values of protons in relation to photons are not known with absolute certainty for all types of tissues and fractionation schemes (Paganetti, 2002). It is also the case that, while PBT treatment planning and delivery have evolved, so too have other approaches to radiotherapy. For example, intensity-modulated radiation therapy (IMRT) uses sophisticated treatment planning and multiple beam angles to confirm radiation delivery to the target, and has become the de facto standard of care for photon radiotherapy in the U.S. (Esiashvili, 2004). The potential for comparison of PBT and IMRT in clinical trial settings has been the subject of numerous editorials, commentaries, and bioethics exercises in recent years (Efstathiou, 2013; Nguyen, 2007; Zietman, 2007; Goitein, 2008; Combs, 2013; Glimelius, 2007; Glatstein, 2008; Hofmann, 2009; Bekelman, Proton Beam Therapy: Final Evidence Report Page 5 WA – Health Technology Assessment March 28, 2014 2013; Bekelman, 2012). The intensity of this debate has created opportunities for the development of randomized trials, several of which are well underway (see Section 6 on page 22). Due to the growth in popularity of proton beam therapy as well as concerns regarding its use in certain patient populations, there is interest in understanding the clinical benefits, potential harms, and costs associated with proton beam therapy relative to treatment alternatives in multiple types of cancer as well as certain noncancerous conditions. Accordingly, a review of the available evidence on PBT was conducted under the auspices of the Washington Health Care Authority’s health technology assessment program. Proton Beam Therapy: Final Evidence Report Page 6 WA – Health Technology Assessment March 28, 2014 Washington State Agency Utilization Data Figure 1. Proton Beam Therapy Patients 2009-2012, Patient Counts and Costs (Paid $) Avg 4 Yr Annual PEB Proton Beam Patients 2009 2010 2011 2012 Overall % Total** Chnge PEB Average Annual Members 210,501 213,487 212,596 212,684 0.3% Total Proton Beam Patients 7 5 7 4 20 -10.6% * Proton Beam Patients by Diagnosis Category Patient Counts (Medicare primary patients) Brain cancer 1 1 2 Eye cancer 1 1 2 Lung cancer 1 (1) 1 (1) Prostate Cancer 6 (4) 3 (3) 5 (5) 2 (2) 14 (12) Spinal cord cancer 1 1 1 Total Paid (PEB Primary only) $290,083 $53,639 $37,133 $83,088 $463,943 3.8% * xxxx(Imaging and planning included) % of total for direct day of treatment costs) 94.3% 62.4% 98.2% 90.6% 90.2% † Average Paid per Patient, PEB Primary $96,694 $26,820 $18,567 $83,088 $66,278 Total treatment day counts 255 105 208 87 655 -6.2% * Average treatment days per patient -9.2% (4-134 range) 36.4 21.0 29.7 21.8 32.8 Proton Beam Patients by Diagnosis Category - treatment counts (average where possible) Brain cancer 31† 5† 18.0 Eye cancer 4† 24† 28.0 Lung cancer 30† 30.0† Prostate Cancer 74.7 31.7 38.4 16.5 41.8 Spinal cord cancer 6† 11† 17.0† *Average annual % change adjusted for population **Unique patients are counted over the 4 year period † Single value - not average ‡ Total paid includes imaging and planning up to 21 days ahead of first treatment and surveillance imaging to 7 days after last treatment. Note: L&I and Medicaid reported no Proton Beam Therapy in the 2009-2012 timeframe. Seventy percent of PEB/UMP proton beam treatments were for prostate cancer, and 10% were pediatric patients. Proton Beam Therapy: Final Evidence Report Page 7 WA – Health Technology Assessment March 28, 2014 Figure 2. PEB/UMP Proton Beam Therapy Patients by Diagnosis and Age Group, 2009-2012 PEB/UMP Proton Beam Therapy Patients by Diagnosis and Age Group, 2009-2012 All patients are male 8 On the chart: 7 Matching color indicates same 6 diagnosis Patient Count 5 Matching pattern indicates same age 4 group. 3 Note: Younger patients are shown 2 lower and with more solid patterns 1 0 2009 2010 2011 2012 Lung 66-85 0 0 0 1 Prostate 66-85 5 3 5 1 Prostate 51-65 1 0 0 1 Eye 51-65 0 1 0 0 Brain 51-65 0 0 1 0 Spinal 35-50 0 1 1 0 Eye 0-20 0 0 0 1 Brain 0-20 1 0 0 0 Note: Patients were clustered in younger and older age groups. The prostate patients (all red patterned areas above) were between 63 and 79 years old. Proton Beam Therapy: Final Evidence Report Page 8 WA – Health Technology Assessment March 28, 2014 Figure 3a, 3b. PEB Proton Beam Therapy Patients – Treatment Center Location by Year and Diagnosis, 2009-2012 PEB Proton Beam Therapy Patients 2009- 2012 Treatment Centers by Year 8 7 Proton Therapy Center Houston 6 Florida Proton Therapy Institute 5 University of Calif. San 4 Francisco University of Pennsylvania 3 2 Massachusetts General Hospital 1 Loma Linda University Medical 0 2009 2010 2011 2012 PEB Proton Beam Therapy Patients 2009-2012, Treatment Centers by Diagnosis Category 18 16 Proton Therapy Center 14 Houston Florida Proton Therapy 12 Institute 10 University of Calif. San Francisco 8 University of Pennsylvania 6 Massachusetts General 4 Hospital Loma Linda University Medical 2 0 Prostate Brain Eye Lung Spine Proton Beam Therapy: Final Evidence Report Page 9 WA – Health Technology Assessment March 28, 2014 2. Proton Beam Therapy: What Patients Can Expect Following an initial consultation with the treatment team, patients are then scheduled for a pretreatment planning and simulation session. At this session, any required immobilization devices are provided. These devices are customized to the patient and to the site of PBT treatment. The skin is also marked to identify the site of beam entry. Treatment simulation is performed with the patient immobilized, using one of several imaging systems to develop a precise treatment plan—computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET). Proton treatments themselves are typically delivered in daily fractions (Monday through Friday). Each treatment session may take 15-60 minutes, depending on the type and location of the tumor. The total duration of the treatment course also will vary by type and location of the tumor, and may last up to 8 weeks. A depiction of a typical PBT treatment room can be found in Figure 3 below. Figure 3. Proton beam therapy treatment room. Source: ProCure Proton Therapy Centers. http://www.procure.com/Portals/1/Media/Gantry-New_1_display.jpg Potential systemic side effects of any course of PBT include fatigue, skin irritation, and hair loss. Other side effects vary by type of condition. For example, PBT for prostate cancer may be associated with bladder and bowel dysfunction as well as sexual side effects. The risks of PBT in breast cancer, on the other hand, include cardiotoxicity and pneumonitis (inflammation of lung tissue). Finally, as previously mentioned, all forms of radiotherapy including PBT pose a risk of secondary malignancy. Proton Beam Therapy: Final Evidence Report Page 10 WA – Health Technology Assessment March 28, 2014 3. Clinical Guidelines and Training Standards Major guideline statements as well as competency and/or accreditation standards regarding proton beam therapy can be found in the sections that follow below. Documents are organized by the organization or association. National Comprehensive Cancer Network (NCCN) (2013 – 2014) http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site PBT is considered appropriate for use in the treatment of non-small-cell lung cancer (NSCLC). For unresectable high- and low-grade chondrosarcomas of the skull base and axial skeleton, PBT may be indicated to allow for high-dose treatment. PBT may be appropriate for patients with Hodgkin and Non-Hodgkin lymphoma as well as soft tissue sarcomas; however, long-term studies are necessary to confirm benefits and harms. Currently, PBT is not recommended for use in prostate cancer, as superior or equivalent effects have not been demonstrated in comparison to conventional external-beam therapy. For ethmoid and maxillary sinus tumors, PBT is an investigative therapeutic technique only. Guidelines for treatment options in ocular tumors are under development. No other cancer types of interest for this review are described in NCCN guidelines. American Society for Radiation Oncology (ASTRO) (2013) https://www.astro.org/Practice-Management/Reimbursement/Proton-Beam-Therapy.aspx http://www.choosingwisely.org/doctor-patient-lists/american-society-for-radiation-oncology/ In a position statement, ASTRO concludes that the evidence supporting the use of PBT in prostate cancer continues to develop and define its role among current alternate treatment modalities. ASTRO strongly supports the provision of coverage with evidence development to evaluate the comparative effectiveness of PBT relative to other options including IMRT and brachytherapy. As part of the Choosing Wisely® campaign, ASTRO provided a list of items that physicians and patients should discuss, including the topic of PBT, listed below: “Don’t routinely recommend proton beam therapy for prostate cancer outside of a prospective clinical trial or registry.” Proton Beam Therapy: Final Evidence Report Page 11 WA – Health Technology Assessment March 28, 2014 American College of Radiology (ACR) (2011-2013) http://www.acr.org/Quality-Safety/Appropriateness-Criteria The ACR Appropriateness Criteria® consider PBT for treatment planning in T1 and T2 prostate cancer to be appropriate but with lower ratings than for IMRT (6-7 versus 8-9, based on a 1-9 scale). PBT-based treatment plans are considered inappropriate (rated 1-2) in spinal and non-spinal bone metastases, and for NSCLC patients with poor performance status or requirements for palliative treatment. The use of PBT as boost therapy in cervical cancer is not considered to be appropriate by the ACR. The ACR appropriateness criteria do not evaluate PBT in the treatment of other cancers or noncancerous conditions. American Cancer Society (ACS) (2013) In a detailed patient guide, the ACS concludes that use of protons in prostate cancer may theoretically cause less damage to normal tissue surrounding the area of focus, but no current studies demonstrate the advantages of PBT over photon therapy. More comparative studies are necessary to evaluate the outcomes between the different modalities, with identification of the appropriate therapy for different kinds of cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-radiation- therapy http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/radiation/radiationth erapyprinciples/radiation-therapy-principles-how-is-radiation-given-external-beam-rad Alberta Health Services (2013) http://www.albertahealthservices.ca/hp/if-hp-cancer-guide-rt002-proton-beam-RT.pdf PBT is recommended as a therapeutic option in patients with ocular melanoma, CNS lesions (including craniopharyngioma, germ cell tumors and low-grade gliomas), sarcomas (including chordoma and chondrosarcoma), and benign conditions such as arteriovenous malformations (AVMs) and meningiomas. Additional pediatric conditions that may be considered for PBT are ependymomas, rhabdomyosarcoma, Ewing’s sarcoma, pineal tumors, and patients requiring craniospinal irradiation. Treatment with PBT for adults with acoustic neuromas, and paranasal sinus and nasal cavity tumors is recommended, as well as for lymphoma in patients less than 30 years of age. PBT is not recommended for the treatment of prostate cancer, NSCLC or other lymphomas. Proton Beam Therapy: Final Evidence Report Page 12 WA – Health Technology Assessment March 28, 2014 Training Standards In documents published by the ACR, and in joint publications with ASTRO and the American Association of Physicists in Medicine (AAPM), qualifications for radiation oncologists and qualified medical physicists are specified. Specific criteria are described below:  Radiation oncologist o certification in Radiology by the American Board of Radiology (ABR); or o certification in Radiation Oncology or Therapeutic Radiology by the ABR, the American Osteopathic Board of Radiology, the Royal College of Physicians and Surgeons of Canada (RCPSC) or the Collège des Médecins du Québec; or o satisfactory completion of a radiation oncology residency program approved by the American Council of Graduate Medicine Education, the RCPSC, the Collège des Médecins du Québec or the American Osteopathic Association; and o specific training in proton therapy; and o completion of continuing medical education  Qualified medical physicist o certification in Therapeutic Medical Physics by the ABR, the Canadian College of Physicists in Medicine, or the American Board of Medical Physics; and o meet state/local radiation control agency qualifications to practice radiation oncology physics and/or provide oversight of a facility; and o specific training in proton therapy including treatment planning, quality assurance and equipment configuration; and o completion of continuing medical education http://www.acr.org/~/media/ACR/Documents/PGTS/guidelines/Radiation_Oncology.pdf http://www.acr.org/~/media/ACR/Documents/PGTS/guidelines/Rad_Onc_Proton_Therapy.pdf http://www.acr.org/~/media/ACR/Documents/PGTS/standards/ProtonTherapy.pdf ProCure, a company that develops and manages proton therapy centers in the U.S., operates a Training and Development Center in Bloomington, IN. Clinical and technical training programs focused on proton therapy are offered for radiation oncologists, medical physicists, dosimetrists, radiation therapists and other support staff. http://www.procure.com/Media/SeattleCenterMedia/ProCureTrainingandDevelopmentCenter.aspx Proton Beam Therapy: Final Evidence Report Page 13 WA – Health Technology Assessment March 28, 2014 4. Medicare and Representative Private Insurer Coverage Policies Centers for Medicare and Medicaid Services (CMS) Local Coverage Determination (LCD) While there is no current National Coverage Determination (NCD) for PBT, an LCD involving Washington State provides coverage of PBT for treatment with curative intent or for advanced disease (if life expectancy is greater than two years) for the following indications (Group 1): • Unresectable benign or malignant tumors of the CNS, including glioblastoma, acoustic neuroma and arteriovenous malformations • Intraocular melanomas • Pituitary neoplasms • Chordomas and chondrosarcomas • Advanced, unresectable tumors of the head and neck • Malignant tumors of the paranasal and other accessory sinuses • Unresectable retroperitoneal sarcoma • Solid tumors in children Coverage of PBT is provided for the following investigational conditions (Group 2) as long as patients are enrolled in a clinical trial or registry: • Unresectable lung cancers, upper abdominal cancers, and left breast tumors • Advanced, unresectable pelvic tumors, pancreatic and adrenal tumors • Skin cancer with nerve innervation of the skull base • Unresectable lesions of the liver, biliary tract, anal canal and rectum • Non-metastatic prostate cancer, with documented clinical staging and demonstration of clinical necessity of PBT Representative Regional Private Insurer Policies The Regence Group http://blue.regence.com/trgmedpol/medicine/med49.pdf The Regence Group provides coverage of PBT for primary therapy of uveal melanoma, postoperative therapy in patients with non-metastatic chordoma or low-grade (I or II) chondrosarcoma, and treatment of CNS tumors and retinoblastoma in pediatric patients (<21 years). PBT is considered investigational in the treatment of other benign and malignant conditions including acoustic neuroma, brain tumors, breast tumors, head and neck tumors (other than skull-base), olfactory neuroblastoma, and primary or Proton Beam Therapy: Final Evidence Report Page 14 WA – Health Technology Assessment March 28, 2014 metastatic disease in solid organs. PBT is not considered medically necessary for the treatment of clinically localized prostate cancer. Premera Blue Cross https://www.premera.com/medicalpolicies/CMI_056943.htm Premera provides coverage of PBT for primary therapy of uveal melanoma, postoperative therapy in patients with non-metastatic chordoma or low-grade (I or II) chondrosarcoma, and treatment of CNS tumors and retinoblastoma in pediatric patients (<21 years). Use of PBT for all other conditions is considered investigational, including NSCLC. PBT is not considered medically necessary for the treatment of clinically localized prostate cancer. Blue Shield of California https://www.blueshieldca.com/provider/content_assets/documents/download/public/bscpolicy/ChrgP art_RadThpy.pdf Blue Shield of California provides coverage of PBT for primary therapy of uveal melanoma, postoperative therapy in patients with non-metastatic chordoma or low-grade (I or II) chondrosarcoma, and treatment of CNS tumors and retinoblastoma in pediatric patients. Use of PBT for all other conditions is considered investigational, including NSCLC. Blue Shield will provide coverage of 3D-CRT or IMRT for clinically localized prostate cancer, but does not cover PBT, as it is not considered to be cost-effective for this condition. Representative National Private Insurer Policies Aetna http://www.aetna.com/cpb/medical/data/200_299/0270.html Aetna considers the use of PBT to be medically necessary in the treatment of uveal melanomas, skull- base chordomas or chondrosarcomas, CNS lesions adjacent to critical structures, pediatric malignancies (≤21 years), pituitary neoplasms and retroperitoneal soft tissue sarcomas. PBT is not considered to be medically necessary in clinically-localized prostate cancer as its effectiveness has not been proven over radiation alternatives. PBT is considered investigational in the treatment of all other conditions including lung cancer. Anthem Blue Cross Blue Shield http://www.anthem.com/medicalpolicies/policies/mp_pw_a053258.htm Anthem provides coverage of PBT for primary therapy of uveal melanoma, postoperative therapy in patients with non-metastatic chordoma or low-grade (I or II) chondrosarcoma, CNS lesions adjacent to critical structures, and pituitary adenomas and intracranical arteriovenous malformations lacking Proton Beam Therapy: Final Evidence Report Page 15 WA – Health Technology Assessment March 28, 2014 alternate treatment options. PBT is covered as initial monotherapy in the treatment of localized prostate cancer. The use of PBT is considered investigational and not medically necessary in all other conditions. Humana http://apps.humana.com/tad/tad_new/Search.aspx?searchtype=beginswith&docbegin=P&policyType= medical Humana provides coverage of PBT in the treatment of uveal melanoma that is not amenable to other treatment options and inoperable intracranial arteriovenous malformations. PBT may be used to treat tumors close to vital structures of the brain including CNS tumors, chordomas, meningiomas and pituitary tumors. PBT may be medically necessary for treatment of prostate cancer in patients with comorbid inflammatory bowel disease or with a history of pelvic radiation therapy. UnitedHealthcare https://www.unitedhealthcareonline.com/ccmcontent/ProviderII/UHC/en- US/Assets/ProviderStaticFiles/ProviderStaticFilesPdf/Tools%20and%20Resources/Policies%20and%20Pr otocols/Medical%20Policies/Medical%20Policies/Proton_Beam_Radiation_Therapy.pdf UnitedHealthcare considers PBT to be preferential treatment for uveal melanomas, primary intracranial and skull base tumors, spinal cord tumors and intracranial arteriovenous malformations. PBT is not covered for other indications, including NSCLC and prostate cancer. Proton Beam Therapy: Final Evidence Report Page 16 WA – Health Technology Assessment March 28, 2014 5. Previous Health Technology Assessments Recent technology assessments focusing on the use of PBT were identified from national and international organizations as described below. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer: An Update of a 2008 Comparative Effectiveness Review (draft – 2013) http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productid=1434 Overall, the evidence supporting the comparative effectiveness of external beam radiation therapy for the treatment of prostate cancer remains inadequate. Contemporary RCTs are important for the evaluation of benefits and harms among the available treatment modalities, including PBT. Local Therapies for Unresectable Primary Hepatocellular Carcinoma (2013) http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productid=1511 Moderate strength of evidence was found to support better survival in patients undergoing radiofrequency ablation compared to percutaneous injections. Evidence for the comparative effectiveness of other local therapies is insufficient, and no studies evaluating PBT were included in the assessment. Local Nonsurgical Therapies for Stage I and Symptomatic Obstructive Non-Small-Cell Lung Cancer (2013) http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productid=1532 Data supporting the use of PBT in medically operable and unresectable stage I NSCLC were insufficient to evaluate the comparative effectiveness of treatment. Future clinical comparative studies are necessary to determine appropriate localized therapy in this patient population. Comparative Effectiveness and Safety of Radiotherapy Treatments for Head and Neck Cancer (2010) http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productid=1766 No comparative data evaluating PBT and alternate therapies were identified for the treatment of head and neck cancers. The evidence is insufficient to draw conclusions about the benefits and harms of PBT. Proton Beam Therapy: Final Evidence Report Page 17 WA – Health Technology Assessment March 28, 2014 Particle Beam Radiation Therapies for Cancer (2009) http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and- reports/?pageaction=displayproduct&productid=174 Overall, charged particle therapy (including PBT) did not lead to significantly improved patient outcomes compared to alternate treatment modalities. RCTs and non-randomized comparative studies with appropriate statistical adjustment are important to assess the comparative benefits and harms of charged particle therapy with other treatments. Further research regarding treatment planning and therapy delivery to inform treatment protocols is also necessary. BlueCross BlueShield Technology Assessment Center (BCBS-TEC) Proton Beam Therapy for Non-Small-Cell Lung Cancer (2011) http://www.bcbs.com/blueresources/tec/press/proton-beam-therapy-for.html Overall, the data were insufficient to compare PBT to stereotactic body radiotherapy (SBRT) in the treatment of NSCLC. With only case series data identified, the comparative effectiveness of PBT is unknown. Proton Beam Therapy for Prostate Cancer (2011) http://www.bcbs.com/blueresources/tec/press/proton-beam-therapy-for-1.html BCBS-TEC found inadequate evidence to evaluate the comparative effectiveness of PBT and/or photon therapy compared to alternate treatment modalities. Based on the paucity of available data, the use of PBT alone or with photon therapy did not meet the TEC criteria. California Technology Assessment Forum (CTAF) Proton Therapy for Prostate Cancer (2012) http://www.ctaf.org/assessments/proton-beam-therapy-prostate-cancer CTAF concluded that while PBT provided a net benefit in the treatment of prostate cancer, its comparative benefit to alternate treatment modalities has not been established. Its role as a therapeutic option for localized prostate cancer remains uncertain with respect to safety, efficacy and improvement in patient outcomes. Proton Beam Therapy: Final Evidence Report Page 18 WA – Health Technology Assessment March 28, 2014 Institute for Clinical and Economic Review Brachytherapy & Proton Beam Therapy for Treatment of Clinically-localized, Low-risk Prostate Cancer (2008) http://www.icer-review.org/bt-pbt/ At the time of its review, ICER determined that the data supporting the comparative clinical effectiveness of PBT versus alternative management options in clinically-localized, low-risk prostate cancer were insufficient, and the comparative value of PBT was low. National Institute for Health and Care Excellence (NICE) Currently, NICE has not produced any guidance on the use of PBT in the treatment of cancers, and patients residing in the UK travel abroad to obtain treatment. Utilizing a specialized program, the National Health Service (NHS) evaluates and facilitates the use of PBT for approved patients overseas. The Department of Health recently announced plans for the construction of two proton beam centers in the UK, with scheduled completion by 2017. Proton Beam Therapy: Final Evidence Report Page 19 WA – Health Technology Assessment March 28, 2014 6. Ongoing Clinical Studies Information on ongoing clinical studies that have been submitted to the U.S. National Institutes of Health’s registry of publicly- and privately-supported studies (www.clinicaltrials.gov) is presented in the table below and on the following pages. We focused on randomized controlled trials comparing proton beam therapy alone to an alternate treatment modality with a projected study enrollment of more than 50 patients. We concentrated on trials evaluating the various conditions that are the focal point of this review, and excluded comparative studies of carbon ion therapy, as this treatment modality is not currently available in the U.S. Estimated Primary Title/ Trial Sponsor Design Comparators Patient Population Completion Outcomes Date Image-guided RCT PBT (74 Gy) • n=250 Tumor June 2015 adaptive conformal • 18-85 years recurrence, photon versus proton PBT (66 Gy) • Unresected, evaluated 4-8 therapy locoregionally advanced weeks after (MD Anderson Photon therapy NSCLC (stage II-IIIb) w/out treatment, Cancer Center) evidence of hematogenous then every 3-4 metastases months for 3 NCT00915005 • Suitable for concurrent years chemoradiation therapy • FEV1 ≥ 1 liter Proton therapy vs. RCT PBT • n=400 Reduction in January 2016 IMRT for low or • ≥18 years mean EPIC intermediate risk IMRT • Histologically confirmed bowel scores prostate cancer adenocarcinoma of the at 24 months (PARTIQoL) prostate (Massachusetts • Clinical stages T1c-T2b General Hospital) NCT01617161 Randomized RCT PBT • n=80 Toxicity February comparison of proton • ≥18 years (graded by 2016 and carbon ion Carbon ion • Histologically or imaging CTCAE) at 1 radiotherapy therapy confirmed skull base year w/advanced photon meningioma radiotherapy in skull Hypo- • Macroscopic tumor, base meningiomas: fractionated Simpson grade 4 or 5 the PINOCCHIO Trial photon therapy • Karnofsky score ≥60 (University Hospital Heidelberg) Conventional photon therapy NCT01795300 Proton Beam Therapy: Final Evidence Report Page 20 WA – Health Technology Assessment March 28, 2014 Estimated Primary Title/ Trial Sponsor Design Comparators Patient Population Completion Outcomes Date Proton beam RCT PBT + sorafenib • n=220 Overall June 2016 radiotherapy plus • 18-80 years survival, sorafenib versus Sorafenib • Tumor burden exceeds followed on sorafenib for patients San Francisco criteria average for 5 w/hepatocellular years carcinoma exceeding San Francisco criteria (Loma Linda University) NCT01141478 Stereotactic body RCT SBPT • n=120 Therapy- August 2016 radiotherapy (SBRT) • ≥18 years related versus stereotactic SBRT • Histological confirmation toxicities proton therapy or clinically diagnosed (including (SBPT) primary NSCLC radiation- (MD Anderson • Centrally located stage I induced Cancer Center) or selective stage II primary pneumonitis/ tumors fibrosis/fistula, NCT01511081 • Isolated recurrent disease esophagitis/ • Zubrod status = 0-2 stricture/fistul a Glioblastoma RCT IMPT • n=80 Time to May 2017 multiforme (GBM) • ≥18 years cognitive proton vs. IMRT IMRT • Histological diagnosis of failure at 4 (MD Anderson glioblastoma or gliosarcoma months Cancer Center) (WHO grade IV) adapted RPA class III, IV or V NCT01854554 • Mini Mental Status Exam score ≥21 • Karnofsky score ≥70 Proton beam therapy RCT PBT • n=180 • Progression- April 2018 (PBT) versus • ≥18 years free survival at intensity-modulated IMRT • Histologically confirmed 6 weeks radiation therapy adenocarcinoma or • Total toxicity (IMRT) trial squamous cell carcinoma of burden (MD Anderson the cervical or thoracic (composite of Cancer Center) esophagus or serious gastroesophageal junction adverse events NCT01512589 or cardia of stomach and • Karnofsky score ≥60 postoperative • ECOG criteria = 0, 1, or 2 complications) at 12 months Proton Beam Therapy: Final Evidence Report Page 21 WA – Health Technology Assessment March 28, 2014 Estimated Primary Title/ Trial Sponsor Design Comparators Patient Population Completion Outcomes Date Comparison between RCT PBT • n=144 Local December radiofrequency • ≥18 years progression- 2018 ablation and RFA • HCC patients free survival hypofractionated w/recurrent or residual up to 2 years proton beam tumors after other radiation for treatments recurrent/residual • No evidence of HCC extrahepatic metastasis (National Cancer • Largest tumor diameter Center, Korea) <3cm w/≤2 tumors • No previous RT to target NCT01963429 tumors • Child-Pugh score ≤7 • ECOG criteria = 0, 1, or 2 Comparing photon RCT PBT + • n=560 Overall December therapy to proton chemotherapy • ≥18 years survival at last 2020 therapy to treat • Histologically or follow-up patients w/lung Photon therapy cytologically proven cancer + NSCLC (Radiation Therapy chemotherapy • Patients w/non- Oncology Group) operable disease or refuse surgery NCT01993810 • Clinical stage TII, TIIIA, TIIIB • Zubrod status = 0-1 • FEV1 ≥ 1 liter Intensity-modulated RCT IMPT • n=360 Rates and August 2023 proton beam therapy • ≥18 years severity of late (IMPT) versus IMRT • Histologically grade 3-5 intensity-modulated documented squamous toxicity photon therapy cell carcinoma of the between IMPT (IMRT) oropharynx and IMRT, (MD Anderson Cancer • ECOG criteria = 0, 1, or 2 evaluated 90 Center) days after treatment NCT01893307 CTCAE: Common Terminology Criteria for Adverse Events; ECOG: Eastern Cooperative Oncology Group; EPIC: Expanded Prostate Cancer Index; FEV1: forced expiratory volume in 1 second; HCC: hepatocellular carcinoma; IMPT: intensity-modulated proton therapy; IMRT: intensity-modulated radiation therapy; NSCLC: non-small cell lung cancer; PBT: proton beam therapy; PSA: prostate specific antigen; RCT: randomized controlled trial; RFA: radiofrequency ablation; RPA: recursive partitioning analysis; RT: radiation therapy; SBPT: stereotactic body proton therapy; SBRT: stereotactic radiation therapy; WHO: World Health Organization Proton Beam Therapy: Final Evidence Report Page 22 WA – Health Technology Assessment March 28, 2014 7. Methods Objectives The primary objectives of the systematic review were to:  Evaluate and compare the published evidence on the impact of proton beam therapy relative to other radiotherapy modalities and non-radiation treatment alternatives on survival, control of cancerous and noncancerous tumors, health-related quality of life, and other patient outcomes for populations with both primary and recurrent disease;  Evaluate and compare the harms of proton beam therapy and treatment alternatives, including generalized effects (e.g., fatigue), specific toxicities relative to treatment location (e.g., bladder and bowel dysfunction in prostate cancer), and secondary malignancy;  Examine the differential effectiveness and safety of proton beam therapy according to patient subgroups of interest, including age, sex, race/ethnicity, disability, presence of comorbidities, tumor characteristics (e.g., tumor volume and location, proliferative status, genetic variation) and treatment protocol (e.g., dose, duration, timing of intervention, use of concomitant therapy); and  Assess the published evidence on costs and cost-effectiveness of proton beam therapy in multiple patient populations. The target populations for this appraisal included patients who received proton beam therapy (PBT) for treatment of primary or recurrent disease. A total of 19 categories (16 cancer types, three types of noncancerous tumors) of disease were selected for this review (see “Patient Populations” on page 27). We did not evaluate the use of PBT for palliative purposes only, as the expert guidance we received suggested that its use for this purpose is currently minimal. We focused primary attention on randomized controlled trials and comparative cohort studies that involved explicit comparisons of PBT to one or more treatment alternatives and measures of clinical effectiveness and/or harm. For the purposes of this review, we distinguished between comparative cohort studies that drew patients from a common pool of subjects and those that involved comparisons of non-contemporaneous case series (i.e., comparison of a current series to a series from another published study or historical control group), given the increased likelihood of selection and/or measurement biases with the latter design. Case series of PBT alone were abstracted and summarized in evidence tables, but were not the primary focus of evaluation for each key question. Proton Beam Therapy: Final Evidence Report Page 23 WA – Health Technology Assessment March 28, 2014 Importantly, studies that involved comparisons of treatment planning algorithms or modeled simulations of outcomes were not explicitly abstracted. As noted in the Background section to this document, there are significant uncertainties that remain with the delivery of proton beams for a variety of tumor types and locations, including physical uncertainty at the end of the beam range and penumbra effects, as well as concerns regarding the effects of neutron radiation produced by PBT and a lack of precise understanding of PBT’s radiobiological effectiveness for all tumor types and tissue depths. Because of these concerns, we felt that any estimation of the clinical significance of PBT therapy must come from studies in which actual patient outcomes were measured. We do recognize and make explicit mention, however, of clinical areas in which simulation studies are likely to remain the cornerstone of evidence, given logistical and ethical challenges posed by conducting clinical trials in these areas (e.g., pediatric tumors, very rare cancers). One notable exception to this rule was the use of modeling to answer questions of cost and/or cost-effectiveness, as clinical outcomes in these studies were typically derived from actual clinical outcome data from other published studies. Uses of PBT and relevant comparators are described in detail in the sections that follow. Of note, while PBT is considered part of a “family” of heavy ion therapies that includes carbon-ion, neon-ion, and other approaches, it is the only heavy ion therapy currently in active use in the U.S. Studies that focused on these other heavy-ion therapies were therefore excluded (unless they involved comparisons to PBT). While all potential harms of PBT and its comparators were recorded, the primary focus was on adverse effects requiring medical attention (where such designations were available). Radiation-related toxicities may have also been labeled “early” (i.e., typically occurring within 90 days of treatment) or “late” (occurring >90 days after treatment or lasting longer than 90 days). In addition, because the risk of secondary malignancy is felt to be of great interest because of its link to radiation of normal tissues, these outcomes were abstracted when reported. Finally, published studies of the economic impact of PBT are summarized in response to Key Question 5 regarding the costs and cost-effectiveness of PBT. In addition, a straightforward budget impact analysis is included that employs data from the HCA to estimate the effects of replacing existing radiation treatments with PBT for certain conditions. Analytic Framework The analytic framework for this review is shown in the Figure on the following page. Note that the figure is intended to convey the conceptual links involved in evaluating outcomes of PBT and its alternatives, and is not intended to depict a clinical pathway through which all patients would flow. Proton Beam Therapy: Final Evidence Report Page 24 WA – Health Technology Assessment March 28, 2014 Analytic Framework: Proton Beam Therapy Quality of Life Patients with Local Tumor Treatment with Control Metastatic a condition Proton Beam Disease Mortality of focus Therapy Tumor Recurrence Local Tumor Symptoms Potential Harms: Acute Toxicity Quality of Life Late Toxicity Treatment Risks Mortality Radiation of Normal Tissue The available literature varies with respect to how directly the impact of PBT is measured. Some studies are randomized or observational comparisons focused directly on survival, tumor control, health-related quality of life, and long-term harms, while in other studies a series of conceptual links must be made between intermediate effectiveness measures (e.g., biochemical recurrence in prostate cancer) or measures of harm (e.g., early toxicity) and longer-term outcomes. Patient Populations The focus of this appraisal was on children and adults treated with PBT for a variety of conditions. The condition categories of interest are listed below, and included 16 cancer types and three types of noncancerous conditions as listed in Table 1 below. Table 1. Conditions of interest for evidence review of proton beam therapy. Condition Category Specific Condition Types Cancer Bone cancer Lung cancer Brain, spinal, & paraspinal tumors Lymphomas Breast cancer Ocular tumors Esophageal cancer Pediatric cancers Gastrointestinal cancers Prostate cancer Gynecologic cancers Sarcomas Head & neck cancers Seminoma Liver cancer Thymoma Noncancerous Conditions Arteriovenous malformations Other benign tumors Hemangiomas Proton Beam Therapy: Final Evidence Report Page 25 WA – Health Technology Assessment March 28, 2014 As mentioned previously, studies of the use of PBT to treat primary and recurrent cancers were included in the project scope, while studies of PBT’s use in palliative care were not. All levels of disease within each condition type were considered for this evaluation. Certain patient subpopulations were also identified as of interest in evaluating whether PBT’s clinical effects and/or harms differed in these groups. These included subpopulations defined by demographic characteristics (e.g., age, sex, race/ethnicity), disability, presence of comorbidities, tumor characteristics (e.g., tumor volume and location, proliferative status, genetic variation) and treatment protocol (e.g., dose, duration, timing of intervention, use of concomitant therapy). Intervention For in-scope uses, all approaches to PBT were considered, including monotherapy, use of PBT as a “boost” mechanism to conventional radiation, and combination therapy with other treatment modalities such as chemotherapy and surgery. Note that comparisons of different doses of PBT were included as part of our evaluation of subgroup data (Key Question 4). As mentioned previously, studies of PBT’s use for curative intent as well as its deployment for “salvage” purposes (i.e., failure of initial therapy or disease recurrence) were considered relevant. We placed no limitations on the use of PBT by manufacturer, software system, or treatment planning protocol. However, where available, both dose and duration of therapy were recorded. Comparators All relevant comparators of interest were included in this evaluation. Primary comparators included other radiation alternatives such as intensity-modulated radiation therapy (IMRT), stereotactic radiation techniques and other external beam therapies, and brachytherapy. Other treatment alternatives were specific to each condition type treated, and may have included chemotherapy, surgical procedures, and other devices (e.g., laser therapy for ocular tumors). Outcomes A variety of patient clinical outcomes were assessed as measures of effectiveness for this evaluation, as listed below:  Disease-free and/or overall survival  Disease-related and/or all-cause mortality  Measures of tumor regression and control  Incidence of metastases Proton Beam Therapy: Final Evidence Report Page 26 WA – Health Technology Assessment March 28, 2014  Tumor recurrence (including intermediate measures such as biochemical recurrence)  Health-related quality of life (HrQoL)  Requirements for subsequent therapy Where possible, our preference was for techniques of survival or actuarial analysis (e.g., Kaplan-Meier, Cox proportional hazards) to measure survival and/or mortality outcomes. We accepted unadjusted rates of these measures if that was the only method used to report them. We also captured other outcomes specific to particular conditions. Examples included visual acuity for ocular tumors and shunt requirements for arteriovenous malformations. Information on the costs and cost-effectiveness of PBT relative to treatment alternatives also was collected from available studies, including initial costs of treatment as well as downstream costs such as management of toxicity and long-term morbidity, requirements for subsequent therapy, and work or productivity loss. Potential Harms While the focus of attention was on adverse effects requiring medical attention, all available data on treatment-related harms were abstracted where available. These included generalized effects from treatment (e.g., fatigue, erythema) as well as more localized toxicities specific to each condition (e.g., urinary incontinence in prostate cancer, pulmonary toxicity in lung or breast cancer). Where reported as such, toxicities were separated into early (≤90 days following treatment) or late (>90 days following treatment) effects. Relevant grades on standardized toxicity scales such as those promulgated by the Radiation Therapy Oncology Group (RTOG) and the European Organization for the Research and Treatment of Cancer (EORTC) were used to determine which toxicities would require medical attention. We also collected information on secondary malignancy risk due to treatment radiation exposure where reported. Because PBT and other radiotherapy alternatives involve delivery of a substantial radiation dose, there is concern that such exposure could lead to development of secondary malignancy in the treated field (or even outside of it), particularly in younger patients or those who have a life expectancy of 15 years or more (Bostrom, 2007). There is considerable controversy on extrapolating cancer death risks from those experienced by adults with high radiation exposure at Hiroshima and Nagasaki to the potential risks at much lower radiation doses. Linear extrapolation has been the approach generally used, although the uncertainties inherent in this approach become progressively greater at lower doses. Also controversial is whether a natural threshold of radiation exposure exists before excess risk from specific exposures can be realized. The current guidance from a variety of regulatory authorities is that no threshold exists, but this has also been intensely debated. On the other hand, exposure to ionizing radiation has increased; a recent estimate indicates that the average per capita annual exposure in the U.S. has risen from approximately Proton Beam Therapy: Final Evidence Report Page 27 WA – Health Technology Assessment March 28, 2014 3.6 milliSieverts (mSv) in the early 1980s to 6.25 mSv in 2006, an increase that has been attributed almost entirely to medical imaging (Schauer, 2009). Historically, the literature on the association of radiotherapy techniques and secondary cancer risk was limited to registry-based studies or dose extrapolations combining information on planned dose with risk coefficients from standards organizations such as the National Council of Radiation Protection and Measurements (NRCP). These studies have not provided definitive answers, however, due to concerns regarding selection bias, changes in technology over long periods of follow-up, and sensitivity to assumptions made in dose-extrapolation models. As a result, there is no consensus regarding the long- term effects of radiation received during PBT or radiation alternatives. We therefore opted to abstract effective radiation dose where reported, and to include explicit measures of the incidence of secondary malignancy where available. Timeframe Data on all relevant measures were abstracted at all relevant timepoints, regardless of study duration. Study Designs Data from both RCTs and selected types of observational studies were considered for measures of effectiveness. Observational studies of interest included those making explicit prospective or retrospective comparisons of PBT to one or more treatment alternatives within the same setting as well as comparisons of non-contemporaneous series of PBT and alternative therapies from different settings. Case series of PBT were abstracted and summarized in evidence tables, but were not a primary focus of the review due to their non-comparative nature. No limits were placed on study selection based on sample size, duration, location, or frequency of outcome measurement. As mentioned previously, studies that involved simulated outcomes only were not included in this review. Literature Search and Retrieval The general timeframe for literature search and retrieval was January 1990 – February 2014. We focused on English-language reports only. As noted previously, RCTs and comparative cohort studies were limited to those comparing PBT with alternative treatment strategies. The one exception was comparisons of different PBT dosing regimens, which were used to inform Key Question 4 (subgroups of interest). Proton Beam Therapy: Final Evidence Report Page 28 WA – Health Technology Assessment March 28, 2014 The electronic databases we searched as part of the systematic review included MEDLINE, EMBASE, and The Cochrane Library (including the Database of Abstracts of Reviews of Effects [DARE]) for health technology assessments (HTAs), systematic reviews, and primary studies. Reference lists of all eligible studies were also searched and cross-referenced against public comments received by the HCA. The strategies used for MEDLINE, EMBASE, and The Cochrane Library are shown in Appendix B. Studies were not further restricted by instrumentation, manufacturer, or testing protocol. Figure 4 on the following page shows a flow chart of the results of all searches for RCTs (n=6), comparative cohort studies (n=29), non-contemporaneous case series (n=8), and single case series (n=260). Proton Beam Therapy: Final Evidence Report Page 29 WA – Health Technology Assessment March 28, 2014 Figure 4. PRISMA flow chart showing results of literature search. Titles and abstracts identified Additional records through MEDLINE, EMBASE, identified through Cochrane and DARE alternate sources n = 14 n = 8,505 Records after duplicates removed n = 7,127 Records screened Records excluded through title/abstract review n = 7,127 n = 6,170 Full-text articles excluded: n = 636 Full-text articles  No outcomes of interest: n = 82 assessed for eligibility  Not a study design of interest: n = 117  Not a patient population of interest: n = 78 n = 957  Dosimetry/simulation studies: n = 277  Case reports: 81  Foreign language: n = 1 Articles included in Articles included in analysis, n = 321* analysis  Randomized trials = 6* n = 321  Comparative cohorts = 29†  Non-contemporaneous case series = 8  Single-arm case series = 260  Economic studies = 16† * Nine studies evaluated six unique randomized trials. † One study reported on clinical and economic outcomes. Proton Beam Therapy: Final Evidence Report Page 30 WA – Health Technology Assessment March 28, 2014 Study Quality We used criteria published by the U.S. Preventive Services Task Force to assess the quality of RCTs and comparative cohort studies, using the categories “good”, “fair”, or “poor”. Guidance for quality rating using these criteria is presented below (AHRQ, 2008).  Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study (follow-up at least 80 percent); reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention to confounders in analysis. In addition, for RCTs, intention to treat analysis is used.  Fair: Studies will be graded "fair" if any or all of the following problems occur, without the fatal flaws noted in the "poor" category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow- up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are accounted for. Intention to treat analysis is done for RCTs.  Poor: Studies will be graded "poor" if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied at all equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention to treat analysis is lacking. Data from all retrieved studies were included in evidence tables regardless of study quality. However, the focus of attention in presentation of results was primarily on good- or fair-quality studies. Study quality was not assessed for single-arm case series, as the focus of quality ratings was on the level of bias in assessing the comparative impact of PBT versus alternatives on measures of effectiveness and harm. The overall strength of evidence for PBT use to treat each condition type was determined primarily on the number of good- or fair-quality comparative studies available for each condition type and key question, although the totality of evidence (including case series) was considered in situations where future comparative study was unlikely (e.g., pediatrics, rare cancers). We followed the methods of the U.S. Agency for Healthcare Research and Quality (AHRQ) in assigning strength of evidence as follows: Low, Moderate, High, and No Evidence (AHRQ, 2014). A “no evidence” rating is made when no studies meeting entry criteria for the review are identified. While the remaining ratings are based on an overall value judgment, this is informed by assessment of the evidence across several domains, as listed below: Proton Beam Therapy: Final Evidence Report Page 31 WA – Health Technology Assessment March 28, 2014  Risk of bias: aspects of study design and conduct, control for confounding, etc.  Consistency: direction and magnitude of findings, use of uniform outcome measures, etc.  Directness: focus on most important clinical outcomes and/or comparisons to most relevant alternatives  Precision: degree of certainty around estimates of treatment effect Net Health Benefit Because of the large number of conditions and comparators under study, a standardized system was used to describe our judgment of the overall net health benefit (that is, taking into account both clinical effectiveness and potential harms) of PBT in comparison to its major treatment alternatives. The five categories of net health benefit were derived from ICER’s rating matrix for clinical effectiveness (Ollendorf, 2010), and are listed on the following page:  Superior: Evidence suggests a moderate-to-large net health benefit vs. comparator(s)  Incremental: Evidence suggests a small net health benefit vs. comparators(s)  Comparable: Evidence suggest that, while there may be tradeoffs in effectiveness or harms, overall net health benefit is comparable vs. comparator(s)  Inferior: Evidence suggests a negative net health benefit vs. comparator(s)  Insufficient: Evidence is insufficient to determine the presence and magnitude of a potential net health benefit vs. comparators(s) When the net health benefit was rated superior, incremental, comparable, or inferior, we have provided additional information on the specific comparisons of both clinical benefits and harms. For example, if we have given an overall rating of an incremental net health benefit, we give information on whether that rating was based on evidence demonstrating small increases in effectiveness with no difference in harms, or on evidence demonstrating equivalent effectiveness and a small reduction in harms. Data Synthesis Because of an expected paucity of RCT data within any single condition type, no attempt was made to quantitatively synthesize available evidence; all analyses were qualitative in nature only. Detailed evidence tables are presented in Appendices C, D and F for all key outcomes and study designs evaluated in this review. Proton Beam Therapy: Final Evidence Report Page 32 WA – Health Technology Assessment March 28, 2014 8. Results Evidence Quality Our summary of the net health benefit of PBT vs. alternative treatments and the strength of available evidence on net health benefit, as well as an evaluation of consistency of these findings with clinical guideline statements and public/private coverage policy, can be found in Table 3 on page 37. Detailed descriptions of the evidence base for each key question can be found in the sections that follow. The level of comparative evidence was extremely limited for certain conditions and entirely absent for others. We identified a total of six RCTs and 37 nonrandomized comparative studies across all 19 condition types. A detailed listing of RCTs can be found in Table 2 on the following page. Importantly, five of the six RCTs involved different treatment protocols for PBT and had no other comparison groups; while these are included for completeness, primary attention was paid to studies (RCTs and otherwise) that compared PBT to an alternative form of treatment. Most of the comparative studies identified also had major quality concerns. For example, nearly all non- randomized comparative studies were retrospective in nature, and many involved comparisons of a PBT cohort to a non-contemporaneous group receiving alternative therapy. Major differences in patient demographics and baseline clinical characteristics as well as duration of follow-up were often noted between groups. Of the 6 RCTs identified, 1, 4, and 1 were judged to be of good, fair, and poor quality respectively. Corresponding figures for non-randomized comparative studies were 1, 20, and 16. We also examined the possibility of publication bias by cross-referencing the results of our literature search with a list of completed randomized controlled trials of PBT available on the U.S. National Institutes of Health’s clinicaltrials.gov website. A single RCT was identified on clinicaltrials.gov (NCT00388804) that has not been published, a study comparing multiple radiation modalities (including PBT) with short-course androgen suppression therapy vs. PBT alone in men with intermediate-risk prostate cancer. The study was terminated due to slower-than-expected patient accrual. As noted on Table 3, we judged PBT to have superior net health benefit for ocular tumors, and incremental net health benefit for adult brain/spinal tumors and pediatric cancers. We felt PBT to be comparable to alternative treatment options for patients with liver, lung, and prostate cancer as well as one noncancerous condition (hemangiomas). Importantly, however, the strength of evidence was low or moderate for all of these conditions. We determined the evidence base for all other condition types to be insufficient to determine net health benefit, including two of the four most prevalent cancers in the U.S.: breast and gastrointestinal (lung and prostate are the other two). Current authoritative guideline statements and coverage policies relevant to Washington State reflect these uncertainties through coverage restrictions or limitations on recommendations for use. Proton Beam Therapy: Final Evidence Report Page 33 WA – Health Technology Assessment March 28, 2014 The lack of comparative data for rare and childhood cancers is not surprising, and in fact is considered appropriate by many (Macbeth, 2008). Because information from dosimetry, planning, and simulation studies indicates that the radiation dose from PBT would be consistently lower than other radiation modalities in children, and because of the increased sensitivity of children to any level of ionizing radiation in comparison to adults, many in the clinical community feel that there is not sufficient equipoise to ethically justify comparative study of PBT in pediatric populations (Efstathiou, 2013; Macbeth, 2008). It should be noted, however, that this opinion is not universal, and other commentators have noted that the clinical data accrued to date on PBT in pediatric cancers is lacking critical information on measures of long-term effectiveness and harm (De Ruysscher, 2012). The situation is more complex with adult cancers, particularly those that are more prevalent. As mentioned in the Background, significant uncertainties remain regarding proton physics and the relative biological effectiveness of PBT in all tissues (Rana, 2013; Paganetti, 2002; Goitien, 2008). It is because of these unknowns that we opted in this review not to abstract information from dosimetry, planning, and simulation studies, as evidence on the clinical impact of these uncertainties can only be obtained by measuring patient outcomes. Table 2. Randomized controlled trials of proton beam therapy. Cancer Type Measurement of Measurement Comparison N (Author, Year) Clinical Outcomes of Harms Prostate Dose/fractionation 82 Yes Yes (Kim, 2011) comparison Prostate Dose/fractionation 391 Yes Yes (Zietman, 2010) comparison Uveal melanoma Dose/fractionation 188 Yes Yes (Gragoudas, 2000) comparison Skull-base chordoma Dose/fractionation 96 No Yes and chondrosarcoma comparison (Santoni, 1998) Uveal melanoma PBT vs. PBT + TTT 151 No Yes (Desjardins, 2006) Prostate PBT + photon vs. 202 Yes Yes (Shipley, 1995) Photon PBT: proton beam therapy; TTT: transpupillary thermotherapy Proton Beam Therapy: Final Evidence Report Page 34 WA – Health Technology Assessment March 28, 2014 Table 3. Summary table assessing strength of evidence, direction of benefit, and consistency with relevant guideline statements and coverage policy. Net Health Incidence Type of Net Strength of Guideline Condition Benefit vs. Coverage Policies (per 100,000) Health Benefit Evidence Recommendations Comparators Cancer Bone 1.3 Insufficient --- + M M Brain/spinal 9.6 Incremental B: = H: ↓ + U U Breast 97.7 Insufficient --- o NM NR/NC Esophageal 7.5 Insufficient --- o NM NR/NC GI 100.6 Insufficient --- o NM NR/NC Gynecologic 38.2 Insufficient --- o NM NR/NC Head/neck 17.2 Insufficient --- + NM M Liver 12.8 Comparable B: = H: = + NM M Lung 95.0 Comparable B: = H: = ++ M M Lymphomas 32.9 Insufficient --- o NR/NC NR/NC Ocular 1.2 Superior B: ↑ H: ↓ ++ U U Pediatric 9.1 Incremental B: = H: ↓ ++ U U Prostate 99.4 Comparable B: = H: = ++ M M Sarcomas 4.8 Insufficient --- o NM M Seminoma 4.0 Insufficient --- o NM NM Thymoma 0.2 Insufficient --- o NM NM Noncancerous AVMs 1.0 Insufficient --- o NM M Hemangiomas 2.0 Comparable B: = H: = + NM NM Other 2.0 Insufficient --- o NM M B: Benefits; H: Harms Strength of Evidence: Low=+; Moderate=++; High=+++; No evidence=o Legend: U=Universally recommended or covered; M=Mixed recommendations or coverage policies; NM=Not mentioned in guidelines or coverage policies; NR/NC=Not recommended or not covered Proton Beam Therapy: Final Evidence Report Page 35 WA – Health Technology Assessment March 28, 2014 Impact of Proton Beam Therapy with Curative Intent on Patient Outcomes for Multiple Cancers and Noncancerous Conditions (KQ1) Evidence on the effects of PBT with curative intent (i.e., as a primary therapeutic option) are summarized by condition in the sections that follow and presented in Appendices C, D, and F. As with all of the key questions, the primary focus was on active comparisons of PBT to one or more therapeutic alternatives, although findings from available case series are also summarized for each topic. Note that, given the paucity of comparative studies, all studies are summarized regardless of quality. Cancers Bone Tumors We identified a single poor-quality retrospective comparative cohort study that evaluated PBT for primary and recurrent sacral chordomas in 27 patients. Among these patients 21 were treated with surgery and combination PBT /photon therapy (mean radiation dose: 72.8 Gray Equivalents [GyE]), in comparison to six patients who received PBT/photons alone (mean dose: 70.6 GyE) (Park, 2006). Two- thirds of patients in each group were male, but groups differed substantially in terms of age (mean of 68 years in the radiation-only group vs. 54 years in the radiation+surgery group) and duration of follow-up (mean of 5 and 8 years in the two groups). For patients with primary tumors, Kaplan-Meier estimates of local control, disease-free survival and overall survival exceeded 90% among those treated by surgery and radiation (n=14). Only two of the six patients with primary tumors received radiation alone, one of whom had local failure at four years, distant metastases at five years, and died at 5.5 years. (NOTE: see KQ2 on page 44 for discussion of results specific to recurrent cancers.) Four case series were identified involving 166 patients treated for a variety of bone cancers (Chen, 2013; Ciernik, 2011; Staab, 2011; Hug, 1995). Overall survival ranged from 50-78% in these studies. Brain, Spinal, and Paraspinal Tumors We identified two poor-quality retrospective comparative cohort studies of primary PBT for brain, spinal, and paraspinal tumors. One was an evaluation of PBT (mean dose: 54.6 GyE) vs. photon therapy (mean dose: 52.9 Gy) in 40 adults (mean age: 32 years; 65% male) who received surgical and radiation treatment of medulloblastoma at MD Anderson Cancer Center (Brown, 2013). PBT patients were followed for a median of 2.2 years, while photon patients were followed for a median of nearly five years. No statistical differences between radiation modalities were seen in Kaplan-Meier assessment of either overall or progression-free survival at two years. A numeric difference was seen in the rate of local or regional failure (5% for PBT vs. 14% for photon), but this was not assessed statistically. The second study involved 32 patients treated for intramedullary gliomas at Massachusetts General Hospital (Kahn, 2011) with either PBT (n=10) or IMRT (n=22). While explicit comparisons were made between groups, the PBT population was primarily pediatric (mean age: 14 years), while the IMRT Proton Beam Therapy: Final Evidence Report Page 36 WA – Health Technology Assessment March 28, 2014 population was adult (mean age: 44 years). Patients in both groups were followed for a median of 24 months; dose was >50 GyE or Gy in approximately 75% of patients. While the crude mortality rate was lower in the PBT group (20% vs. 32% for IMRT, not tested), in multivariate analyses controlling for age, tumor pathology, and treatment modality, PBT was associated with significantly increased mortality risk (Hazard Ratio [HR]: 40.0, p=0.02). The rate of brain metastasis was numerically higher in the PBT group (10% vs. 5% for IMRT), but this was not statistically tested. Rates of local or regional recurrence did not differ between groups. We identified six case series of brain, spinal, and other nervous system cancers (see Appendix F, Table 2 for specific citations). Five-year overall survival ranged from 23-100% depending on disease and stage. Breast Cancer We identified no comparative studies of the clinical effectiveness of primary PBT in breast cancer. We identified four case series of PBT in 112 patients with breast cancer (see Appendix F, Table 3 for specific citations). Overall survival ranged from 96-100% in these studies. Esophageal Cancer We identified no comparative studies of the clinical effectiveness of primary PBT in esophageal cancer. There were five PBT case series comprising 208 patients with esophageal cancer (see Appendix F, Table 4 for specific citations). Overall survival ranged from 21-100% depending on disease stage. Gastrointestinal Cancers We identified no comparative studies of the clinical effectiveness of primary PBT in gastrointestinal cancers. We identified four case series of PBT in 180 patients with gastrointestinal cancers (three of which were in pancreatic cancer, one in cholangiocarcinoma) (see Appendix F, Table 5 for specific citations). One-year survival ranged from 36-79% depending on disease location and stage. Gynecologic Cancers We identified no comparative studies of the clinical effectiveness of primary PBT in gynecologic cancers. Two gynecologic case series were identified in 40 patients (see Appendix F, Table 6 for specific citations). Overall survival ranged from 59-93% in these studies. Head and Neck Cancers We identified two poor-quality retrospective comparative cohorts of primary PBT in head and neck cancer. One was an evaluation of 33 patients treated with either PBT alone or PBT+photon therapy to a target dose of 76 Gy for a variety of head and neck malignancies in Japan (Tokuuye, 2004). Treatment groups differed substantially in terms of age (mean: 67 vs. 54 years for PBT and PBT+photon respectively), gender (82% vs. 44% male), and duration of follow-up (mean: 5.9 vs. 3.1 years). Numeric differences in favor of PBT+photon therapy were seen for local control, recurrence, and mortality, but these were not statistically tested, nor were multivariate adjustments made for differences between groups. Proton Beam Therapy: Final Evidence Report Page 37 WA – Health Technology Assessment March 28, 2014 The other study was a very small (n=6) comparison of endoscopic resection followed by either PBT or IMRT as well as endoscopy alone in patients with malignant clival tumors (Solares, 2005). Limited description of the study suggests that PBT was used only in cases of residual disease, while it is unclear whether IMRT was also used in this manner or as an adjuvant modality. One of the IMRT patients died of causes unrelated to disease; no other deaths were reported. A total of 27 PBT case series were identified that involved patients with head, neck, or skull base tumors (see Appendix F, Table 7 for specific citations). Five-year survival ranged widely by and even within cancer type; for example, survival ranged from 50-100% for skull base tumors. Liver Cancer We identified two fair-quality prospective comparative cohort studies from Japan with evidence of the clinical effectiveness of primary use of PBT in liver cancer. One was an evaluation of 35 patients with unresectable hepatocellular carcinoma (HCC) who were treated with PBT (mean dose: 76.5 GyE) either alone or in combination with chemotherapy and were followed for up to 4 years (Matsuzaki, 1995). While statistical testing was not performed, rates of local tumor control and the proportion of patients experiencing reductions in tumor volume were nearly identical between groups. The other study was also prospective but compared PBT to another heavy-ion modality not in circulation in the U.S. (carbon ion). In this study, a fair-quality comparison of 350 patients (75% male; age ≥70: 50%) with HCC who received PBT (53-84 GyE) or carbon-ion (53-76 GyE) therapy and were followed for a median of 2.5 years (Komatsu, 2011), no statistically-significant differences were observed in 5-year Kaplan-Meier estimates of local control, no biological evidence of disease, or overall survival between treated groups. We identified 21 case series focusing on PBT for the treatment of liver cancer (see Appendix F, Table 8 for specific citations), almost all of which were conducted in Japan. Five-year survival estimates ranged from 21-58% in these studies. Lung Cancer We identified three fair-quality comparative cohort studies examining the clinical effectiveness of PBT in lung cancer. Two studies retrospectively compared outcomes with PBT to those with IMRT or older three-dimensional conformal radiotherapy (3D-CRT) at MD Anderson Cancer Center (Lopez Guerra, 2012; Sejpal, 2011). The Lopez Guerra study involved 250 patients with non-small-cell lung cancer (NSCLC) (median age 71.5 years, 57% male) who were treated with 66 Gy of photons or 74 GyE of protons and followed for up to one year to assess a key measure of lung function known as diffusing capacity of lung for carbon monoxide (DLCO). While this measure did not differ between PBT and IMRT at 5-8 months after treatment, DLCO declined significantly more in the 3D-CRT group as compared to PBT after adjustment for pretreatment characteristics and other lung function measures (p=0.009). Proton Beam Therapy: Final Evidence Report Page 38 WA – Health Technology Assessment March 28, 2014 The study by Sejpal and colleagues focused on survival in 202 patients (median age 64 years, 55% male) with locally-advanced, unresectable NSCLC who were followed for a median of 1.5 years and treated with 74 GyE of PBT or 63 Gy of either IMRT or 3D-CRT (Sejpal, 2011). Actuarial estimates of median overall survival were 24.4, 17.6, and 17.7 months for PBT, IMRT, and 3D-CRT respectively, although these differences were not statistically significant (p=0.1061). A third study was a prospectively-measured cohort but, as with the study of liver cancer mentioned above, compared PBT to carbon ion therapy, evaluating 111 Japanese NSCLC patients (median age 76 years, 67% male) over a median of 3.5 years (Fujii, 2013). No statistically-significant differences between groups were observed in three-year actuarial estimates of local control, progression-free survival, or overall survival. A total of 15 case series were identified with information on outcomes in patients with lung cancer (see Appendix F, Table 9 for study citations). Overall 2-year survival (the most common measured timepoint) ranged from 64-98% depending on cancer stage. Lymphomas We identified no comparative studies or case series focusing on the clinical effectiveness of primary PBT in lymphomas. Ocular Tumors In comparison to other cancer types, the evidence base for ocular tumors was relatively substantial. A total of seven comparative studies were identified of the clinical benefits of primary PBT in such cancers—a single RCT, four retrospective cohort studies, a comparison of a recent case series to the treatment groups from the RCT, and a comparison of noncontemporaneous case series. The RCT compared PBT alone to a combination of PBT and transpupillary thermotherapy (TTT) in 151 patients (mean age: 58 years; 52% male) treated for uveal melanoma and followed for a median of 3 years in France (Desjardins, 2006). Combination therapy was associated with a statistically-significantly (p=0.02) reduced likelihood of secondary enucleation; no other outcomes differed significantly between groups. In a separate, poor-quality comparison of these findings to a separate series of patients undergoing PBT with endoresection of the scar (Cassoux, 2013), rates of secondary enucleation did not differ between groups, but rates of neovascular glaucoma were significantly lower in the PBT+endoresection group vs. the groups from the RCT (7% vs. 58% and 49% for PBT alone and PBT+TTT respectively, p<0.0001). Of note, however, median follow-up was less than two years in the PBT+endoresection series vs. 9 years in the RCT. Three of the cohort studies were all fair-quality and involved comparisons to surgical enucleation in patients with uveal melanoma at single centers (Mosci, 2012; Bellman, 2010; Seddon, 1990). PBT was associated with statistically-significant improvements in overall survival rates relative to enucleation at 2-5 years in two of these studies (Bellman, 2010; Seddon, 1990). Rates of metastasis-related and all cancer-related death were statistically-significantly lower among PBT patients through two years of Proton Beam Therapy: Final Evidence Report Page 39 WA – Health Technology Assessment March 28, 2014 follow-up in the Seddon study (n=1,051), but were nonsignificant at later timepoints (Seddon, 1990). The 5-year metastasis-free survival rate in the Bellman study (n=67) was 50% higher among PBT patients in a Cox regression model controlling for baseline characteristics (59.0% vs. 39.4% for enucleation, p=0.02). In the third study, Kaplan-Meier curves for all-cause mortality, melanoma-related mortality and metastasis-free survival did not statistically differ for 132 patients treated with PBT and enucleation (Mosci, 2012). Metastasis-free survival also did not differ in Cox regression adjusting for age, sex, and tumor thickness. Another fair-quality study assessed the impact of PBT + chemotherapy vs. PBT alone in 88 patients with uveal melanoma (aged primarily between 20-55 years; 63% male) who were followed for 5-8 years (Voelter, 2008). Five-year overall survival rates did not statistically differ between groups on either an unadjusted or Cox regression-adjusted basis. Finally, a poor-quality comparison of noncontemporaneous case series evaluated treatment with PBT + laser photocoagulation or PBT alone in 56 patients with choroidal melanoma (Char, 2003). At one year, there were no differences in visual acuity between groups. A total of 28 case series were identified in ocular cancers with information on the effects of PBT treatment for primary tumors (see Appendix F, Table 11 for specific citations). Estimates of 5-year overall survival ranged from 69-100% in these studies. Pediatric Cancers We identified no comparative studies of the clinical effectiveness of primary PBT in pediatric cancers. A total of 35 case series were identified of PBT in a variety of childhood cancers (see Appendix F, Table 12 for specific citations). Overall survival ranged from 50-100% in these series at a variety of timepoints. Prostate Cancer The largest evidence base available was for prostate cancer (10 studies). However, only 6 of these studies reported clinical outcomes and compared PBT to alternative treatments. These included an RCT, a prospective comparative cohort, and four comparisons of noncontemporaneous case series. (NOTE: comparisons of different dose levels of PBT are reported as part of the evidence base for Key Question 4 on patient subgroups.) The included RCT was a fair-quality comparison of 202 patients (median age 69 years) with advanced (stages T3-T4) prostate cancer who were randomized to receive either photon therapy with a proton boost (total dose: 75.2 GyE) or photons alone (67.2 Gy) and were followed for a median of five years (Shipley, 1995). Kaplan-Meier estimates of local tumor control, disease-specific survival, and overall survival were similar at both 5- and 8-year timepoints among the entire intent-to-treat population as well as those completing the trial (n=189). However, in patients with poorly-differentiated tumors (Gleason grades 4 or 5), local control at 8 years was significantly better in patients receiving PBT+photons (85% vs. 40% for photons alone, p=0.0014). Proton Beam Therapy: Final Evidence Report Page 40 WA – Health Technology Assessment March 28, 2014 The prospective cohort study was a fair-quality comparison of patient-reported health-related QoL at multiple timepoints among 185 men (mean age: 69 years) with localized prostate cancer who were treated with PBT, PBT+photons, photons alone, surgery, or watchful waiting (Galbraith, 2001). Overall QoL, general health status, and treatment-related symptom scales were employed. No differences in overall QoL or general health status were observed at 18 months of follow-up, although men treated with PBT monotherapy reported better physical function in comparison to surgery (p=0.01) or photon radiation (p=0.02), and better emotional functioning in relation to photon radiation (p<0.001). Men receiving PBT+photons also reported significantly fewer urinary symptoms at 18 months in comparison to watchful waiting (p<0.01). Outcomes were also assessed in three comparisons of noncontemporaneous case series. One was a fair-quality evaluation of high-dose PBT+photons (79.2 GyE) in 141 patients enrolled in a clinical trial at MGH and Loma Linda University who were matched on clinical and demographic criteria to 141 patients treated with brachytherapy at MGH (Coen, 2012). Patients were followed for a median of eight years. Eight-year actuarial estimates of overall survival, freedom from metastasis, and biochemical failure did not statistically differ between groups. The proportion of patients achieving a nadir PSA level of ≤0.5 ng/mL as of their final measurement was significantly higher In the brachytherapy group (92% vs. 74% for PBT, p=0.0003). Two additional studies were deemed to be of poor quality due to a lack of control for confounding between study populations. One was a comparison of a cohort of 206 brachytherapy patients treated at the University of California San Francisco compared with same MGH/Loma Linda PBT+photon group described above (Jabbari, 2010). The difference in the percentage of patients achieving nadir PSA after a median of 5.4 years of follow-up was similar to that reported in the Coen study above (91% vs. 59%), although statistical results were not reported. Five-year estimates of disease-free survival (using biochemical failure definitions) did not statistically differ between groups. The other study involved comparisons of bowel- and urinary-related QoL in three distinct cohorts receiving PBT (n=95; 74-82 GyE), IMRT (n=153; 76-79 Gy), or 3D-CRT (n=123; 66-79 Gy) (Gray, 2013). Statistical changes were assessed within (but not between) each cohort immediately following treatment as well as at 12 and 24 months of follow-up, and were also assessed for whether the change was considered “clinically meaningful” (>0.5 SD of baseline values). Some differences in QoL decrements were seen at earlier timepoints. However, at 24 months, all groups experienced statistically and clinically significant decrements in bowel QoL, and none of the groups had significant declines in urinary QoL. A fourth, poor-quality comparison of case series (Hoppe, 2013) involved an evaluation of patient- reported outcomes on the Expanded Prostate Cancer Index Composite (EPIC) questionnaire among a cohort of 1,243 patients receiving PBT for prostate cancer at the University of Florida and a group of 204 patients receiving IMRT from a previous multicenter study (Sandler, 2010). Statistically-significant differences between treatment groups were observed for many baseline characteristics, only some of which were adjusted for in multivariate analyses. No differences were observed in summary scores for Proton Beam Therapy: Final Evidence Report Page 41 WA – Health Technology Assessment March 28, 2014 bowel, urinary, and sexual QoL at two years, although more IMRT patients reported specific bowel frequency (10% vs. 4% for PBT, p=0.05) and urgency (15% vs. 7%, p=0.02) problems at two years. We identified eight case series with information on effectiveness in prostate cancer (see Appendix F, Table 13 for specific citations). Rates of overall survival ranged from 71-100% in these studies. Soft Tissue Sarcomas We identified no comparative studies of the clinical effectiveness of primary PBT in sarcomas. Two case series were identified in 41 patients (see Appendix F, Table 14 for specific citations). Overall survival at 3-4 years ranged from 83-87% in these studies. Seminomas We identified no comparative studies or case series focusing on the clinical effectiveness of primary PBT in seminomas. Thymomas We identified no comparative studies or case series focusing on the clinical effectiveness of primary PBT in thymomas. Noncancerous Conditions Arteriovenous Malformations We identified no comparative studies of the clinical effectiveness of primary PBT in arteriovenous malformations. We identified three case series of PBT in AVMs, totaling 78 patients (Nakai, 2012; Hattangadi, 2011; Ito, 2011). Overall survival in these studies ranged from 81-91%. Hemangiomas We identified a single comparative study of PBT’s clinical effectiveness in hemangiomas, a poor-quality retrospective cohort study of 44 patients (mean age 41 years, gender unreported) with diffuse or circumscribed choroidal hemangiomas who were treated with either PBT (20-23 GyE) or photon therapy (16-20 Gy) and followed for an average of 2.5 years (Höcht, 2006). Unadjusted outcomes were reported for the entire cohort only; reduction in tumor thickness, resolution of retinal detachment, and stabilization of visual acuity were observed in >90% of the overall sample. In Kaplan-Meier analysis of outcomes adjusting for differential follow-up between treatment groups, therapeutic modality had no statistically-significant effects on stabilization of visual acuity (p=0.43). Two hemangioma series reported on clinical effectiveness of PBT in 84 patients (Levy-Gabriel, 2009; Hannouche, 1997). Overall survival was 100% in both studies. Proton Beam Therapy: Final Evidence Report Page 42 WA – Health Technology Assessment March 28, 2014 Other Benign Tumors We identified two comparative studies of PBT’s clinical effectiveness in other benign tumors, both of poor quality. One was a retrospective cohort of consisting of 20 patients with giant-cell bone tumors (mean age: 40 years; 35% male) who were treated with PBT+photon therapy (mean: 59 GyE) or photons alone (mean: 52 Gy) and followed for median of 9 years (Chakravati, 1999). Patients could also have received partial tumor resection. Of note, however, the PBT population consisted entirely of young adults (mean age: 23 years), while the photon-only population was much older (mean: 46 years); no attempt was made to control for differences between treatment groups. Rates of disease progression, progression-free survival, and distant metastases were numerically similar between groups, although these rates were not statistically tested. The other study was a small cohort study comparing PBT alone, photon therapy alone, or PBT + photons in 25 patients with optic nerve sheath meningioma (ONSM) (Arvold, 2009). On an overall basis, visual acuity improved in most patients. Rates did not numerically differ between treatment groups, although these were not tested statistically. We identified seven case series with information on the clinical effectiveness of PBT in other benign tumors (primarily meningiomas) (see Appendix F, Table 15 for specific citations). Overall survival ranged from 72-100% in these studies. Proton Beam Therapy: Final Evidence Report Page 43 WA – Health Technology Assessment March 28, 2014 Impact of Proton Beam Therapy on Outcomes in Patients with Recurrent Cancer or Noncancerous Conditions (KQ2) The evidence base comparing PBT to alternative treatment approaches in patients with recurrent disease and/or failure of initial treatment is extremely limited. Across all conditions, a total of seven comparative studies were identified that included patients with recurrent disease or prior failed treatment. In addition, some of these studies included a mix of primary and recurrent disease without formal subgroup or stratified analyses to differentiate outcomes between them. Both comparative studies and case series are described in detail in the sections that follow. Cancers Bone Tumors In a previously-described study of 27 patients with sacral chordomas who were treated with PBT/photon radiation alone or in combination with surgery (Park, 2006), seven radiation/surgery patients and four radiation-only patients had recurrent disease. Among patients in the radiation/surgery group, four patients died of disease 4-10 years after treatment; the remainder was alive with disease at last follow- up. In the radiation-only group, two of four patients died of disease at 4-5 years of follow-up; the other two were alive with disease at last follow-up. No case series were identified that were comprised of all or a majority of recurrent cancers. Brain, Spinal, and Paraspinal Tumors We identified no comparative studies or case series of the clinical effectiveness of PBT for recurrent disease in patients with brain, spinal, and paraspinal tumors. Breast Cancer We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with breast cancer. Esophageal Cancer We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with esophageal cancer. Gastrointestinal Cancers We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with gastrointestinal cancers. Proton Beam Therapy: Final Evidence Report Page 44 WA – Health Technology Assessment March 28, 2014 Gynecologic Cancers We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with gynecologic cancers. Head and Neck Cancers In a previously-described study comparing PBT with or without photon radiation in 33 patients with a variety of head and neck cancers (Tokuuye, 2004), four patients were identified as having recurrent disease, three of whom received PBT alone. Two of the three PBT-only patients were alive with local tumor control at last follow-up (5 and 17 years respectively); one patient had their cancer recur three months after PBT and died in month 7 of follow-up. The one PBT+photon patient died at 2.5 years of follow-up, but was described as having local tumor control. Two case series were identified with information on recurrent or persistent disease in 32 patients (McDonald, 2013; Lin, 1999). Overall survival was reported to be 50-80% at two years. Liver Cancer Two studies were identified with information on recurrent disease. One was a poor-quality comparison of PBT to conventional photon radiation in eight patients with recurrent HCC after hepatectomy (Otsuka, 2003). Five patients were treated with PBT (68.8-84.5 GyE), and three with photons (60-70 Gy). Seven of eight patients died of liver failure or lung metastasis a median of 1.5 years after radiation; the one patient alive at the end of follow-up was a photon patient. The rate of local tumor control was 78%, and did not differ between treatment groups. The other study was a previously-described prospective comparison of PBT to carbon-ion therapy in 350 patients with primary or recurrent HCC (Komatsu, 2011). No subgroup analyses were performed, but prior treatment history for HCC was found not to have a statistically-significant impact on local tumor control (p=0.73). Prior treatment was not examined as a risk factor for overall survival, however. Two case series were identified with information on PBT in populations that were comprised mostly or all with liver cancer (Abei, 2013; Fukumitsu, 2009). Five-year overall survival estimates ranged from 33- 39% in these studies. Lung Cancer In a previously-described study of patients with locally-advanced, unresectable NSCLC who were treated with PBT, IMRT, or 3D-CRT (Sejpal, 2011), 22% of the study sample was identified as having a prior malignancy of any type. The effects of prior malignancy on overall survival were not reported, however. One case series was identified with data on 33 PBT patients with recurrent disease (McAvoy, 2013). Overall survival was estimated to be 47% and 33% at one and two years respectively. Proton Beam Therapy: Final Evidence Report Page 45 WA – Health Technology Assessment March 28, 2014 Lymphomas We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with lymphomas. Ocular Tumors We identified a single comparative study of PBT in recurrent ocular cancer. In this fair-quality, comparative cohort study, a total of 73 patients with uveal melanoma had recurrence of disease following an initial course of PBT at Massachusetts General Hospital (Marucci, 2011). Patients (mean age: 58 years) were treated with either a second course of PBT (70 GyE) in five fractions or surgical enucleation and followed for 5-7 years. The likelihood of overall survival at five years was significantly (p=0.04) longer in the PBT group (63% vs. 36% for enucleation), as was the probability of being free of metastasis at this timepoint (66% vs. 31% respectively, p=0.028). Findings were similar after Cox proportional hazards regression adjusting for tumor volume and year of retreatment as well as patient age. The likelihood of local tumor recurrence at five years was 31% in the PBT group. No local recurrences were found in the enucleation group, which is not surprising given the nature of the treatment. Three case series were identified in which most or all patients had recurrent ocular cancers (Lumbroso- LeRouic, 2006; Marucci, 2006; Wuestmeyer, 2006). Overall survival ranged from 74-100% in these studies. Pediatric Cancers We identified no comparative studies of the clinical effectiveness of PBT for recurrent disease in patients with pediatric cancers. Two case series were identified in which most or all patients had recurrent disease (Chang, 2011; Hug, 2002b). Overall survival ranged from 85-100% in these studies. Prostate Cancer We identified no comparative studies of the clinical effectiveness of PBT for recurrent disease in patients with prostate cancer. We identified no case series that focused on patients with recurrent prostate cancer. Soft Tissue Sarcomas We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with sarcomas. Seminomas We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with seminomas. Proton Beam Therapy: Final Evidence Report Page 46 WA – Health Technology Assessment March 28, 2014 Thymomas We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with thymomas. Noncancerous Conditions Arteriovenous Malformations We identified no comparative studies or case series of the clinical effectiveness of PBT for recurrent disease in patients with arteriovenous malformations. Hemangiomas We identified no comparative studies or case series focusing on the clinical effectiveness of PBT for recurrent disease in patients with hemangiomas. Other Benign Tumors In a previously-described retrospective cohort of consisting of 20 patients with giant-cell bone tumors who were treated with PBT+photon therapy or photons alone (Chakravati, 1999), five of 20 were identified as having recurrent disease. Two of the five were treated with PBT+photon therapy, one of whom had progression of disease at eight months but no further progression after retreatment at five years of follow-up. The other patient was free of local progression and metastases as of 9 years of follow-up. In the three photon patients, one had local progression at 12 months but no further progression as of year 19 of follow-up, one patient was free of progression and metastases as of five years of follow-up, and one patient had unknown status. We identified a single case series with information on PBT’s effects in patients with recurrent meningioma (29 of 46 total patients) (Wenkel, 2000). Overall survival was 93% at 5 years and 77% at 10 years. Proton Beam Therapy: Final Evidence Report Page 47 WA – Health Technology Assessment March 28, 2014 Comparative Harms of Proton Beam Therapy in Patients with Multiple Cancers or Noncancerous Conditions (KQ3) As with information on clinical effectiveness, data on potential harms of PBT come from RCTs, comparative cohort studies, and case series, although comparative harms data are still lacking for many condition types. Across all condition types, a total of 25 studies reported comparative information on treatment-related harms; differences in the types of harms relevant to each condition, as well as variability in harms classification even within conditions, precludes any attempt to summarily present harms data across all 19 condition categories. However, summary statements regarding our overall impression of the effects of PBT on patient harms are provided within each condition type in the sections that follow. In addition, summary statistics from case series data on harms requiring medical attention are provided for each cancer type, with a focus on severe (grade 3) or life-threatening (grade 4) events only. Secondary Malignancy Of note, observational data on secondary malignancy with PBT are generally lacking. Two studies were identified with comparative information. One was a fair-quality matched retrospective cohort study comparing 1,116 patients in a linked Medicare-SEER database who received either PBT or photon radiation for a variety of cancers and were followed for a median of 6.4 years (Chung, 2013). On an unadjusted basis, the incidence rates of any secondary malignancy and malignancies occurring in the prior radiation field were numerically lower for PBT, but not statistically-significantly so. After adjustment for age, sex, primary tumor site, duration of follow-up, and year of diagnosis, PBT was associated with a risk of secondary malignancy approximately one-half that of photon therapy (HR=0.52; 95% CI: 0.32, 0.85; p=0.009). There are challenges with these findings, however. First and foremost, the lower rate of secondary malignancy with PBT appeared to be manifested almost entirely in the first five years after radiotherapy, a time period in which a second cancer event is not typically attributed to prior radiation (Bekelman, 2013). In addition, patients were accrued over a very long time period (1973- 2001), only the very end of which included highly conformal photon techniques like IMRT. The second study was a poor-quality retrospective cohort study comparing PBT to photon radiotherapy in 86 infants who were treated for retinoblastoma and followed for a median of 7 years (PBT) or 13 years (photon radiotherapy) (Sethi, 2013). Therapy was received at two different centers (PBT at MGH and photon radiotherapy at Children’s Hospital Boston). Kaplan-Meier analyses were conducted to control for differential follow-up but no adjustments were made for other differences between groups. Ten-year estimates of the cumulative incidence of secondary malignancy were numerically lower for PBT, but not statistically-significantly so (5% vs. 14% for photon, p=0.12). However, when malignancies were restricted to those occurring in-field or thought to be radiation-induced, a significant difference in favor of PBT was observed (0% vs. 14%, p=0.015). In addition, significant differences in favor of PBT in Proton Beam Therapy: Final Evidence Report Page 48 WA – Health Technology Assessment March 28, 2014 both cumulative incidence and radiotherapy-related malignancy were observed for the subgroup of patients with hereditary disease. Other harms are presented in detail for each condition type in the sections that follow. Cancers Bone Tumors Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with bone cancer. In a previously-described study of 27 patients with sacral chordomas who were treated with PBT/photon radiation alone or in combination with surgery (Park, 2006), multiple descriptive harms were reported. Patients receiving radiation alone reported numerically lower rates of abnormal bowel or bladder function as well as difficulty ambulating in comparison to those receiving combination therapy, but rates were not statistically tested. PBT patients also reported higher rates of return to work, although this was also not tested statistically. Of the four bone cancer case series, three reported data on harms. Toxicities were minimal in all but one study, which reported late grade 3 and 4 effects in 15% and 16% of patients respectively (Ciernik, 2011). Brain, Spinal, and Paraspinal Tumors Limited, low-quality evidence suggests that PBT is associated with reductions in acute radiation- related toxicity relative to photon radiation in patients with brain and spinal tumors. In a previously-described study comparing PBT to photon therapy in 40 adult patients treated for medulloblastoma (Brown, 2013), PBT was associated with statistically-significantly lower rates of weight loss (median % of baseline: -1.2% vs. 5.8% for photon, p=0.004) as well as requirements for medical management of esophagitis (5% vs. 57% respectively, p<0.001). PBT patients also experienced less RTOG grade 2 or greater nausea and vomiting (26% vs. 71%, p=0.004). In a second poor-quality study comparing primarily 10 pediatric patients (mean age: 14 years) receiving PBT for spinal cord gliomas to 22 adults receiving IMRT for the same condition (mean age: 44 years) (Kahn, 2011), no cases of long-term toxicity or myelopathy were reported in either group. Minor side- effect rates were reported for the overall cohort only. In two case series grading severity of adverse effects in 39 patients with glioma or glioblastoma (Hauswald, 2012; Mizumoto, 2010), grade 3 and 4 hematologic effects occurred in 65% and 30% of patients respectively. In one study, 10% of patients also developed grade 3 leukoencephalopathy (Mizumoto, 2010). Proton Beam Therapy: Final Evidence Report Page 49 WA – Health Technology Assessment March 28, 2014 Breast Cancer Evidence is insufficient to determine the comparative harms of PBT in patients with breast cancer. We identified no comparative studies of the potential harms of PBT in patients with breast cancer. Two case series graded the severity of treatment-related harms in breast cancer (MacDonald, 2013; Bush, 2011). Acute effects grade 3 or higher were recorded in 0% and 8% of patients in these studies respectively. No late effects were observed. Esophageal Cancer Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with esophageal cancer, particularly in comparison to IMRT. Two studies were identified that examined comparative harms in patients treated with PBT for esophageal cancer. One was a relatively large, fair-quality, retrospective comparative cohort study of 444 patients (median age: 61 years; 91% male) who were treated with chemotherapy and radiation (PBT, IMRT, or 3D-CRT) followed by surgical resection (Wang, 2013). Patients were followed for up to 60 days after hospital discharge. After adjustment for patient characteristics and clinical variables, 3D-CRT was associated with a significantly greater risk of postoperative pulmonary complications vs. PBT (Odds Ratio [OR]: 9.13, 95% CI: 1.83, 45.42). No significant differences were observed between PBT and IMRT, however. No differences in the rate of gastrointestinal complications were observed for any treatment comparison. In addition, a fair-quality comparative study was identified that examined early impact on lung inflammation and irritation in 75 patients receiving PBT, IMRT, or 3D-CRT for esophageal cancer (McCurdy, 2013); patients were followed for up to 75 days following radiation. Nearly all outcome and toxicity measures were reported for the entire cohort only. However, the rate of pneumonitis was found to be significantly higher among PBT patients (33% vs. 15% for IMRT/3D-CRT, p=0.04). Of the six case series evaluating esophageal cancer, five reported data on harms in 278 patients. Commonly reported acute effects were grade 3 pneumonitis (2-7%) and esophagitis (5-12%). Three studies identified late grade 5 effects in 2-5% of patients (Lin, 2012; Mizumoto, 2010; Sugahara, 2005). Gastrointestinal Cancers Evidence is insufficient to determine the comparative harms of PBT in patients with gastrointestinal cancers. We identified no comparative studies of the potential harms of PBT in patients with gastrointestinal cancers. A total of seven case series identified acute and late effects in 255 patients. Grade 3 and 4 acute effects consisted primarily of hematologic and gastrointestinal harms, ranging from 0-100%. Reported late effects also varied (0-20%) with two studies reporting late grade 5 events in 2-3% of patients (Takatori, 2013; Terashima, 2012). Proton Beam Therapy: Final Evidence Report Page 50 WA – Health Technology Assessment March 28, 2014 Gynecologic Cancers Evidence is insufficient to determine the comparative harms of PBT in patients with gynecologic cancers. We identified no comparative studies of the potential harms of PBT in patients with gynecologic cancers. One of two identified case series reported on late effects in 25 patients with uterine cervical carcinoma (Kagei, 2003). Grade 4 gastrointestinal and genitourinary harms were each identified in 4% of patients. Head and Neck Cancers Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with head and neck cancer. In a previously-described study comparing PBT with versus without photon radiation in 33 patients with a variety of head and neck cancers (Tokuuye, 2004), rates of tongue ulceration, osteonecrosis, and esophageal stenosis differed somewhat between treatment groups, but were not statistically tested. Overall toxicity rates were estimated to be 22.8% at both three and five years, but were not stratified by treatment modality. In a separate, fair-quality study comparing rates of vision loss from radiation-induced optic neuropathy in 75 patients treated with PBT or carbon-ion therapy for head and neck or skull base tumors (Demizu, 2009), unadjusted rates of vision loss were similar between modalities (8% and 6% for PBT and carbon- ion respectively, not statistically tested). In multivariate analyses controlling for demographic and clinical characteristics, treatment modality had no effect on rates of vision loss (p=0.42). Another comparison of PBT and carbon-ion therapy in 59 patients with head and neck or skull base tumors (Miyawaki, 2009) was of poor quality (due to no control for differences between patient groups) and focused on the incidence of radiation-induced brain changes. The incidence of CTCAE brain injury of any grade was significantly (p=0.002) lower in the PBT group. MRI-based assessment of brain changes showed a lower rate in the PBT group (17% vs. 64% for carbon-ion), although this was not tested statistically. Harms were reported in 18 case series of PBT in head and neck cancers. Rates of severe toxicities ranged widely depending on cancer type. For example, rates of grade 3 or worse mucositis ranged from 6-30%. Rates of severe complications such as temporal lobe damage and cerebrospinal fluid leakage were <5% in most studies. Liver Cancer Limited, low-quality evidence suggests that PBT is associated with comparable rates of toxicity to other radiation modalities in patients with liver cancer. Two comparative studies were identified with comparative information on radiation-related harms. In a previously-described study of eight patients with recurrent HCC after hepatectomy (Otsuka, 2003), there were no instances of bone marrow depression or gastrointestinal complications in either group. Serum aspartate aminotransferase (AST) level s increased in the three photon patients and 4/5 PBT patients, although this was not tested statistically. Proton Beam Therapy: Final Evidence Report Page 51 WA – Health Technology Assessment March 28, 2014 In the other study, a previously-described comparison of PBT to carbon-ion therapy in 350 patients with primary or recurrent HCC (Komatsu, 2011), rates of toxicities as graded by the Common Terminology Criteria for Adverse Events (CTCAE) framework were comparable between groups, including dermatitis, GI ulcer, pneumonitis, and rib fracture. The rate of grade 3 or higher toxicities was similar between groups (3% vs. 4% for PBT and carbon-ion respectively), although this was not statistically tested. Potential harms were reported in 23 case series. Rates of grade 3 toxicities ranged from 0-23% (higher rates observed with hematologic events). Rates of late grade 3 effects were ≤2%. Grade 4 events were reported in one series (rib fracture in 4%, bile duct stenosis and hepatic failure in 7%). Lung Cancer Moderate evidence suggests that rates of treatment-related toxicities with PBT are comparable to those seen with other radiation modalities in patients with lung cancer. A total of three comparative studies assessed harms in patients with lung cancer. One was a study of severe radiation-induced esophagitis (within six months of treatment) among 652 patients treated for NSCLC with PBT, IMRT, or 3D-CRT at MD Anderson Cancer Center (Gomez, 2012). Rates of grade 3 or higher esophagitis were 6%, 8%, and 28% for PBT, 3D-CRT, and IMRT respectively (p<.05 for PBT and 3D- CRT vs. IMRT). In a previously-described noncontemporaneous case series comparison of patients with locally- advanced, unresectable NSCLC who were treated with PBT, IMRT, or 3D-CRT (Sejpal, 2011), hematologic toxicity rates did not differ by radiation modality. Significant differences in favor of PBT were seen in rates of grade 3 or higher esophagitis (5%, 39%, and 18% for PBT, IMRT, and 3D-CRT respectively, p<0.001) as well as pneumonitis (2%, 6%, and 30%, p<0.001), while rates of grade 3 or higher dermatitis were significantly greater in the PBT group (24% vs. 17% and 7% for IMRT and 3D-CRT, p<0.001). Finally, in a previously-described comparison of PBT to carbon-ion therapy in 111 patients in Japan (Fujii, 2013), rates of pneumonitis, dermatitis, and rib fracture did not differ statistically between radiation modalities across all toxicity grades. Harms were reported in 14 lung cancer case series. Rates of grade 3 or worse effects ranged from 0- 21% (higher rates were observed for pulmonary effects). Lymphomas Evidence is insufficient to determine the comparative harms of PBT in patients with lymphomas. We identified no comparative studies of the potential harms of PBT in patients with lymphomas. One case series identified no grade 3 or worse acute effects in 10 patients (Li, 2011). Proton Beam Therapy: Final Evidence Report Page 52 WA – Health Technology Assessment March 28, 2014 Ocular Tumors Limited, low-quality evidence suggests comparable rates of harm for PBT relative to treatment alternatives in patients with ocular tumors. We identified three comparative studies assessing the harms of PBT for ocular cancers. In the previously-described Desjardins RCT comparing PBT with thermotherapy to PBT alone in 151 patients with uveal melanoma (Desjardins, 2006), no statistically-significant differences were observed between groups in rates of cataracts, maculopathy, pappilopathy, glaucoma, or intraocular pressure. The combination therapy group had a significantly lower rate of secondary enucleation (p=0.02), although actual figures were not reported. In a previously-described comparison of PBT to enucleation in 132 patients treated for unilateral choroidal tumors (Mosci, 2012), rates of eye loss in the PBT arm were assessed and estimated to be 26% at five years of follow-up. Harms data were collected in 25 case series of ocular cancers (see Appendix F, Table 11 for specific citations). The most common harm reported was secondary enucleation, which occurred in 4-35% of patients in these studies. Pediatric Cancers PBT’s theoretical potential to lower radiation-induced toxicity in children serves as the comparative evidence base. Comparative studies are lacking, most likely due to a lack of clinical equipoise. Other than the study of secondary malignancy described above, we identified no comparative studies of the potential harms of PBT in patients with pediatric cancers. A total of 18 case series were identified with information on patient harms (see Appendix F, Table 12 for specific citations). Grade 3 or worse effects were rare in most studies, occurring in less than 4% of patients. Prostate Cancer Moderate evidence suggests that rates of major harms are comparable between PBT and photon radiation treatments, particularly IMRT. We identified four comparative studies of the harms associated with PBT and alternative treatments in patients with prostate cancer. The previously-described RCT of PBT+photon therapy vs. photons alone (Shipley, 1995) examined rates of rectal bleeding, urethral stricture, hematuria, incontinence, and loss of full potency; no patients in either arm had grade 3 or higher toxicity during radiation therapy. Actuarial estimates of rectal bleeding at eight years were significantly higher in the PBT+photon arm (32% vs. 12% for photons alone, p=0.002), although this was primarily grade 2 or lower toxicity. Rates of urethral stricture, hematuria, incontinence, and loss of potency did not differ between groups. Three additional studies involved retrospective comparisons using available databases. The most recent was a matched comparison of 314 PBT and 628 IMRT patients treated for early-stage prostate cancer Proton Beam Therapy: Final Evidence Report Page 53 WA – Health Technology Assessment March 28, 2014 using the linked Chronic Condition Warehouse-Medicare database with a focus on complications occurring within 12 months of treatment (Yu, 2013). At six months, rates of genitourinary toxicity were significantly lower in the PBT arm (5.9% vs. 9.5%, p=0.03). This difference was not apparent after 12 months of follow-up, however (18.8% vs. 17.5%, p=0.66). Rates of gastrointestinal and other (e.g., infection, nerve damage) complications did not statistically differ at either timepoint. Another recent study compared matched cohorts of men with prostate cancer in the linked Medicare- SEER database who were treated with PBT or IMRT (684 patients in each arm) and followed for a median of four years (Sheets, 2012). IMRT patients had a statistically-significantly lower rate of gastrointestinal morbidity (12.2 vs. 17.8 per 100 person-years, p<0.05). No other statistical differences were noted in genitourinary morbidity, erectile dysfunction, hip fracture, or use of additional cancer therapy. Finally, Kim and colleagues conducted an analysis of nearly 30,000 men in the Medicare-SEER database who were treated with PBT, IMRT, 3D-CRT, brachytherapy, or conservative management (observation alone) and evaluated for gastrointestinal toxicity (Kim, 2011). All forms of radiation had higher rates of GI morbidity than conservative management. In pairwise comparisons using Cox proportional hazards regression, PBT was associated with higher rates of GI morbidity than conservative management (HR: 13.7; 95% CI: 9.1, 20.8), 3D-CRT (HR: 2.1; 95% CI: 1.5, 3.1), and IMRT (HR: 3.3; 95% CI: 2.1, 5.2). Harms were assessed in 13 prostate cancer case series (see Appendix F, Table 13 for specific citations). Urinary toxicity of grade 3 or 4 ranged from <1-4% for acute toxicities and 1-8% for late toxicities. Gastrointestinal toxicities were less frequently reported, and ranged from 0.2-1% at both acute and late timepoints. Soft Tissue Sarcomas Evidence is insufficient to determine the comparative harms of PBT in patients with sarcomas. We identified no comparative studies of the potential harms of PBT in patients with sarcomas. Late effects were identified in one case series evaluating 10 patients, with 8% reporting Grade 3 brain necrosis. Seminomas Evidence is insufficient to determine the comparative harms of PBT in patients with seminomas. We identified no comparative studies or case series of the potential harms of PBT in patients with seminomas. Thymomas Evidence is insufficient to determine the comparative harms of PBT in patients with thymomas. We identified no comparative studies or case series of the potential harms of PBT in patients with thymomas. Proton Beam Therapy: Final Evidence Report Page 54 WA – Health Technology Assessment March 28, 2014 Noncancerous Conditions Arteriovenous Malformations Evidence is insufficient to determine the comparative harms of PBT in patients with arteriovenous malformations. We identified no comparative studies of the potential harms of PBT in patients with arteriovenous malformations. A single case series reported on severe adverse effects of PBT in AVMs (Vernimmen, 2005). Acute grade 4 epilepsy occurred in 3% of 64 patients, while late grade 3-4 effects occurred in 6%. Hemangiomas Limited evidence suggests comparable rates of harm for PBT relative to treatment alternatives in patients with hemangiomas. A single, previously-described retrospective comparative cohort study assessed outcomes in patients with circumscribed or diffuse hemangiomas treated with PBT or photon radiation (Höcht, 2006). Small differences in unadjusted rates of optic nerve/disc atrophy, lacrimation (formation of tears) and ocular pressure as well as effects on the retina, lens, and iris were observed between groups, but most side effects were grade 1 or 2. The rate of retinopathy was substantially higher in PBT patients (40% vs. 16% for photons). However, in Cox proportional hazards regression adjusting for between-group differences, no effects of radiation modality on outcomes was observed, including retinopathy (p=0.12). One case series of hemangiomas reported no acute or late effects in 13 patients (Hannouche, 1997). Other Benign Tumors Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with other benign tumors. The previously-described Arvold study comparing PBT, PBT+photon, and photon therapy alone in 25 patients treated for optic nerve sheath meningiomas (Arvold, 2009) showed numerically lower rates of acute orbital pain and headache for both PBT groups compared to photon therapy, and numerically higher rates of late asymptomatic retinopathy. None of these comparisons were tested statistically, however. Three case series were identified with the severity of harms recorded (Nöel, 2005; Weber, 2003; Wenkel, 2000). Grade 3 or 4 toxicities occurred in 4-17% of patients in two meningioma studies. In a study of vestibular schwannoma in 88 patients, 6% of patients had severe facial nerve dysfunction (Weber, 2003). Proton Beam Therapy: Final Evidence Report Page 55 WA – Health Technology Assessment March 28, 2014 Differential Effectiveness and Safety of Proton Beam Therapy in Key Patient Subgroups (KQ4) The sections below summarize available information on how the effectiveness and safety of PBT differs relative to treatment alternatives in specific patient subgroups as delineated in Key Question 4. Because the focus of this question is on differential effects of PBT in key subgroups, the focus of this section is on comparative studies only. Case series with subgroup data available are noted as such in evidence tables, however. Patient Demographics Limited comparative subgroup data are available on the differential impact of PBT according to patient demographics. In a retrospective comparison of PBT and surgical enucleation in uveal melanoma, the rate of death due to metastatic disease through two years of follow-up increased with older age in the surgical group but not in the PBT group (Seddon, 1990). In a retrospective analysis of secondary malignancy with PBT vs. photon radiation in multiple cancer types (Chung, 2013), reductions in malignancy rates with PBT of 5% were seen with each year of increasing age (mean age was 59 years in both groups). In other comparative studies, patient demographics had no impact on the effect of treatment (Tokuuye, 2004; Marucci, 2011). Clinical Characteristics In a comparison of secondary malignancy rates in 86 infants with retinoblastoma treated with PBT or photon radiation (Sethi, 2013), statistically-significant reductions in the estimated incidence of secondary malignancy at 10 years were observed in favor of PBT for the subset of patients with hereditary disease (0% vs. 22% for photons, p=0.005). No significant differences were observed in the overall cohort, however. In other comparative studies, clinical characteristics, including prior therapy received, had no effect on treatment outcomes (Brown, 2013; Tokuuye, 2004). Tumor Characteristics The impact of tumor characteristics on estimates of treatment effect was measured in six comparative studies. In one study comparing PBT to carbon-ion therapy in liver cancer (Komatsu, 2011), larger tumor sizes were associated with a greater risk of cancer recurrence in PBT patients but not in those receiving carbon-ion therapy. In the Shipley RCT comparing PBT+photon therapy to photons alone in men with prostate cancer (Shipley, 1995), the 8-year estimate of local control was significantly higher in patients receiving PBT among those with poorly-differentiated tumors (85% vs. 40% for photons, p=0.0014). No Proton Beam Therapy: Final Evidence Report Page 56 WA – Health Technology Assessment March 28, 2014 differences were observed among those with well- or moderately-differentiated tumors. In the other studies, tumor characteristics (e.g., volume, thickness, level of prostate cancer risk) had no differential impact on outcomes (Tokuuye, 2004; Sejpal, 2011; Mosci, 2012; Coen, 2012). Treatment Protocol Four RCTs were identified that involved comparisons of different dosing regimens for PBT. Two of these were in men with prostate cancer (Kim, 2013; Zietman, 2010). In the more recent study, five different fractionation schemes were compared in 82 men with stage T1-T3 prostate cancer, with total doses ranging from 35-60 GyE (Kim, 2013); patients were followed for a median of approximately 3.5 years. Rates of biochemical failure using two different definitions did not differ statistically between treatment groups. Similarly, no significant differences were observed in rates of acute and late skin, gastrointestinal, or genitourinary toxicity between arms. In another RCT conducted at MGH and Loma Linda University, 395 men with stage T1b-T2b prostate cancer were randomized to receive a conventional dose of combination PBT+photon therapy (70.2 GyE total dose) or a “high dose” of combination therapy (79.2 GyE) (Zietman, 2010). Patients were followed for a median of 9 years. Significant differences in favor of the high-dose group were seen for disease control as measured by a PSA nadir value <0.5 ng/mL (59.8% vs. 44.7% for high and conventional dose respectively, p=0.003) and 10-year estimates of biochemical failure (16.7% vs. 32.3%, p=0.0001). Survival and mortality rates did not differ. Acute GI toxicity was significantly more frequent in the high- dose group (63% vs. 44% for conventional, p=0.0006); no differences were observed in other measures of toxicity. A quality-of-life subset analysis of this RCT found no differences between groups in patient- reported measures of urinary obstruction and irritation, urinary incontinence, bowel problems, or sexual dysfunction (Talcott, 2010). Gragoudas and colleagues examined the impact of two different total doses of PBT (50 vs. 70 GyE) on clinical outcomes and potential harms in 188 patients with melanoma of the choroid or ciliary body (Gragoudas, 2006). Patients were followed for up to five years. No statistical differences were observed in any measure of effectiveness (visual acuity, vision preservation, local recurrence, death from metastases) or harm (hemorrhage, subretinal exudation, glaucoma, uveitis, secondary enucleation). The fourth RCT involved 96 patients with chordomas and skull base tumors who received combination PBT and photon therapy at total doses of either 66.6 or 72 GyE (Santoni, 1998). Patients were followed for a median of 3.5 years. This RCT focused on harms alone. No significant differences were observed in the rate of temporal lobe damage between groups or in grade 1, 2, or 3 clinical symptoms such as headache and motor function. Proton Beam Therapy: Final Evidence Report Page 57 WA – Health Technology Assessment March 28, 2014 Finally, in a previously-described comparative cohort study assessing outcomes for both PBT and carbon-ion therapy (Fujii, 2013), no differences were observed in estimates of local control, progression- free survival, or overall survival when stratified by number of fractions received or total radiation dose. Costs and Cost-Effectiveness of Proton Beam Therapy in Patients with Multiple Cancers and Noncancerous Conditions (KQ5) A total of 16 studies were identified that examined the costs and cost-effectiveness of PBT in a variety of settings and perspectives (see Appendix E for study details). Studies are organized by cancer type in the sections that follow. Five of the 16 studies focused attention on the operating costs, reimbursement, and/or viability of proton treatment centers for multiple types of cancer, and are summarized at the end of this section. Breast Cancer Three studies modeled the costs and cost-effectiveness of PBT in breast cancer. One U.S.-based study examined reimbursement for treatment with 3D-conformal partial breast irradiation using protons or photons vs. traditional whole breast irradiation (Taghian, 2004). Payments included those of treatment planning and delivery as well as patient time and transport. Total per-patient costs were substantially higher for PBT vs. photon partial irradiation ($13,200 vs. $5,300) but only modestly increased relative to traditional whole breast irradiation ($10,600), as the latter incurred higher professional service fees and involved a greater amount of patient time. Two additional studies from the same group assessed the cost-effectiveness of PBT vs. photon radiation among women with left-sided breast cancer in Sweden (Lundkvist, 2005a and 2005c). In the first of these, photon radiation was assumed to increase the risk of ischemic and other cardiovascular disease as well as pneumonitis relative to PBT (Lundkvist, 2005a); clinical effectiveness was assumed to be identical. Reductions in adverse events led to a gain in quality-adjusted life years (QALYs) equivalent to approximately one month (12.35 vs. 12.25 for photon). Costs of PBT were nearly triple those of photon therapy, however ($11,124 vs. $4,950), leading to an incremental cost-effectiveness ratio (ICER) of $65,875 per QALY gained. The other study used essentially the same model but focused attention only on women at high risk of cardiac disease (43% higher than general population) (Lundkvist, 2005c). In this instance, a much lower ICER was observed ($33,913 per QALY gained). Head and Neck Cancer Two studies modeled the cost-effectiveness of PBT in head and neck cancers. In one study, Ramaekers and colleagues used a Markov model to assess the cost-effectiveness of intensity-modulated PBT (IMPT) or IMRT therapy among patients with locally-advanced, Stage III-IV head and neck cancers in the Netherlands (Ramaekers, 2013). IMPT and IMRT were assumed to result in equivalent rates of disease progression and survival, but IMPT was assumed to result in lower rates of significant dysphagia (difficulty swallowing) and xerostomia (dry mouth syndrome). IMPT was found to result in one additional month of quality-adjusted survival (6.62 vs. 6.52 QALYs for IMRT), but treatment costs were Proton Beam Therapy: Final Evidence Report Page 58 WA – Health Technology Assessment March 28, 2014 estimated to be 24% higher. The resulting ICER was estimated to be $159,421 per QALY gained vs. IMRT. Use of IMPT only in patients at high risk of radiation toxicity (and IMRT in all others) resulted in an ICER that was approximately half of the base case ($75,106 per QALY gained). Head and neck cancer was also evaluated in the above-mentioned Swedish model (Lundkvist, 2005c). The base case involved a 65 year-old cohort with head and neck cancers of all stages. PBT was assumed not only to reduce the risk of xerostomia and acute mucositis (ulceration of mucous membranes), but also to reduce overall mortality at 8 years by 25% based on modeled delivery of a higher curative dose. As a result, PBT generated an additional 1.02 QALYs over photon radiation at an additional cost of approximately $4,000, resulting in an ICER of $3,769 per QALY gained. Lung Cancer Two studies from the same center evaluated the economic impact of PBT in lung cancers among patients in the Netherlands (Grutters, 2011; Grutters, 2010). One was a Markov model comparing PBT to carbon-ion therapy, stereotactic radiation therapy, and conventional radiation in patients with stage 1 non-small-cell lung cancer (NSCLC) over a 5-year time horizon (Grutters, 2010). Effects of therapy included both overall and disease-related mortality as well as adverse events such as pneumonitis and esophagitis. For inoperable NSCLC, PBT was found to be both more expensive and less effective than either carbon-ion or stereotactic radiation and was therefore not included in subsequent analyses focusing on inoperable disease. While not reported in the paper, PBT’s derived cost-effectiveness relative to conventional radiation (based on approximately $5,000 in additional costs and 0.35 additional QALYs) was approximately $18,800 per QALY gained. The second study was a “value of information” analysis that examined the implications of adopting PBT for Stage I NSCLC in three scenarios: (a) without further research; (b) along with the conduct of a clinical trial; and (c) delay of adoption while a clinical trial is conducted (Grutters, 2011). Costs included those of treatment (currently abroad as the Netherlands has no proton facilities), the clinical trial vs. conventional radiation, and adverse events due to suboptimal care. These were calculated and compared to the expected value of sampling information (reduced uncertainty), obtained through simulation modeling of uncertainty in estimates both before and after the trial. The analysis found that adoption of PBT along with conduct of a clinical trial produced a net gain of approximately $1.9 million for any trial with a sample size <950, while the “delay and trial” strategy produced a net loss of ~$900,000. Results were sensitive to a number of parameters, including treatment costs abroad and costs of suboptimal treatment. Pediatric Cancers Three decision analyses were available that focused on pediatric cancers, all of which focused on a lifetime time horizon in children with medulloblastoma who were treated at 5 years of age (Mailhot Vega, 2013; Lundkvist, 2005b; Lundkvist, 2005c). In a US-based model that incorporated costs and patient preference (utility) values of treatment and management of adverse events such as growth hormone deficiency, cardiovascular disease, hypothyroidism, and secondary malignancy (Maillhot Vega, Proton Beam Therapy: Final Evidence Report Page 59 WA – Health Technology Assessment March 28, 2014 2013), PBT was found to generate lower lifetime costs ($80,000 vs. $112,000 per patient for conventional radiation) and a greater number of QALYs (17.37 vs. 13.91). Reduced risks for PBT were estimated based on data from dosimetric and modeling studies. Sensitivity analyses on the risk of certain adverse events changed the magnitude of PBT’s cost-effectiveness, but it remained less costly and more effective in all scenarios. The same Swedish group that examined breast and head/neck cancer also assessed medulloblastoma in two modeling studies (Lundkvist, 2005b; Lundkvist, 2005c). As with the analysis above, PBT was assumed to reduce both mortality and nonfatal adverse events relative to conventional photon therapy. On a per-patient basis, PBT was assumed to reduce lifetime costs by approximately $24,000 per patient and increase quality-adjusted life expectancy by nearly nine months (12.8 vs. 12.1 QALYs) (Lundkvist, 2005b). On a population basis, 25 medulloblastoma patients treated by PBT would have lifetime costs reduced by $600,000 and generate an additional 17.1 QALYs relative to conventional photon radiation (Lundkvist, 2005c). Prostate Cancer We identified four studies examining the costs and cost-effectiveness of PBT for prostate cancer. The analysis of the 2008-2009 Chronic Condition Warehouse previously reported under KQ 3 (harms) also examined treatment costs for matched Medicare beneficiaries with prostate cancer who received PBT or IMRT (Yu, 2013). Median Medicare reimbursements were $32,428 and $18,575 for PBT and IMRT respectively (not statistically tested). A relatively recent Markov decision analysis estimated the lifetime costs and effectiveness of PBT, IMRT, and stereotactic body radiation therapy (SBRT) for localized prostate cancer (Parthan, 2012). Clinical effectiveness and impact on mortality were assumed to be equivalent across all three groups. SBRT was found to have the lowest treatment costs and shortest time in treatment of the three modalities, and produced slightly more QALYs (8.11 vs. 8.05 and 8.06 for IMRT and PBT respectively) based on an expected rate of sexual dysfunction approximately half that of IMRT or PBT. SBRT was cost-saving or cost-effective vs. PBT in 94% of probabilistic simulations. An earlier decision analysis estimated the potential cost-effectiveness of a hypothetically-escalated PBT dose (91.8 GyE) vs. 81 Gy delivered with IMRT over a 15-year time horizon (Konski, 2007). The model focused on mortality and disease progression alone (i.e., toxicities were assumed to be similar between groups), and assumed a 10% reduction in disease progression from PBT’s higher dose. This translated into QALY increases of 0.42 and 0.46 years in 70- and 60-year-old men with intermediate-risk disease respectively. Costs of PBT were $25,000-$27,000 higher in these men. ICERs for PBT vs. IMRT were $63,578 and $55,726 per QALY for 70- and 60-year-old men respectively. Finally, the Lundkvist model also evaluated costs and outcomes for a hypothetical cohort of 300 65 year- old men with prostate cancer (Lundkvist, 2005, e30). PBT was assumed to result in a 20% reduction in cancer recurrence relative to conventional radiation as well as lower rates of urinary and gastrointestinal toxicities. PBT was estimated to be approximately $8,000 more expensive than Proton Beam Therapy: Final Evidence Report Page 60 WA – Health Technology Assessment March 28, 2014 conventional radiation over a lifetime but result in a QALY gain of nearly 4 months (0.297). The resulting cost-effectiveness ratio was $26,481 per QALY gained. Facility-based Analyses Two recent U.S.-based studies modeled the case distribution necessary to service the debt incurred from the construction of new proton facilities (Elnahal, 2013; Johnstone, 2012). The more recent of these examined the impact of accountable care organization (ACO) Medicare reimbursement scenarios on debt servicing, by assessing the potential mix of complex or pediatric cases along with noncomplex and prostate cases that could be delivered with session times <30 minutes (Elnahal, 2013). Overall, replacing fee-for-service reimbursement with ACO payments would be expected to reduce daily revenue by 32%. Approximately one-quarter of complex cases would need to be replaced by noncomplex cases simply to cover debt, and PBT facilities would need to operate 18 hours per day. The earlier study assessed the fee-for-service case distribution required to service debt in PBT facilities of various sizes (Johnstone, 2012). A single-room facility would be able to cover debt while treating only complex and pediatric cases if 85% of treatment slots were filled, but could also achieve this by treating four hours of noncomplex (30 minutes per session) and prostate (24 minutes) cases. Three- and four- room facilities could not service debt by treating complex and pediatric cases alone; an estimated 33- 50% of volume would need to be represented by simple/prostate cases to service debt in larger facilities. An additional U.S. study examined the potential impact on reimbursement of replacing 2007 radiation therapy volume at Rhode Island Hospital (i.e., IMRT, stereotactic radiation, GammaKnife®) with PBT in all instances, based on Medicare reimbursement rates (Dvorak, 2010). No impact on capital expenditures was assumed. A total of 1,042 patients were treated with other radiation modalities, receiving nearly 20,000 treatment fractions. Estimated Medicare reimbursement was approximately $6 million at baseline. Replacing all of these fractions with PBT would increase reimbursement to approximately $7.3 million, representing a 22% increase. It was further estimated that 1.4 PBT gantries would be necessary to treat this patient volume. Two additional studies modeled the costs of new construction of proton facilities in Europe (Peeters, 2010; Goitien, 2003). Both assumed a 30-year facility lifetime and 13-14 hours of daily operation. Taking into account both construction and daily operating costs, the total institutional costs to deliver PBT was estimated to be 2.4-3.2 times higher than that of conventional photon radiation in these studies. The Peeters study also estimated the costs to operate a combined proton-carbon ion facility, and estimated these costs at approximately 5 times higher than that of a photon-only facility (Peeters, 2010). Proton Beam Therapy: Final Evidence Report Page 61 WA – Health Technology Assessment March 28, 2014 Budget Impact Analysis: Prostate and Lung Cancer To provide additional context for an understanding of the economics of PBT, we performed a simple budget impact analysis based on 2012 radiation therapy volume within the Public Employees Benefits Board (PEBB) at the HCA. We focused on prostate and lung cancer as two common cancers for which treatment with PBT would be considered. In 2012, 110 prostate cancer patients received treatment with IMRT or brachytherapy. Considering only the costs of treatment delivery (i.e., not of planning or follow-up), allowed payments averaged $19,143 and $10,704 for IMRT and brachytherapy respectively, and totaled approximately $1.8 million for the population. A single PEBB prostate cancer patient was referred for PBT; in this patient, allowed payments totaled $27,741 for 21 treatment encounters ($1,321 per encounter). Applying this payment level to all 110 patients would result in a total of approximately $3.1 million, or a 73% increase. Comparisons of weighted average payments per patient can be found in Figure 5 on the following page. Figure 5. Comparisons of average per-patient payments in PEBB plan based on current radiation therapy volume and expected payments for proton beam therapy. $30,000 $25,000 $20,000 $15,000 Std Rx $27,741 PBT $10,000 $16,105 $13,210 $5,000 $7,138 $0 Prostate Lung NOTE: “Std Rx” refers to the current mix of radiation treatments used in each population (IMRT and brachytherapy for prostate cancer, IMRT and radiosurgery for lung cancer) In 2012, 33 PEBB patients received radiation treatment for lung cancer. Allowed payments for treatment delivery averaged $15,963 and $4,792 for IMRT and radiosurgery respectively, and totaled approximately $240,000 for the population. Because PEBB had no lung cancer referrals for PBT, we assumed that treatment with 10 fractions would cost the same per fraction as for prostate cancer Proton Beam Therapy: Final Evidence Report Page 62 WA – Health Technology Assessment March 28, 2014 ($1,321), summing to a total cost of $13,210. Based on these assumptions, converting all 33 patients to PBT would raise total payment to approximately $440,000 annually, or an 84% increase. Because volume of radiation treatments in the PEBB plan for these cancers was relatively low, and a single case was referred out of state for PBT, these payment estimates might be considered too variable for comparison. We conducted an additional analysis for prostate cancer patients using national Medicare payment estimates from a publicly-available analysis of changes in Hospital Outpatient Prospective Payment System (HOPPS) rates conducted by Revenue Cycle, Inc. for Varian Medical Systems (Varian, Inc., 2014). We used 2013 payment estimates for HDR brachytherapy, IMRT, and PBT. We assumed 40 fractions were delivered each for IMRT and PBT. Payment estimates, including simulation, planning, and treatment, were $8,548, $21,884, and $30,270 for brachytherapy, IMRT, and PBT respectively. Based on the 2012 mix of treatments in the PEBB plan (70 IMRT, 40 brachytherapy), expected Medicare HOPPS payments would total approximately $1.9 million. If all 110 patients were treated instead with PBT, expected payments would be approximately $3.3 million. This represents a 78% increase, which is similar in magnitude to that estimated using actual PEBB payments. There are clear limitations to this analysis in that we do not know whether patients treated by PBT would have the same severity mix as the existing population, or whether some of these patients would not even be candidates for PBT. We also did not estimate total costs of care for these patients, so any potential cost-offsets are not represented here. Nevertheless, this analysis represents a reasonable estimate of the treatment expenditures the PEBB plan could expect to incur if all prostate and lung cancer patients currently receiving other radiation modalities were switched to PBT. Proton Beam Therapy: Final Evidence Report Page 63 WA – Health Technology Assessment March 28, 2014 9. Summary and Recommendations for Future Research Proton beam therapy (PBT) has been used for clinical purposes for over 50 years and has been delivered to tens of thousands of patients with a variety of cancers and noncancerous conditions. Despite this, evidence of PBT’s comparative clinical effectiveness and comparative value is lacking for nearly all conditions under study in this review. As mentioned previously, it is unlikely that significant comparative study will be forthcoming for childhood cancers despite uncertainty over long-term outcomes, as the potential benefits of PBT over alternative forms of radiation appear to be generally accepted in the clinical and payer communities. In addition, patient recruitment for potential studies may be untenable in very rare conditions (e.g., thymoma, arteriovenous malformations). In other areas, however, including common cancers such as breast and prostate, the poor evidence base and residual uncertainty around the effects of PBT is highly problematic. We rated the net health benefit of PBT relative to alternative treatments to be “Superior” (moderate- large net health benefit) in ocular tumors and “Incremental” (small net health benefit) in adult brain/spinal and pediatric cancers. We judged the net health benefit to be “Comparable” (equivalent net health benefit) in several other cancers, including liver, lung, and prostate cancer, as well as hemangiomas. It should be noted, however, that we made judgments of comparability based on a limited evidence base that provides relatively low certainty that PBT is roughly equivalent to alternative therapies. While further study may reduce uncertainty and clarify differences between treatments, it is currently the case that PBT is far more expensive than its major alternatives, and evidence of its short or long-term relative cost-effectiveness is lacking for many of these conditions. It should also be noted that we examined evidence for 11 cancers and noncancerous conditions not listed above, and determined that there was insufficient evidence to obtain even a basic understanding of PBT’s comparative clinical effectiveness and comparative value. For relatively common cancers, the ideal evidence of PBT’s clinical impact would come from randomized clinical trials such as those currently ongoing in liver, lung, and prostate cancer (see Section 6 for further details). To allay concerns regarding the expense and duration of trials designed to detect survival differences, new RCTs can focus on validated intermediate endpoints such as tumor progression or recurrence, biochemical evidence of disease, development of metastases, and near-term side effects or toxicities. In any event, overall and disease-free survival should be included as secondary measures of interest. In addition, the availability of large, retrospective databases that integrate clinical and economic information should allow for the development of robust observational studies even as RCTs are being conceived of and designed. Advanced statistical techniques and sampling methods have been used to create observational datasets of patients treated with PBT and alternative therapies using national databases like the Medicare-SEER database and Chronic Conditions Warehouse used in some of the studies summarized in this review. These studies will never produce evidence as persuasive as Proton Beam Therapy: Final Evidence Report Page 64 WA – Health Technology Assessment March 28, 2014 randomized comparisons because of concerns regarding selection and other biases, and administrative databases lack the clinical detail necessary to create rigorously-designed observational datasets. The continued growth of electronic health records from integrated health systems may allow for the creation of more detailed clinical and economic comparisons in large, well-matched patient groups receiving alternative radiation modalities. 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Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294(10):1233-1239. 367. Zografos L, Ducrey N, Beati D, et al. Metastatic melanoma in the eye and orbit. Ophthalmology. 2003;110(11):2245-2256. Proton Beam Therapy: Final Evidence Report Page 88 WA – Health Technology Assessment March 28, 2014 368. Zografos L, Egger E, Bercher L, Chamot L, Munkel G. Proton beam irradiation of choroidal hemangiomas. Am J Ophthalmol. 1998;126(2):261-268. Proton Beam Therapy: Final Evidence Report Page 89 Appendix A Definitions WA – Health Technology Assessment March 28, 2014 General Evaluation Tools American Joint Committee on Cancer (AJCC) criteria Based on the extent of a tumor, the spread of the cancer to the lymph nodes, and presence of metastasis, the AJCC developed the TNM staging system which allows clinicians to evaluate different cancers in a standardized manner. The basic parameters are described below. T: description of the primary tumor TX Tumor cannot be evaluated T0 No evidence of tumor Tis Early cancer without spread to nearby tissue T1-T4 Size and/or extent of tumor N: impact of tumor on nearby lymph nodes NX Lymph nodes cannot be evaluated N0 No lymph node involvement N1-N3 Number and/or size of spread M: presence of metastasis M0 No distant metastasis M1 Distant metastasis Source: American Joint Committee on Cancer. Cancer staging references. http://cancerstaging.org/references- tools/Pages/What-is-Cancer-Staging.aspx. World Health Organization (WHO) classification for histological typing of tumors In an effort to help provide a uniform histological definition for various cancer types, the WHO has established a classification system based on the microscopic characteristics of tumors. Rooted in the collaborative work of centers worldwide, the definition and grading of tumors continually evolves to reflect current findings and knowledge including incorporation of genetic profiles. Karnofsky Performance Status (KPS) The KPS is a standardized assessment of how well cancer patients conduct daily activities. The scale ranges in 10-point increments from 100 (normal activity without any special care) to 0 (dead). Intermediate points balance a patient’s care needs with his/her ability to carry out normal activities. Proton Beam Therapy: Final Evidence Report Page 91 WA – Health Technology Assessment March 28, 2014 Eastern Cooperative Oncology Group (ECOG) Performance Status The ECOG Performance Status (also referred to as the WHO Performance Status or the Zubrod performance status) is derived from the KPS and offers an alternate assessment of a patient’s functional status. The scale ranges from 0 (fully active) to 5 (dead) with the intermediate grades as described below. Grade 0 Fully active without restriction Grade 1 Restricted in physically strenuous activity, but ambulatory and able to carry out light housework or office work Grade 2 Ambulatory and capable of self-care, but unable to work; active for >50% of waking hours Grade 3 Limited self-care; confined to bed or chair >50% of waking hours Grade 4 Completely disabled; confined to bed or chair; incapable of self-care Grade 5 Dead Source: Péus D, Newcomb N, Hofer S. Appraisal of the Karnofsky Performance Status and proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak. 2013;13(1):72. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) The CTCAE is a widely disseminated and utilized catalog of adverse events encountered in oncology medicine. Adverse events are organized by System Organ Class (SOC) (e.g., cardiac disorders, renal and urinary disorders) with guiding clinical descriptions for evaluation of severity. The general principles for grading adverse event severity are listed below. Grade1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate activities of daily living (ADL) Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Grade 4 Life-threatening consequences; urgent intervention needed; urgent intervention indicated Grade 5 Death related to adverse event Source: National Cancer Institute. Cancer Therapy Evaluation Program (CTEP). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Proton Beam Therapy: Final Evidence Report Page 92 WA – Health Technology Assessment March 28, 2014 Radiation Therapy Oncology Group (RTOG)/ European Organisation for Research and Treatment of Cancer (EORTC) morbidity scoring system Widely utilized along with CTCAE, the RTOG/EORTC scoring system establishes parameters for separate evaluation of acute and late radiation effects in tissues and organs. Events are evaluated on a scale ranging from 0 (no change from baseline) to 5 (death) for organs or body areas impacted by therapy. The range of acute effects in the lungs is described below. Lung – acute effects 0 1 2 3 4 5 No change Mild symptoms Persistent Severe cough Severe Death related over baseline of dry cough or cough unresponsive respiratory to effects dyspnea on requiring to narcotic insufficiency; exertion narcotic, antitussive continuous antitussive agent or oxygen or agents; dyspnea at assisted dyspnea with rest; clinical or ventilation minimal effort radiologic but not at rest evidence of acute pneumonitis; intermittent oxygen or steroids may be required Source: Radiation Therapy Oncology Group (RTOG). Acute radiation morbidity scoring criteria. http://www.rtog.org/researchassociates/adverseeventreporting/acuteradiationmorbidityscoringcriteria.aspx . Late radiation effects are similarly evaluated on a scale ranging from 0 (no effects) to 5 (death) for organs or body areas impacted by therapy. The range of late events in the lungs is described below. Lung – late effects 0 1 2 3 4 5 None Asymptomatic Moderate Severe Severe Death related or mild symptomatic symptomatic respiratory to effects symptoms (dry fibrosis or fibrosis or insufficiency; cough); slight penumonitis pneumonitis; continuous radiographic (severe cough); dense oxygen or appearances low grade radiographic assisted fever; patchy changes ventilation radiographic appearances Proton Beam Therapy: Final Evidence Report Page 93 WA – Health Technology Assessment March 28, 2014 Source: Radiation Therpay Oncology Group (RTOG). RTOG/EORTC late radiation morbidity scoring schema. http://www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchema.aspx . Late Effects Normal Tissues (LENT) scoring system and the SOMA scale (subjective, objective, management and analytic) The LENT/SOMA grading system represents early efforts by the RTOG and the European Organisation for Research and Treatment of Cancer (EORTC) to establish a universal system for evaluation of late radiation effects in normal tissue. Use of SOMA allows for incorporation of different data including clinical assessment and patient experience. The parameters for the grading system are described below. Grade 1 Minor symptoms that require no treatment Grade 2 Moderate symptoms requiring conservative treatment Grade 3 Severe symptoms, requiring more aggressive treatment, with significant negative impact on daily activities Grade 4 Irreversible functional damage, with major therapeutic intervention required Grade 5 Death or loss of organ Source: Pavy JJ, Denekamp J, Letschert J, et al. EORTC Late Effects Working Group. Late effects toxicity scoring: the SOMA scale. Radiother Oncol. 1995;35(1):11-15. Proton Beam Therapy: Final Evidence Report Page 94 WA – Health Technology Assessment March 28, 2014 Cancer-specific Evaluation Tools Pediatric Cancers Chang staging system Originally based on the size and extent of the tumor and any evidence of metastasis, the Chang staging system provides information for describing pediatric medulloblastoma. Modified to reflect diagnostic findings based on imaging and cerebrospinal fluid (CSF) analysis, the M-stage delineates the extent of metastasis as described below. M0 No gross subarachnoid or hematogenous metastasis M1 Microscopic tumors cells found in the CSF Gross nodular seeding in the cerebellum, cerebral subarachnoid space, or in the third or fourth M2 ventricles M3 Gross nodular seeding in spinal subarachnoid space M4 Extraneural metastasis Source: MacDonald T. Pediatric medulloblastoma (2012). http://reference.medscape.com/article/987886- overview. Prostate Cancer Expanded Prostate Cancer Index Composite (EPIC) EPIC is a health-related quality-of-life assessment tool that evaluates patient function in men with prostate cancer. Included domains are urinary, bowel, sexual and hormonal health. Men are asked to evaluate their experiences and symptoms over the previous 4-week period. Gleason score Following a biopsy of the prostate, cancerous tissue will be graded based on microscopic findings. The Gleason score typically ranges from 2 to 10, with higher scores indicating a greater likelihood of the cancer spreading. Gleason score Related description of findings ≤6 Well-differentiated, less likely to spread 7 Moderately differentiated 8 - 10 Poorly differentiated, more likely to spread Source: American Cancer Society. Prostate cancer. How is prostate cancer staged? http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-staging. Proton Beam Therapy: Final Evidence Report Page 95 WA – Health Technology Assessment March 28, 2014 American Society for Therapeutic Radiology and Oncology (ASTRO): Biochemical failure In consensus with RTOG, ASTRO has established the following definition for biochemical failure in patients who have received radiation therapy for prostate cancer: a rise in the prostate-specific antigen (PSA) of 2 ng/ml or more above the lowest measured PSA level. Liver Cancer Child-Pugh Classification Designed to assess the severity of liver cirrhosis on a 15-point scale, the Child-Pugh assessment is based on clinical and biochemical measurements associated with liver function. For each item, up to 3 points are assigned for increasing abnormality. The parameters and summary grades are listed below. Measurements  Grade of hepatic encephalopathy  Ascites  Total bilirubin  Serum albumin  Prothrombin time (sec. prolonged or INR) Child-Pugh classification: Grade A = 5-6 points; Grade B = 7-9 points; Grade C = 10-15 points Barcelona Clinic Liver Cancer (BCLC) staging system Combining information regarding tumor burden, liver function and patient status, the BCLC is an evidence-based algorithm designed to stage liver cancer and propose various treatment strategies. Specific treatment pathways may be found at the following link: http://www.medscape.com/viewarticle/720694_3 Proton Beam Therapy: Final Evidence Report Page 96 Appendix B Search Strategy WA – Health Technology Assessment March 28, 2014 Search Strategy for Medline Databases searched: • Medline 1946 to present with weekly update • EBM Reviews - Cochrane Central Register of Controlled Trials, September, 2013 • EBM Reviews – Database of Abstracts of Reviews of Effects, 3rd Quarter 2013 1. exp Protons/ 2. proton.mp 3. proton beam.mp 4. proton beam therapy.mp 5. exp Proton Therapy/ 6. proton*.mp 7. proton$ therap$.mp 8. protontherap$.mp 9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10. (neoplasm* or cancer* or carcinoma*).mp 11. 9 and 10 12. Limit 11 to (English language and humans and yr=”1990 – Current”) 13. Proton Pump Inhibitors/ 14. 12 not 13 15. Limit 14 to (comment or letter or “review”) 16. 14 not 15 Proton Beam Therapy: Final Evidence Report Page 98 WA – Health Technology Assessment March 28, 2014 Search Strategy for EMBASE 1. ‘proton’/exp 2. proton:de,lnk,ab,ti 3. ‘proton therapy’/exp 4. ‘proton therapy’:de,lnk,ab,ti 5. ‘proton radiation’:de,lnk,ab,ti 6. proton*:de,lnk,ab,ti 7. 1 or 2 or 3 or 4 or 5 or 6 8. neoplasm*:de,lnk,ab,ti 9. cancer*:de,lnk,ab,ti 10. carcinoma*:de,lnk,ab,ti 11. 8 or 9 or 10 12. 7 and 11 13. ‘proton pump inhibitor’/exp 14. 12 not 13 Search limits included: • Publication year (2000-2014) • Humans • English language • Publication type (inclusion of article, article in press or editorial) Proton Beam Therapy: Final Evidence Report Page 99 Appendix C Comparative Studies WA – Health Technology Assessment March 28, 2014 Table 1. Bone Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms* Quality Notes Criteria Protocol Main Findings* Study Site Characteristics Park (2006) PBT ± photon Inclusion PBT ± photon Local failure • Reported for Poor • Baseline data N=6 • Patients treated • Mean total dose: PBT ± photon: 50% patients achieving available for Retrospective • Male: 67% with PBT ± photon 70.6 GyE PBT ± photon local control primary and Comparative • Age: 68 w/or without surgery • 2 patients w/surgery:38% following treatment recurrent disease Cohort • Tumor type for primary and received only PBT ± photon, n=3 treated with both Primary: 33% recurrent sacral photon therapy, Metastases PBT ± photon modalities Massachusetts Recurrent: 67% chordomas mean dose = 61 Gy PBT ± photon: 83% w/surgery, n=13 General Hospital, • Prior surgery: 67% PBT ± photon • Outcome MA, USA • Mean tumor size PBT ± photon w/surgery: 24% Abnormal bowel analyses by (cm): 5.6 w/surgery function primary and Study Objective • Mean total • Status at last f/u PBT ± photon: 33% recurrent disease PBT ± photon dose:72.8 GyE No evidence of disease PBT ± photon available Evaluation of PBT w/surgery • 3 patients PBT ± photon: 17% w/surgery: 69% with surgery in N=21 received only PBT ± photon the treatment of • Male: 62% photon therapy, w/surgery: 48% Abnormal bladder sacral chordoma • Age: 54 mean dose = 63.7 function • Tumor type Gy Alive w/disease PBT ± photon: 0% Primary: 67% PBT ± photon: 33% PBT ± photon Intervention Recurrent: 33% PBT ± photon w/surgery: 38% Comparator • Prior surgery w/surgery: 29% Follow-up (recurrent group Sexual dysfunction PBT ± photon only): 100% Mortality (reported in 9 F/U: 61.3 months • Mean tumor size PBT ± photon: 50% patients receiving (mean), (range, (cm): 7.6 PBT ± photon PBT ± photon 35-91) • Positive surgical w/surgery: 24% w/surgery): 67% margins: 76% PBT ± photon Difficulty w/surgery ambulating F/U: 99.6 months PBT ± photon: 0% (mean), (range, PBT ± photon 26-261) w/surgery: 23% Return to work PBT ± photon: 100% PBT ± photon w/surgery: 57% (2 patients w/unknown status) * No p-values reported. F/U: follow-up; N: number; PBT: proton beam therapy Proton Beam Therapy: Final Evidence Report Page 101 WA – Health Technology Assessment March 28, 2014 Table 2. Brain, Spinal, and Paraspinal Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms Quality Notes Criteria Protocol Main Findings Study Site Characteristics Brown (2013) PBT Inclusion • All patients Locoregional Suppression of WBC Poor • Data on grades of N=19 • Patients underwent failure* (median % baseline) acute toxicities Retrospective • Male: 74% w/histologically surgical resection PBT: 5% PBT: 55% available Comparative • Age: 29.9 (median) confirmed Photon: 14% Photon: 46% Cohort • Chang stage medulloblastoma • All patients p=0.04 • Subgroup M0: 95% • Patients ≥16 years received 2-year overall analyses of harms, MD Anderson M1:0% at radiation therapy prescribed survival Decreased excluding patients Cancer Center, TX, M2: 5% radiation dose + PBT: 94% hemoglobin receiving USA M3: 0% boost dose Photon: 90% (median % baseline) chemotherapy Study Objective M4: 0% p=NS PBT: 97% available • Gross residual PBT Photon: 88% Evaluation of tumor at RT • Mean total dose 2-year progression- p=0.009 different radiation 2 <1.5 cm : 74% (GyE): 54.6 ± 1.1 free survival therapy for 2 ≥1.5 cm : 26% PBT: 94% Medical medulloblastoma • Any chemotherapy: Photon Photon: 85% management of 84% • Mean total dose p=NS esophagitis Intervention (Gy): 52.9 ± 6.3 PBT: 5% Comparator Photon Photon: 57% Follow-up N=21 p<0.001 PBT • Male: 57% F/U: 26.3 months • Age: 32.7 (median) Median weight loss (median), (range, • Chang stage PBT: -1.2% 11-63) M0: 71% Photon: -5.8% M1: 5% p=0.004 Photon M2: 0% F/U: 57.1 months M3: 19% (median), (range, M4: 5% 4-103) • Gross residual tumor at RT 2 <1.5 cm : 81% 2 ≥1.5 cm : 19% • Any chemotherapy: 81% • Significant differences between groups including f/u, Chang stage * P-value not reported. F/U: follow-up; HR: hazard ratio; IMRT: intensity-modulated radiation therapy; N; number; NS: not significant; PBT: proton beam therapy; WBC: white blood cell Proton Beam Therapy: Final Evidence Report Page 102 WA – Health Technology Assessment March 28, 2014 Table 2. Brain, Spinal, and Paraspinal Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Treatment Protocol Harms Quality Notes Patient Characteristics Criteria Main Findings Study Site Kahn (2011) PBT Inclusion PBT Local recurrence* • No patients Poor N=10 • Patients w/primary • Total dose (Gy) PBT: 20% experienced Retrospective • Male: 50% intramedullary <50: 30% IMRT: 23% significant long-term Comparative • Age: 14 gliomas 50-52: 50% toxicity Cohort • Tumor pathology • Tumor types >52: 20% Brain metastasis* Astrocytoma: 60% included PBT: 10% • No cases of Massachusetts Ependymoma: 40% astrocytoma, IMRT IMRT: 5% myelopathy General Hospital, • WHO grade ependymoma, and • Total dose (Gy) reported MA, USA Low: 60% oligodendroglioma <50: 14% Mortality* Study Objective High: 40% 50-52: 50% PBT: 20% • Surgery >52: 36% IMRT: 32% Evaluation of Biopsy: 30% long-term Partial resection: 70% • Fraction sizes Multivariate analysis outcomes of ranged from 1.0 – • PBT significantly spinal cord glioma IMRT 2.0 Gy associated with patients treated N=22 worse overall w/radiation • Male: 50% • For entire patient survival therapy • Age: 44 cohort, 31% of HR 40 (p=0.02) • Tumor pathology patients received Intervention Astrocytoma: 55% adjuvant Comparator Ependymoma: 45% chemotherapy Follow-up • WHO grade PBT Low: 91% High: 0% IMRT • Surgery Biopsy: 45% F/U: 24 months Partial resection: 55% (median) • Overall, 91% of patients were Caucasian; 3% were each African American, Hispanic and Asian • Significant differences between groups including age * P-value not reported. F/U: follow-up; HR: hazard ratio; IMRT: intensity-modulated radiation therapy; N; number; NS: not significant; PBT: proton beam therapy; WBC: white blood cell; WHO: World Health Organization Proton Beam Therapy: Final Evidence Report Page 103 WA – Health Technology Assessment March 28, 2014 Table 3. Breast Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Harms Quality Notes Study Design Patient Criteria Protocol Assessed Study Site Characteristics Main Findings No comparative studies identified Proton Beam Therapy: Final Evidence Report Page 104 WA – Health Technology Assessment March 28, 2014 Table 4. Esophageal Cancer: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings McCurdy (2013) Presented for entire Inclusion • Total radiation NR Pneumonitis (grade Fair cohort only (N=75) • Patients treated for dose for all ≥2) Retrospective • Male: 76% esophageal cancer patients was 50.4 • PBT:33% Comparative • Age: 64 (median), w/CT treatment Gy or CGE • Photon: 15% Cohort (range, 42-82) planning and follow- p=0.04 •Smoking status up PET/CT imaging MD Anderson Never: 27% 25-75 days after Cancer Center, TX, Former: 69% radiation therapy USA Current: 4% • Volume receiving Study Objective • Clinical stage radiation ≥5 Gy must I: 0% be ≥30%, and volume Evaluation of IIA: 15% receiving ≥40 Gy treatment effects IIB: 5% must be ≥2% to the lungs III: 60% following IV: 17% radiation therapy • Radiation therapy for esophageal PBT: 32% cancer IMRT: 57% 3D-CRT: 11% Intervention • Chemotherapy: Comparator 100% Follow-up PBT IMRT 3D-CRT F/U: up to 75 days following completion of radiation therapy 3D-CRT: 3D conformal radiation therapy; CT: computed tomography; F/U: follow-up; GI: gastrointestinal; IMRT: intensity-modulated radiation therapy; N: number; PBT: proton beam therapy; PET: positron emission tomography Proton Beam Therapy: Final Evidence Report Page 105 WA – Health Technology Assessment March 28, 2014 Table 4. Esophageal Cancer: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Study Design Treatment Protocol Assessed Harms Quality Notes Patient Characteristics Criteria Study Site Main Findings Wang (2013) PBT Inclusion • All patients treated NR Univariate analyses Fair • Potential patient N=72 • Patients treated with neoadjuvant • Incidence of overlap w/ McCurdy Retrospective • Male: 93% with preoperative chemoradiation, postoperative (2013) Comparative • Age: 63 (median), (range, 29-76) concurrent with or without pulmonary Cohort • Clinical stage chemoradiation with chemotherapy complications • Rates of I: 4%; II: 35%; or without • 5-6 weeks after associated w/radiation perioperative MD Anderson III: 56%; IVa: 6% chemotherapy completion of modality (p=0.019) complications Cancer Center, TX, • Receipt of induction followed by surgical neoadjuvant reported by USA chemotherapy: 38% resection therapy, patients • Incidence of radiation modality Study Objective • Surgery intent were evaluated for postoperative GI Planned: 97% surgery complications Evaluation of Salvage: 3% associated w/radiation clinical predictors PBT modality (p=0.04) of postoperative IMRT • Median dose: 50.4 complications in N=164 CGE (range, 45-50.4) Multivariate adjusted patients treated • Male: 90% analyses for esophageal • Age: 60 (median), (range, 27-78) IMRT • Significant increase in cancer • Clinical stage • Median dose: 50.4 risk of postoperative I: 2%; II: 34%; Gy (range, 45-50.4) pulmonary Intervention III: 60%; IVa: 4% complications for 3D- Comparator • Receipt of induction 3D-CRT CRT vs. PBT (OR 9.127, Follow-up chemotherapy: 41% • Median dose: 50.4 95% CI, 1.834-45.424), PBT • Surgery intent Gy (range, 41-59.4) but not for IMRT vs. PBT Planned: 89% (OR 2.228, 95% CI, IMRT Salvage: 11% 0.863-5.755) after adjustment for pre-RT 3D-CRT 3D-CRT diffusing capacity for N=208 carbon monoxide F/U: up to 60 days • Male: 89% (DLCO) level following hospital • Age: 60 (median), (range, 22-79) discharge • Clinical stage • After adjustment, no I: 1%; II: 40%; significant association in III: 54%; IVa: 5% risk of GI complications • Receipt of induction for 3D-CRT vs. PBT (OR chemotherapy: 61% 2.311, 95% CI, 0.69- • Surgery intent 7.74) or IMRT vs. PBT Planned: 94% (OR 1.025, 95% CI, Salvage: 6% 0.467-2.249) 3D-CRT: 3D conformal radiation therapy; CT: computed tomography; F/U: follow-up; GI: gastrointestinal; IMRT: intensity-modulated radiation therapy; N: number; PBT: proton beam therapy; PET: positron emission tomography Proton Beam Therapy: Final Evidence Report Page 106 WA – Health Technology Assessment March 28, 2014 Table 5. Gastrointestinal Cancers: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings No comparative studies identified Table 6. Gynecologic Cancers: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings No comparative studies identified Proton Beam Therapy: Final Evidence Report Page 107 WA – Health Technology Assessment March 28, 2014 Table 7. Head and Neck Cancers (including skull-base tumors): Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms Quality Notes Criteria Protocol Main Findings* Study Site Characteristics Solares (2005) PBT Inclusion NR No evidence of NR Poor • Data on surgical N=2 • Patients disease complications Retrospective undergoing PBT: 0% provided Comparative IMRT transnasal IMRT: 67% Cohort N=3 endoscopic resection Endoscopy: 100% for malignant clival Cleveland Clinic Endoscopy alone lesions Residual disease Foundation, OH, N=1 PBT: 100% USA IMRT: 0% Study Objective Patient Endoscopy: 0% characteristics Evaluation of reported for entire Disease recurrence treatment of clival cohort PBT: 0% tumors utilizing • Male: 67% IMRT: 33% endoscopy and • Age: 50 Endoscopy: 0% radiation therapy • Prior therapy: 67% Mortality Intervention PBT: 0% Comparator IMRT: 33% Follow-up Endoscopy: 0% PBT IMRT Endoscopy alone F/U: 13 months (mean), (range, 8- 24) * P-values not reported. F/U: follow-up; IMRT: intensity-modulated radiation therapy; N: number; NR: not reported; PBT: proton beam therapy Proton Beam Therapy: Final Evidence Report Page 108 WA – Health Technology Assessment March 28, 2014 Table 7. Head and Neck Cancers (including skull-base tumors): Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms* Quality Notes Patient Characteristics Criteria Protocol Main Findings* Study Site Tokuuye (2004) PBT Inclusion PBT Local control Treatment-related Poor • Analyses for N=17 • Patients • Median dose: 75 PBT: 76% Toxicities overall outcomes Retrospective • Male: 82% w/malignant tumors Gy (range, 42-99) PBT + photon: 88% and harms Comparative • Age: 67 of the head and neck • Median dose per • Ulceration available Cohort • Prior therapy • Refusal of surgery fraction: 3.0 Gy Mean control PBT: 24% Chemotherapy: 35% before or after PBT (range, 2.5 – 6) period (months) PBT + photon: 6% University of Resection of previous or tumors inoperable PBT: 69 Tsukuba Proton tumor: 18% PBT + photon PBT + photon: 34 • Osteonecrosis Medical Research Radiation therapy: 6% Exclusion • PBT PBT: 18% Center, Japan Cryotherapy: 24% • Prior PBT Median dose: 32.5 Recurrence PBT + photon: 0% None: 35% • Prior surgical Gy (range, 16-60) PBT: 24% Study Objective • Clinical stage resection of tumor of Median dose per PBT + photon: 13% • Esophageal T1: 12% study focus fraction: 2.5 Gy stenosis Evaluation of PBT T2: 6% (range, 1.5-3) Mean time of PBT: 0% in patients T3: 29% • Photon recurrence PBT + photon: 6% w/head and neck T4: 24% Median dose: 40 (months) cancers Recurrence: 18% Gy (range, 16-75) PBT: 12 • No reported N/A: 12% Median dose per PBT + photon: 18 toxicities fraction: 1.8 Gy PBT: Intervention PBT + photon (range, 1.7-2.1) Mortality PBT + photon: Comparator N=16 PBT: 76% Follow-up • Male: 44% PBT + photon: 50% • Mean time to PBT • Age: 54 toxicities (months) F/U: 71.3 months • Prior therapy PBT: 33 (mean), (range, 9- Chemotherapy: 44% PBT + photon: 24 208) Resection of previous tumor: 6% PBT + photon Radiation therapy: 0% F/U: 36.6 months Cryotherapy: 0% (mean), (range, 6- None: 44% 125) • Clinical stage T1: 0% T2: 31% T3: 0% T4: 50% Recurrence: 6% N/A: 13% * P-values not reported. F/U: follow-up; IMRT: intensity-modulated radiation therapy; N: number; N/A: not available; NR: not reported; PBT: proton beam therapy Proton Beam Therapy: Final Evidence Report Page 109 WA – Health Technology Assessment March 28, 2014 Table 8. Liver Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms* Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Komatsu (2011b) PBT Inclusion PBT 5-year local control Dermatitis Fair Univariate analysis for N=242 • Patients w/HCC • 8 dosing rate Grade 2 PBT Prospective • Male: 75% protocols utilized PBT: 90.2% PBT: 5% • Prior treatment history Comparative • Age ≥70: 52% Exclusion • 52.8-84 GyE Carbon: 93% Carbon: 5% not associated w/local Cohort • Tumor size (mm) • Uncontrolled given in 4-38 control (p=0.73) <50: 71% ascites fractions 5-year local control Increased Hyogo Ion Beam 50-100: 23% • Tumor size >15cm • 150, 190, 210 or rate transaminase Multivariate analyses for Medical Center, >100: 6% 230 MeV beam based on BED10 Grade 2 PBT Japan • BCLC-based category <100 PBT: 2% • Tumor size significantly Study Objective Inoperable: 80% Carbon PBT:93.3% Carbon: 3% associated with local • Child-Pugh • 4 dosing Carbon: 87.4% control rate (p=0.003) Evaluation of A: 76% protocols utilized ≥100 Rib fracture efficacy and B: 23% • 52.8-76 GyE PBT: 80.7% Grade 2 • Baseline characteristics safety of proton C: 1% given in 4-20 Carbon: 95.7% PBT: 3% including Child-Pugh and carbon ion • Previous treatment of fractions Carbon: 3% classification and vascular therapy for HCC target tumor • 250 or 320 MeV 5-year overall invasion significantly Yes: 47% beam survival rate Pneumonitis correlated with overall Intervention PBT: 38% Grade 2 survival rate Comparator Carbon Carbon: 36.3% PBT: 2% Follow-up N=108 Carbon 2% Subgroup analysis PBT • Male: 72% 5-year overall • Patients w/HCC and • Age ≥70: 46% survival rate Nausea/ anorexia/ inferior vena cava tumor Carbon ion • Tumor size (mm) <100 pain/ ascites thrombus receiving PBT therapy <50: 75% PBT: 31.7% Grade 2 (81%) and carbon ion 50-100: 20% Carbon: 32.3% PBT: 2% therapy, curative vs. F/U: 31.0 months >100: 5% ≥100 Carbon: 2% palliative intent: median (median) or until • BCLC-based category PBT: 43.9% survival time greater for death Inoperable: 71% Carbon: 48.4% Grade ≥3 late curative treatment (25.4 • Child-Pugh toxicities vs. 7.7 months, A: 77% • No significant PBT: 3% p=0.0183)† B: 20% differences found Carbon: 4% C: 3% between PBT and • Previous treatment of carbon ion therapy • No deaths due to target tumor treatment-related Yes: 45% toxicities * P-values not reported. † Findings reported in Komatsu (2011a). AST: (serum) aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; BED10: radio-biologic equivalent dose for acute-reacting tissues; F/U: follow-up; HCC: hepatocellular carcinoma; N: number; PBT: proton beam therapy; SD: standard deviation Proton Beam Therapy: Final Evidence Report Page 110 WA – Health Technology Assessment March 28, 2014 Table 8. Liver Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Treatment Protocol Harms* Quality Notes Patient Characteristics Criteria Main Findings* Study Site Otsuka (2003) PBT Inclusion PBT Death from liver • No bone marrow Poor N=5 • Patients w/HCC Mean interval from failure depression or GI Retrospective • Male: 100% who underwent hepatectomy: 21.8 PBT: 40% complications in either Comparative • Mean age: 57 hepatectomy months Photon: 33% group Cohort • Mean initial recurrence • 250 MeV beam interval: 10 months Selection criteria for • 3.0-4.5 Death from lung AST increase University of (range, 4-28) radiotherapy Gy/fraction metastasis (up to 2x baseline) Tsukuba, Japan • Mean tumor size: 2.5 cm following tumor • Mean dose: 75.9 PBT: 60% • PBT: 80% Study Objective • TFactor† recurrence: Gy Photon: 33% • Photon: 100% T1: 40% • Ineligible/ patient Evaluation of T2: 20% refusal of re- Photon Alive Hypoalbuminemia patients T3: 40% hepatectomy Mean interval from PBT: 0% (<3g/dl) w/ascites undergoing • Child-Pugh • Difficult/ hepatectomy: 71.8 Photon: 33% • PBT: 40% radiation therapy A: 60% incomplete primary months • Photon: 33% for recurrent HCC B: 40% surgery • 6 MV beam Mean survival time after • Target tumor with • 2.0 Gy/fraction (months) Bilirubin increase (1.1 hepatectomy Photon single-treatment • Mean dose: 62.5 PBT: 23.8 to 2.2 mg/dl) N=3 volume Gy Photon: 15.5 • PBT: 20% Intervention • 1 patient with 2 • Multiple tumors in • Photon: 0% Comparator recurrences 2 treatment volumes Tumor recurrence Follow-up • Male: 100% PBT: 40% PBT • Mean age: 58 Photon: 0% • Mean initial recurrence Photon interval: 45 months (range, 24-80) F/U: variable • Mean tumor size: 3.9 cm • TFactor† T1: 0% T2: 0% T3: 100% • Child-Pugh A: 66% B: 33% * P-values not reported. † Tfactor based on 3 conditions: 1) solitary tumor; 2) tumor size ≤2cm; 3) no involvement of portal, hepatic veins or bile duct; T1 = all 3 conditions fulfilled; T2 = 2/3 conditions met; T3 = 1/3 conditions met. AST: (serum) aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; BED10: radio-biologic equivalent dose for acute-reacting tissues; F/U: follow-up; HCC: hepatocellular carcinoma; N: number; PBT: proton beam therapy; SD: standard deviation Proton Beam Therapy: Final Evidence Report Page 111 WA – Health Technology Assessment March 28, 2014 Table 8. Liver Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Patient Treatment Protocol Harms Quality Notes Criteria Main Findings* Study Site Characteristics Matsuzaki (1995) PBT Inclusion PBT • Number of tumors • Reported for Fair N=21 • Patients • 250 MeV beam w/reduction in size entire cohort only Prospective (with 26 tumors) w/unresectable HCC • 3-4 Gy/treatment Comparative • Tumor size: • Duration of 3 weeks Cohort 3.6 ± 2.2 (mean, SD) therapy: 17-69 days PBT: 26/26 (100%) • Dose: PBT + chemotherapy: University of PBT + chemotherapy 76.5 ± 9.5 (mean, 18 /18 (100%) Tsukuba, Japan N=14 SD) Study Objective (with 18 tumors) 1 year • Tumor size: Chemotherapy PBT: 24/25 (96%) Evaluation of PBT 4.6 ± 2.1 (mean, SD) • No details PBT + chemotherapy: in the treatment provided 13/13 (100%) of HCC 2 years Intervention PBT: 7/8 (88%) Comparator PBT + chemotherapy: Follow-up 5/5 (100%) PBT • Local tumor control PBT + (no sign of growth or chemotherapy development of new lesion on F/U: up to 4 years CT/ultrasound) 2 years PBT: 25/26 (96%) PBT + chemotherapy: 18/18 (100%) * P-values not reported. AST: (serum) aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; BED10: radio-biologic equivalent dose for acute-reacting tissues; F/U: follow-up; HCC: hepatocellular carcinoma; N: number; PBT: proton beam therapy; SD: standard deviation Proton Beam Therapy: Final Evidence Report Page 112 WA – Health Technology Assessment March 28, 2014 Table 9. Lung Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Fujii (2013) PBT Inclusion • Treatment Local recurrence Pneumonitis (p=0.443) Fair • 3-year overall N=70 • Patients protocols PBT: 17% • Grade 0-1 survival and local Prospective • Male: 71% w/histologically varied Carbon: 24% PBT: 84% control rates Comparative • Age: 76 (median), (range, confirmed primary according to p=NR Carbon: 90% available for Cohort 48-88) NSCLC staged as 1A treatment different dosing • Smoking (yes): 73% or 1B period Regional lymph • Grade 2 protocols Hyogo Ion Beam • Median tumor diameter • Medical node and/or distant PBT: 16% Medical Center, (mm) (range): 30 (11-48) inoperability or PBT metastases without Carbon: 5% Japan •Tumor stage refusal of surgery • Total dose local progression Study Objective T1a: 11% • WHO performance ranged from PBT: 34% • Grade 3 T1b: 40% status ≤2 52.8 – 80 GyE, Carbon: 20% PBT: 0% Evaluation of PBT T2a: 49% • No history of given in 4 – 20 p=NR Carbon: 5% and carbon ion • Operability (yes): 49% previous lung cancer fractions therapy for the •Median BED10 (GyE10) • No prior chest 3-year overall Dermatitis (p=0.424) treatment of (range): 96 (89-122) radiation therapy or Carbon survival • Grade 0-1 Stage I NSCLC chemotherapy • Total dose PBT: 72% PBT: 82% Carbon ranged from Carbon: 76% Carbon: 89% Intervention N=41 52.8 – 70.2 Comparator • Male: 63% GyE, given in 4 3-year progression- • Grade 2 Follow-up • Age: 76 (median), (range, – 26 fractions free survival PBT: 14% PBT 39-89) PBT: 44% Carbon: 7% F/U: 45 months • Smoking (yes): 71% Carbon: 53% (median), (range, • Median tumor diameter • Grade 3 5-103) (mm) (range): 28 (12-48) 3-year local control PBT: 4% •Tumor stage PBT: 81% Carbon: 2% Carbon ion T1a: 22% Carbon: 78% therapy T1b: 41% • Grade 4 F/U: 39 months T2a: 37% • Differences PBT: 0% (median), (range, • Operability (yes): 46% between groups for Carbon: 2% 5-72) •Median BED10 (GyE10) 3-year outcomes (range): 122 (89-122) were not Rib fracture (p=0.532) statistically • Grade 0-1 • Significant differences significant PBT: 75% between groups including Carbon: 78% median BED10 • Grade 2 PBT: 24% Carbon: 22% • Grade 3 PBT: 1% Carbon: 0% 3D-CRT: 3D conformal radiation therapy; BED10: biological effective dose; DLCO: diffusing capacity of the lung for carbon monoxide; F/U: follow-up; IMRT: intensity-modulated radiotherapy; N: number; NR: not reported; NSCLC: non-small-cell lung cancer; PBT: proton beam therapy; PFT: pulmonary function test; WHO: World Health Organization WA – Health Technology Assessment March 28, 2014 Table 9. Lung Cancer: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Gomez (2012) PBT Inclusion PBT NR Rates of severe Fair • Overlapping N=108 • Patients treated • Median total radiation esophagitis patient Retrospective • Male: 55% for NSCLC with a dose: 74 Gy (grade ≥3) populations Comparative • Age: 67 (median) total radiation dose (RBE) (range PBT: 6% w/Lopez Guerra Cohort • Former and current of ≥50 Gy 50-87.5) IMRT: 28% (2012) and Sejpal smokers: 89% • Radiation therapy 3D-CRT: 8% (2011) MD Anderson • Clinical stage delivered in 1.8-2.5 IMRT p<0.05 Cancer Center, IA: 3%; IB: 11%; IIA: 0%; IIB: Gy fractions • Median total TX, USA 12%; IIIA: 25%; IIIB: 28%; IV: dose: 63 Gy • No grade 5 Study Objective 4%; Recurrent/post-op: 6% Exclusion (range, 50- toxicities seen • Previous 74.25) Evaluation of IMRT irradiation of the radiation-induced N=139 lung 3D-CRT esophagitis in • Male: 55% • History of • Median total patients treated • Age: 64 (median) esophageal cancer dose: 63 Gy for NSCLC • Former and current • Boost field used (range, 54-84) smokers: 94% during treatment Intervention • Clinical stage • Total doses Comparator IA: 2%; IB: 5%; IIA: 1%; IIB: were Follow-up 4%; IIIA: 33%; IIIB: 41%; IV: significantly PBT 9%; Recurrent/post-op: 3% different (p<0.001) IMRT 3D-CRT N=405 3D-CRT • Male: 50% • Age: 65 (median) F/U: up to 6 • Former and current months following smokers: 92% the start of • Clinical stage radiation therapy IA: 8%; IB: 9%; IIA: 1%; IIB: 5%; IIIA: 34%; IIIB: 36%; IV: 6%; Recurrent/post-op: 0% • Significant differences among groups including clinical stage, tumor histology, concurrent therapy 3D-CRT: 3D conformal radiation therapy; BED10: biological effective dose; DLCO: diffusing capacity of the lung for carbon monoxide; F/U: follow-up; IMRT: intensity-modulated radiotherapy; N: number; NR: not reported; NSCLC: non-small-cell lung cancer; PBT: proton beam therapy; PFT: pulmonary function test; WHO: World Health Organization Proton Beam Therapy: Final Evidence Report Page 114 WA – Health Technology Assessment March 28, 2014 Table 9. Lung Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Lopez Guerra PBT Inclusion PBT • Use of 3D-CRT NR Fair • Overlapping (2012) N=60 • Patients w/a • Median total associated w/larger patient • Male: 58% primary diagnosis of dose: 74 GyE post-treatment populations Retrospective • Age: 71 (median) NSCLC (range, 60- declines in lung w/Gomez (2012) Comparative • Race • Patients w/DLCO 87.5) diffusing capacity and Sejpal (2011) Cohort White: 93% analyses before and for carbon Other: 7% after radiation IMRT monoxide (DLCO) MD Anderson • Clinical stage therapy • Median total during 5-8 months Cancer Center, TX, I,II: 40% dose: 66 Gy following USA III,IV: 60% Exclusion (range, 60-74) treatments, as Study Objective • Former and current • Patients compared to PBT smokers: 95% undergoing 3D-CRT (p=0.009) Evaluation in postradiation PFT • Median total pulmonary IMRT analysis following dose: 66 Gy function following N=97 locoregional or (range, 60-84) radiation therapy • Male: 61% distant relapse for NSCLC • Age: 69 (median) • No PFT analyses • All radiation • Race done 1 month prior given in Intervention White: 90% and 2 months after fractions of Comparator Other: 10% diagnosis of radiation 1.2-2.5 Gy Follow-up • Clinical stage pneumonitis PBT I,II: 9% III,IV: 91% IMRT • Former and current smokers: 95% 3D-CRT 3D-CRT F/U: up to 1 year N=93 following • Male: 52% radiation therapy • Age: 74 (median) • Race White: 89% Other: 11% • Clinical stage I,II: 18% III,IV: 82% • Former and current smokers: 95% 3D-CRT: 3D conformal radiation therapy; BED10: biological effective dose; DLCO: diffusing capacity of the lung for carbon monoxide; F/U: follow-up; IMRT: intensity-modulated radiotherapy; N: number; NR: not reported; NSCLC: non-small-cell lung cancer; PBT: proton beam therapy; PFT: pulmonary function test; WHO: World Health Organization Proton Beam Therapy: Final Evidence Report Page 115 WA – Health Technology Assessment March 28, 2014 Table 9. Lung Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Sejpal (2011) PBT Inclusion • All patients Median overall survival • No differences in Fair • Overlapping patient N=62 • Patients w/locally received (months) hematological toxicities populations w/Gomez Non- • Male: 55% advanced, concurrent PBT: 24.4 found among groups (e.g., (2012) and Lopez contemporaneous • Age: 67 (median) unresectable NSCLC chemotherapy IMRT: 17.6 anemia, Guerra (2012) Case Series • Ethnicity: White: 60%; 3D-CRT: 17.7 thrombocytopenia, Non-white: 40% Exclusion PBT p=0.1061 neutropenia) • Data available for all MD Anderson • Prior malignancy: 27% • Prior thoracic • Median total grades of harms, Cancer Center, TX, • Clinical stage irradiation dose: 74 Gy (RBE) Esophagitis including fatigue USA 1B: 3%; 2A: 0%; 2B: 8%; 3A: 40%; • Malignant pleural (range, 63-80.95) • Grade 3 Study Objective 3B: 27%; 4: 8%; Recurrent: 13% effusion PBT: 5% • Analyses of harms • Karnofsky IMRT IMRT: 39% based on treatment Evaluation of acute IMRT performance score • Median total 3D-CRT: 18% modality and gross toxicities associated N=66 <60 dose: 63 Gy tumor volume with treatment of • Male: 61% • Weight loss >10% (range, 60-76) • Grade 4 seen w/IMRT: available locally advanced • Age: 62 (median) in 6 months prior to 4.5% NSCLC • Ethnicity: White: 70%; diagnosis 3D-CRT Non-white: 30% • Median total Pneumonitis Intervention • Prior malignancy: 27% dose: 63 Gy • Grade 3 Comparator • Clinical stage (range, 60-69.9) PBT: 2% Follow-up 1B: 0%; 2A: 0%; 2B: 5%; 3A: 23%; IMRT: 6% PBT 3B: 58%; 4: 11%; Recurrent: 4% • Total doses 3D-CRT: 30% F/U: 15.2 months were significantly (median), (range, 3D-CRT different • No cases of Grade 4 3.3-27.4) N=74 (p<0.001) seen; Grade 5 seen • Male: 50% w/IMRT: 3% IMRT • Age: 61 (median) F/U: 17.4 months • Ethnicity: White: 88%; Dermatitis (median), (range, Non-white: 12% • Grade 3 1.8-65.5) • Prior malignancy: 14% PBT: 24% • Clinical stage IMRT: 17% 3D-CRT 1B: 0%; 2A: 3%; 2B: 3%; 3A: 41%; 3D-CRT: 7% F/U: 17.9 months 3B: 46%; 4: 8%; Recurrent: 0% (median), (range, • No cases of Grade 4 or 2.3-76.1) • Significant differences among 5 seen groups including age, ethnicity, clinical stage, induction • Significant differences chemotherapy among groups across all grades of toxicities 3D-CRT: three-dimensional conformal radiotherapy; BED10: biological effective dose; DLCO: diffusing capacity of the lung for carbon monoxide; F/U: follow-up; IMRT: intensity- modulated radiotherapy; N: number; NSCLC: non-small-cell lung cancer; PBT: proton beam therapy; PFT: pulmonary function test Proton Beam Therapy: Final Evidence Report Page 116 WA – Health Technology Assessment March 28, 2014 Table 10. Lymphomas: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings No comparative studies identified Proton Beam Therapy: Final Evidence Report Page 117 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Cassoux (2013) PBT Inclusion PBT • No significant NR Poor • Potential patient N=57 • Patients • Total dose: 60 differences among population overlap Non- • Male: 60% w/choroidal Gy RBE given in groups in initial w/Desjardins contemporaneous • Age: 56 melanoma >10mm 4 fractions visual acuity (p=.67), (2006) Case Series • Median tumor diameter (mm) diameter and >5mm or in final visual (range): 18 (10-23) thickness PBT + TTT acuity at 2 years Institut Curie, • Median tumor thickness (mm) • Total dose: 60 (p=.54) France (range): 8 (5-11) Gy RBE given in • Tumor location – posterior: 21% 4 fractions 2-year survival •Tumor stage ≥T3: 98% • 3 sessions of without neovascular TTT provided glaucoma PBT + TTT • PBT: 55% N=51 PBT + • PBT + TTT: 62% • Male: 45% endoresection • PBT + • Age: 59 • Total dose: 60 endoresection: 93% • Median tumor diameter (mm) Gy RBE given in P=.0001 (range): 17 (13-23) 4 fractions • Median tumor thickness (mm) • Endoresection 2-year survival (range): 8 (5-12) performed without secondary • Tumor location – posterior: 30% following PBT enucleation •Tumor stage ≥T3: 100% • PBT: 89% • PBT + TTT: 98% PBT + endoresection • PBT + N=63 endoresection: 96% • Male: 67% P=.203 • Age: 57 • Median tumor diameter (mm) 2-year survival (range): 14 (8-19) without metastasis • Median tumor thickness (mm) • PBT: 86% (range): 9 (6-12) • PBT + TTT: 86% • Tumor location – posterior: 26% • PBT + •Tumor stage ≥T3: 81% endoresection: 90% P=NS • Significant differences between groups including tumor diameter & thickness, clinical stage and presence of retinal detachment Proton Beam Therapy: Final Evidence Report Page 118 WA – Health Technology Assessment March 28, 2014 Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Study Objective Evaluation of PBT ± adjunct therapy in patients with choroidal melanoma Intervention Comparator Follow-up PBT F/U: 112 months (median), (range, (107-126) PBT + TTT F/U: 99 months (median), (range, 89-124) PBT + endoresection F/U: 23 months (median), (range 20-26) BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 119 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms Quality Notes Criteria Protocol Main Findings* Study Site Characteristics Mosci (2012) PBT Inclusion PBT 5-year all-cause PBT Fair • After correcting N=70 • Patients • Total dose: 60 mortality Eye retention: 74%, for age, tumor Retrospective • Male: 55% w/unilateral GyE given in 4 • PBT: 34% over 5 years thickness and sex, Comparative • Age: 62.7 ± 14.1 choroidal tumors fractions • Enucleation: 43% no significant Cohort • Mean (SD) tumor classified as T3 and effect seen on thickness (mm): 9.8 ± T4 tumors 5-year melanoma- metastasis-free Ocular Oncology 1.6 related mortality survival associated Service, Italy • Mean (SD) largest Exclusion • PBT: 38% w/type of Study Objective basal diameter (mm): • Previously treated • Enucleation: 39% treatment 15.2 ± 2.7 tumors Evaluation of • Clinical stage • Diffuse, ring or 5-year metastasis- • Analysis of survival following T3: 84% multifocal tumors free survival outcomes based treatment of large T4: 16% • Tumors judged to • PBT: 72% on tumor type uveal tumors be predominantly • Enucleation: 55% revealed no Enucleation ciliary body significant Intervention N=62 melanoma Local recurrence differences Comparator • Male: 61% • Patients PBT: 14% between Follow-up • Age: 66.7 ± 14.5 w/metastatic disease • Secondary treatment type for PBT • Mean (SD) tumor or other primary enucleation: 9/10 both T3 and T4 F/U: 53.4 ± 29.3 thickness (mm): 12.0 tumors (90%) tumors months ± 2.8 • Patients w/history • Second course of • Mean (SD) largest of cancer PBT: 1/10 (10%) Enucleation basal diameter (mm): F/U: 45.5 ± 21.6 14.4 ± 4.5 Visual acuity (PBT) months • Clinical stage BCVA ≥ 0.1 T3: 58% Baseline: 73% T4: 42% 12 months: 47.5% 24 months: 39% • Significant 60 months: 32% difference between groups in tumor thickness * P-values not reported. BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 120 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms Quality Notes Criteria Protocol Main Findings Study Site Characteristics Marucci (2011) PBT Inclusion PBT PBT NR Fair Adjusted analyses N=31 • Patients w/ • 70 CGE in 5 • 5-year cumulative rate • Adjustment for Retrospective •Male: 33% recurrent uveal fractions of local recurrence: 31% tumor volume and Comparative • Age: 66 melanoma, originally (1 patient received • Enucleation: 29% year of re- Cohort • Mean largest tumor treated with PBT 48 CGE) • Visual acuity ≥20/200 treatment, diameter (mm): 14.6 maintained: 5/15 (33%) outcomes more Massachusetts • Tumor location – favorable for PBT General Hospital, posterior: 36% Survival without compared to MA, USA • Visual acuity ≥ metastasis* enucleation: Study Objective 20/200: 71% PBT: 54% Mortality: HR 0.14 Enucleation: 36% (p=0.002) Evaluation of Enucleation Distant metastasis: survival following N=42 Alive w/metastasis* HR 0.15 (p=0.005); treatment with •Male: 46% PBT: 3% similar findings PBT or • Age: 60 Enucleation: 2% with the addition enucleation for • Mean largest tumor of age to the recurrent uveal diameter (mm): 15.7 Death due to metastasis* model melanoma • Tumor location – PBT: 32% posterior: 29% Enucleation: 59% • Patients Intervention • Visual acuity ≥ evaluated were a Comparator 20/200: N/A Death from other causes* subgroup of Follow-up PBT: 10% patients from PBT • Significant Enucleation: 5% Gragoudas (2000) F/U: 74 months differences between (mean), groups in tumor Median survival duration (5-189, range) volume PBT: 90 months Enucleation: 42 months Enucleation p=0.04 F/U: 88 months (mean), Median time free from (10-225, range) metastasis PBT: 97 months Enucleation: 38 months p=0.028 * P-values not reported. BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 121 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Patient Treatment Protocol Harms Quality Notes Criteria Main Findings Study Site Characteristics Bellman (2010) Conservative Inclusion Conservative • No intraocular or NR Fair Size of extraocular 3 N=38 • Patients PBT orbital tumor spread (mm ) Retrospective • Male: 34% w/choroidal • 60 GyE given in 4 recurrence observed (played a role in Comparative • Age ≥63: 50% melanoma and cilio- fractions treatment choice) Cohort • Largest tumor basal choroidal melanoma 5-year overall p=NR diameter, mean presenting w/ Plaque survival rate Institut Curie, ≤15mm: 55% extraocular spread radiotherapy Conservative: 79.3% • Conservative France • Tumor location – • Iodine-125 Enucleation: 40.4% PBT: 14.8 ± 19.9 Study Objective posterior: 5% Exclusion plaque, 2-4 mm p<0.01 Plaque: 4.6 ± 4.8 • Extraocular spread • Patients larger than tumor Evaluation of mean ≤1000mm : 3 w/disseminated base; 90 Gy • Subgroup analysis •Enucleation tumor recurrence 100% melanoma PBT: 57.6% 136.7 ± 346.4 and survival in Enucleation Plaque therapy: uveal melanoma Enucleation • Postoperative 100% with extraocular N=29 orbital p=0.01 spread • Male: 72% radiotherapy, avg. • Age ≥63: 55% dose 50 Gy over 40 5-year metastasis- Intervention • Largest tumor basal days free survival rate Comparator diameter, mean Conservative: 59.0% Follow-up ≤15mm: 38% Enucleation: 39.4% Conservative • Tumor location – p=0.02 treatment (PBT, posterior: 34% plaque • Extraocular spread 3 radiotherapy) mean ≤1000mm : 93% Enucleation • Significant F/U: differences between 38 months (7-79) groups including (median, range) gender, tumor site and height, and retinal detachment BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 122 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Patient Treatment Protocol Harms Quality Notes Criteria Main Findings Study Site Characteristics Voelter (2008) PBT Inclusion • All patients Median overall NR Fair • Data on side N=66 • Patients received PBT survival effects of Retrospective • Male: 59% w/nonmetastatic PBT: 7.4 years fotemustine Comparative • Age uveal melanoma Chemotherapy PBT + chemotherapy: provided Cohort 20-55: 59% • Patients meeting at • Initiated 4-6 9 years >55: 41% least 1 of following weeks following p=0.5 Paul Scherrer • Largest tumor criteria: PBT Institut, diameter >20mm: 1) choroidal • Fotemustine (100 5-year survival rate 2 Switzerland 91% involvement; mg/m ) infused as PBT: 56% Study Objective 2) largest tumor an intra-arterial PBT + chemotherapy: PBT + chemotherapy diameter >20mm; hepatic infusion 75% Evaluation of N=22 3) extrascleral over 4 hours p=0.539 adjuvant • Male: 73% extension; • Once-weekly chemotherapy • Age 4) tumor height administration for 4 • Cox regression following PBT in 20-55: 77% >15mm weeks, followed by model (covariates the treatment of >55: 23% a 5-week break, including largest uveal melanoma • Largest tumor then 1 infusion tumor diameter, age, diameter >20mm: every 3 weeks sex, tumor Intervention 91% • Total treatment thickness): Comparator duration: 6 months death at 5 years, HR Follow-up 0.98 (95% CI, 0.38- PBT 2.61) F/U: 8.5 years (median) PBT + chemotherapy F/U: 4.6 years (median) BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 123 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms Quality Notes Criteria Protocol Main Findings Study Site Characteristics Desjardins (2006) PBT Inclusion PBT • Outcomes • No statistically Fair • In PBT-only N=75 • Patients w/uveal • Total dose: 60 assessed according significant difference group, 7 patients RCT • Male: 60% melanomas GyE given in 4 to original between groups in received TTT • Age: 56 • Tumor diameter fractions of 15 randomization terms of cataracts, following Institut Curie, • Mean tumor ≥15 mm and/or GyE maculopathy, and development of France diameter (mm): 17.6 tumor thickness ≥7 • Mortality reported papillopathy (data complications (e.g., Study Objective • Mean tumor mm PBT + TTT for entire study not shown) massive exudates thickness (mm): 7 • Total dose: 60 cohort only from tumor scar) Evaluation of • Tumor location – Exclusion GyE given in 4 Incidence of transpupillary posterior: 24% • Presence of fractions of 15 glaucoma • In PBT + TTT thermotherapy metastases GyE PBT: 55% group, 9 patients (TTT) combined PBT + TTT • Pre-existing • Spot laser PBT + TTT: 46% did not receive TTT w/PBT in the N=76 glaucoma treatment utilizing p=NS due to retinal treatment of • Male: 43% • Opaque media 810 nm detachment or uveal melanoma • Age: 59 preventing TTT (e.g., wavelength Mean peak vitreous • Mean tumor cataract, vitreous intraocular pressure hemorrhage Intervention diameter (mm): 17.6 hemorrhage) (mmHg) Comparator • Mean tumor PBT: 34.5 Follow-up thickness (mm): 7.6 PBT + TTT: 31 PBT • Tumor location – p=NS posterior: 26% PBT + TTT • Reduction of • Median initial tumor thickness F/U: 38 months visual acuity across greater for PBT + (median) the cohort: 20/60 TTT vs. PBT (p=0.06) (range, 20/400- 20/20) • Significantly lower secondary enucleation rate in PBT + TTT vs. PBT (p=0.02) BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 124 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Patient Harms Quality Notes Criteria Protocol Main Findings Study Site Characteristics Char (2003) PBT + laser Inclusion PBT + laser Mean time to fluid NR Poor N=11 • Patients • Confluent 810 resorption (days) Non- • Male: 55% w/choroidal nm laser spots PBT + laser: 192 contemporaneous • Age: 45.4 melanomas • PBT, total dose: PBT: 263 Case Series • Mean largest w/exudative retinal 56 GyE p<0.04 diameter (mm): 12.3 detachments ≥15% of Site: NR • Largest diameter fundus PBT Change in VA at 1 Study Objective ≤10mm: 18% • Total dose: 56 year • Tumor location – Exclusion GyE (log VA) Evaluation of laser posterior: 73% • No prior tumor PBT + laser (n=8): treatment plus PBT therapy 0.599 in decreasing PBT • Tumors PBT (n=42): 0.584 exudative N=45 overhanging optic p=NR detachments in • Male: 48% nerve choroidal • Age: 60.5 • Tumors contiguous • No significant melanoma • Mean largest to fovea difference in visual diameter (mm): 12.6 • ≥40% ciliary body field scotoma in 2 Intervention • Largest diameter involvement groups Comparator ≤10mm: 20% Follow-up • Tumor location – PBT + laser posterior: 60% F/U: 13.6 months (2-35) (mean, range) PBT F/U: 30.8 months (3-89) (mean, range) BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 125 WA – Health Technology Assessment March 28, 2014 Table 11. Ocular Tumors: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Seddon (1990) PBT Inclusion NR Overall mortality* NR Fair • Survival rates N=556 • Patients PBT: 22% calculated for Retrospective • Male: 48% w/unilateral Enucleation (65-75): 65% yearly intervals Comparative Cohort • Age >60: 42% melanoma involving Enucleation (75-84): 44% after treatment up • Largest tumor diameter the choroid and/or to 10 years Massachusetts General >15mm: 36% ciliary body >9-10-year survival rate* Hospital, MA, USA • Tumor height ≤5mm: 47% • Primary treatment PBT: 0.63 • Adjusted hazards Study Objective • Tumor location – w/enucleation or PBT Enucleation (65-75): 0.50 model (adjustments posterior: 45% Enucleation (75-84): 0.53 including tumor Evaluation of mortality Exclusion height, anterior following enucleation or Enucleation (1965-75) • Patients w/clinical Adjusted overall death margin, age) for PBT for treatment of N=238 evidence of rates (PBT is referent) (RR, interval specific uveal melanoma • Male: 43% metastatic disease 95% CI) death by treatment • Age >60: 43% • Prior treatment of • Metastatic death group available Intervention • Largest tumor diameter the intraocular tumor Enucleation (65-75): Comparator >15mm: 41% • From enucleation 1.7 ( 1.2-2.4) • Significant Follow-up • Tumor height ≤5mm: 43% group, patients Enucleation (75-84): increase in rate of PBT • Tumor location – w/tumors larger in 1.1 (0.8-1.5) death up to 2 years F/U: 5.0 years (median), posterior: 58% area than the largest after treatment for (range, <1-12.9) tumor in the PBT • Cancer death patients Enucleation (1975-84) series Enucleation (65-75): w/enucleation Enculeation N=257 1.6 (1.2-2.1) compared to PBT (1965-June 1975) • Male: 47% Enucleation (75-84): (95% CI available); F/U: 8.8 years (median), • Age >60: 59% 1.0 (0.7-1.4) differences are (range, <1-23.8) • Largest tumor diameter essentially non- >15mm: 47% • All cause mortality significant after 2 Enucleation • Tumor height ≤5mm: 33% Enucleation (65-75): year (July 1975-1984) • Tumor location – 1.6 (1.2-2.1) F/U: 6.7 years (median), posterior: 50% Enucleation (75-84): (range, <1-13.6) 1.2 (0.9-1.6) • Significant differences among groups including age, tumor location, height and diameter * P-values not reported. BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; NS: not significant; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 126 WA – Health Technology Assessment March 28, 2014 Table 12. Pediatric Cancers: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings Sethi (2013) PBT Inclusion PBT NR Secondary Poor • Subgroup N=55 • Patients with • Median RBE malignancy analysis of Retrospective • Male: 44% retinoblastoma dose (Gy): 44 PBT: 2% patients Comparative • Median age at (range, 40-50) Photon: 13% w/hereditary Cohort diagnosis: 7.5 months Exclusion p=NR disease • Median age at • Patients receiving Photon Massachusetts treatment: 14.8 PBT after prior • Median RBE 10-year 10-year General months photon therapy dose (Gy): 45 cumulative cumulative Hospital, MA, • Receipt of • Patients w/ <6 (range, 34-83) incidence of incidence of USA chemotherapy: 56% months follow-up secondary secondary Study Objective malignancy malignancy Photon PBT: 5% PBT: 5% Evaluation of N=31 Photon: 14% Photon: 22% secondary • Male: 55% p=0.12 p=0.021 malignancy in • Median age at patients treated diagnosis: 7.2 months 10-year 10-year for • Median age at cumulative cumulative retinoblastoma treatment: 10.0 incidence of RT- incidence of RT- Intervention months induced or in-field induced or in- Comparator • Receipt of malignancies field Follow-up chemotherapy: 16% PBT: 0% malignancies Photon: 14% PBT: 0% PBT • Significant p=0.015 Photon: 22% F/U: 6.9 years differences between p=0.005 (median), (range groups including year 2-24 years) of treatment, hereditary status, Photon receipt of F/U: 13.1 years chemotherapy, (median), (range median follow-up 1-24 years) F/U: follow-up; N: number; NR: not reported; PBT: proton beam therapy; RBE: relative biological effectiveness; RT: radiation therapy Proton Beam Therapy: Final Evidence Report Page 127 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Gray (2013) PBT Inclusion PBT • No between-group NR Poor • Data available N=95 • Patients •Dose: 74-82 Gy comparisons for 3 domains at Non- • Age: 64 (median) w/localized prostate (RBE) provided time points: 2-3 contemporaneous • Race cancer months and 12 Case Series White: 93%; Black: 6%; • No receipt of IMRT • Mean score change months post- Other: 1% androgen- • Dose: 75.6-79.2 from baseline, 24 treatment Multiple clinical • Clinical stage suppression therapy Gy months post- sites T1: 80%; T2:20%; T3: 0% treatment • Gleason score 3D-CRT Study Objective 4-6: 67%; 7: 32%; 8-10: 1% • Dose: 66.4-79.2 Bowel/rectal Gy QoL* Evaluation of IMRT PBT: -3.7 patient-reported N=153 • All therapy IMRT: -7.4 QoL after different • Age: 69 (median) given in 1.8-2.0 3D-CRT: -4.3 treatments for • Race Gy fractions • All changes prostate cancer White: 79%; Black: 18%; significant Other: 1% • All changes • Clinical stage clinically meaningful Intervention T1: 80%; T2: 20%; T3: 0% (>0.5 SD of baseline) Comparator • Gleason score Follow-up 4-6: 63%; 7: 37%; 8-10: 0% Urinary irritation/ PBT obstruction QoL* 3D-CRT PBT: -2.3 IMRT N=123 IMRT: 1.7 • Age: 70 (median) 3D-CRT: -2.0 3D-CRT • Race • No significant White: 94%; Black: 2%; changes F/U: 24 months Other: 1% • Clinical stage Urinary incontinence T1: 40%; T2: 51%; T3: 6% QoL* • Gleason score PBT: -4.1 4-6: 54%; 7: 31%; 8-10: 12% IMRT: -5.1 3D-CRT: -1.9 • Significant differences among • Only IMRT groups including age, race, PSA and w/significant change clinical stage of tumor from baseline * QoL evaluated for PBT and 3D-CRT using the Prostate Cancer Symptom Indices (PCSI) scale, and for IMRT w/the Expanded Prostate Cancer Index Composite (EPIC) instrument. 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Hoppe (2013) PBT • Patients PBT • QoL evaluated using the EPIC-26 NR Poor • Patient N=1,243 w/localized prostate • Dose: 78-82 Gy questionnaire overlap Non- • Age: 66 cancer (RBE) w/Mendenhall contemporaneous • Race • Median score change from (2012) Case Series White: 91% PBT IMRT baseline, 2 years post-treatment Black: 6% Exclusion • Dose: 75.6- University of Other: 3% • Failure to 79.2 Gy Bowel summary score Florida Proton • PSA >10 ng/ml: 14% complete treatment PBT: -4 Therapy Institute, • Clinical stage • Hypofractionated IMRT: 0 T1: 74% PBT P=.99 FL, USA T2: 26% • Weekly docetaxel Study Objective T3: <1% • Pelvic lymph node Urinary incontinence summary Evaluation of • Gleason score <7: 53% irradiation score patient-reported • Receipt of ADT: 15% PBT: 0 QoL after different IMRT IMRT: 0 treatments for IMRT Exclusion P=.99 prostate cancer N=204 • Pelvic radiation • Age: 69 therapy Urinary irritative/ obstructive • Race summary score Intervention White: 81% PBT: 0 Comparator Black: 17% IMRT: 0 Follow-up Other: 0% P=.99 • PSA >10 ng/ml: 19% PBT • Clinical stage Sexual summary score* T1: 73% PBT: 0 IMRT T2: 27% IMRT: 0 T3: 0% P=.99 F/U: up to 2 years • Gleason score <7: 51% • Receipt of ADT: 24% • In adjusted analyses for baseline differences, patients receiving • Significant differences IMRT reported more “moderate” between groups including problems w/ rectal urgency age, race, size of prostate (p=.02) and bowel frequency and receipt of ADT (p=.05) compared to PBT * Evaluated only in patients not receiving ADT. 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 129 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Yu (2013) PBT Inclusion NR NR • For OR calculation, likelihood Fair • Mahalanobis-matched N=314 • Patients w/early- of complication w/PBT and data utilized Retrospective •Age ≥70: 63.7% stage, treated IMRT as referent Comparative •Race prostate cancer Patterns of care analysis Cohort White: 93% • PBT or IMRT as 6-month toxicities • Age Black: <3.5% primary treatment • Genitourinary Patients 66-69 years 3X Data Source: Other: >3.5% PBT: 5.9% more likely to receive PBT Chronic Condition • Comorbidities Exclusion IMRT: 9.5% than patients 85-94 (3.3% Warehouse – 0:73.6% • Patients without OR 0.60 (95% CI, 0.38,0.96) vs. 1.0%, p<0.001) Medicare linked 1-2: >22.9% Medicare A & B, 9 database ≥3: <3.5% months prior to • GI • Race • Receipt of ADT: 20.7% treatment through 3 PBT: 2.9% White patients more likely Study Objective months after IMRT: 3.6% to receive PBT than black IMRT OR 0.84 (95% CI, 0.42, 1.66) patients (2.2% vs. 0.5%, Evaluation of N=628 p<0.001) early toxicity •Age ≥70: 63.7% • Other associated with •Race PBT: <2.6% • Comorbidities PBT and IMRT White: 93% IMRT: 2.5% Patients w/no Black: 2.9% OR 0.69 (95% CI 0.29, 1.66) comorbidities more likely Other: 4.1% to receive PBt than Intervention • Comorbidities 12-month toxicities patients w/ ≥3 Comparator 0: 73.4% • Genitourinary comorbidities (2.6% vs. Follow-up 1-2: 23.2% PBT: 18.8% 0.8%, p<0.001) PBT ≥3: 3.3% IMRT: 17.5% • Receipt of ADT: 21% OR 1.08 (95% CI, 0.76, 1.54) • Distance IMRT Patients living closer (<75 • GI miles) and farther (>500 F/U: up to 12 PBT: 9.9% miles) more likely to months following IMRT: 10.2% receive PBT than patients treatment OR 0.97 (95% CI, 0.61, 1.53) 75-500 miles from center (4.9%, 4.2% vs. 1.5%, • Other p<0.001) PBT: 4.5% IMRT: 5.6% OR 0.78 (95% CI, 0.41, 1.50) 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 130 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Coen (2012) PBT + photon PBT + photon PBT + photon 8-year overall NR Fair • Subgroup (Subset of Zietman, 2010 – Inclusion • PBT: 28.8 GyE survival analysis of 8-year Non-contemporaneous high dose arm) • Patients • Photon: 50.4 Gy PBT + photon: 93% BF: no significant Case Series N=141 w/clinically localized • Fraction size: Brachytherapy: 96% differences • Age: 67 (median) prostate 1.8 Gy p=0.45 between Massachusetts General • Median PSA (ng/mL): 6.1 adenocarcinoma treatment groups Hospital, MA, USA • T stage • Tumors stage T1b Brachytherapy 8-year freedom in low risk and 125 1c: 74% – T2b • I implant from metastasis intermediate risk Study Objective 2a: 25% • Serum PSA <15 Dose: 145 Gy PBT + photon: 99% patients 2b: 1% ng/ml Brachytherapy: 96% Evaluation of high-dose • Gleason score • No evidence of 103 • Pd implant p=0.21 • Additional data PBT and brachytherapy 6: 89% metastatic disease Dose: 115 Gy on PSA levels for the treatment of 7: 11% 8-year BF rates available (e.g., PSA prostate cancer • No patients received Exclusion PBT + photon: 7.7% bounce, last PSA hormonal therapy • Gleason score >7 Brachytherapy: level) 16.1% Intervention Brachytherapy Brachytherapy p=0.42 Comparator N=141 Inclusion Follow-up • Age: 65 (median) • Patients w/ T1-T2 Median nadir PSA PBT + photon • Median PSA (ng/mL): 5.6 prostate cancer (ng/mL) (data from Zietman, • T stage • Implant PBT + photon: 0.3 2010) 1c: 74% performed 1997- Brachytherapy: 0.1 F/U: 8.6 years (median), 2a: 25% 2002 p=NR (range, 1.2-12.3) 2b: 1% • Gleason score ≤7 • Gleason score • PSA ≤15 ng/mL Mean nadir ≤0.5 Brachytherapy 6: 89% • At least 3 years of ng/mL F/U: 7.4 years (median), 7: 11% f/u available PBT + photon: 74% 125 (range, 3.1-11.3) • I implant: 91% Brachytherapy: 92% 103 • Pd implant: 9% p=0.0003 • No patients received EBRT or ADT 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 131 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Sheets (2012) PBT Inclusion NR NR • Event rate per 100 person- Fair • Propensity- score N=684 • Patients w/a years adjusted data Retrospective • Age ≥70: 63.9% diagnosis of prostate utilized Comparative • Race cancer • P-values not reported Cohort White: 92.5% • No additional • Rate ratios Black: 2.9% cancers, meta-static GI available for IMRT Data source: Other: 4.5% disease, or disease • Procedures vs. PBT for all Surveillance • Concurrent ADT: 31% diagnosis at autopsy PBT: 16.2 harms Epidemiology and • Clinical stage • Patients w/at least IMRT: 17.7 End Results T1: 50.7% 1 year of claims data • Diagnoses (SEER) – Medicare T2: 45.9% prior to diagnosis PBT: 17.8 linked database T3/T4: 3.4% IMRT: 12.2 • Tumor grade Exclusion Study Objective Well/mod diff.: 60.2% • Patients enrolled in Urinary Incontinence Poorly diff.: 39.2% HMOs, or not • Procedures Evaluation of enrolled in Medicare PBT: 7.8 morbidity and IMRT A&B IMRT: 7.6 disease control N=684 • Patients • Diagnoses after different • Age ≥70: 64.3% w/radiation and PBT: 3.3 treatments for • Race brachytherapy or IMRT: 3.1 prostate cancer White: 92.8% prostatectomy Black: 2.3% ED Dysfunction Other: 4.8% • Procedures Intervention • Concurrent ADT: 29.2% PBT: 1.4 Comparator • Clinical stage IMRT: 0.8 Follow-up T1: 50.6% • Diagnoses PBT T2: 46.6% PBT: 7.4 • F/U: 50 months T3/T4: 2.8% IMRT:6.6 (median), (range, • Tumor grade 0.3-90.2) Well/mod diff.: 62.3% Hip Fracture Poorly diff.: 37.1% PBT: 0.7 IMRT IMRT: 0.8 • F/U: 46 months (median), (range, Additional Cancer Therapy 0.4-88.3) PBT: 1.9 IMRT: 2.2 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 132 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Kim (2011) Radiation Inclusion NR NR • Event rate per 1000 Fair (for entire cohort only) • Patients aged 66-85 person-years Retrospective N=28,088 years w/T1-T2 clinically Comparative Cohort • Age ≥70: 76% localized prostate Any GI toxicity • Race cancer PBT: 20.1 Data source: White: 81%; Black: 11%; • Patients enrolled in IMRT: 8.9 Surveillance Other: 8% Medicare A & B for 12 3D-CRT: 9.3 Epidemiology and End • Hormone therapy within 1 year: months prior to Brachytherapy only: Results (SEER) – 44% diagnosis 5.3 Medicare linked • Clinical stage Conservative: 2.1 database T1: 52% Exclusion p=NR Study Objective T2: 48% • Having another cancer • Gleason score prior to prostate cancer GI Bleeding Evaluation of long- 2-4: 5% • Metastasis w/in 6 PBT: 20.1 term risk of GI 5-7: 64% months of diagnosis IMRT: 8.3 toxicities requiring 8-10: 29% • Palliative radiation 3D-CRT: 7.8 intervention following treatment w/in 12 Brachytherapy only: radiation therapy Conservative months of diagnosis 4.4 Intervention N=13,649 • Cryotherapy or Conservative: 0.9 Comparator • Age ≥70: 85% radioisotope therapy p=NR Follow-up • Race • Repeated White: 77%; Black: 13%; brachytherapy Pairwise comparisons Radiation therapy Other: 10% • Primary ADT not for any GI toxicity • Including EBRT, • Hormone therapy within 1 year: combined • PBT vs. brachytherapy and 0% w/radiotherapy Conservative: HR 13.7 EBRT + brachytherapy; • Clinical stage • Radical prostatectomy (9.09-20.8) • EBRT included PBT, T1: 65% in the first 12 months • PBT vs. 3D-CRT: HR IMRT and 3D-CRT T2: 35% after diagnosis 2.13 (1.45-3.13) • PBT included PBT ± • Gleason score • Existing GI toxicity in • PBT vs. IMRT: HR 3D-CRT or IMRT 2-4: 20% year before diagnosis 3.32 (2.12-5.20) 5-7: 59% • Enrollment in an Conservative 8-10: 15% HMO, private insurance management or VA coverage • Significant differences between F/U: at least 6 months groups including age, race, Gleason after cancer diagnosis score, clinical stage 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 133 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Treatment Protocol Harms Quality Notes Patient Characteristics Criteria Main Findings* Study Site Jabbari (2010) PBT + photon (data from Zietman, PBT + photon PBT + photon Interval to reach PSA NR Poor • Analyses by risk 2005) Inclusion • Phase 1-PBT nadir (median) and therapy: Non-contemporaneous N=195 • Patients Dose: 28.8 GyE, PBT + photon: 39.6 bNED in low-risk Case Series • Age: 66 (median) w/clinically localized given in 1.8 GyE months and high-risk • Additional treatment adenocarcinoma of fractions Brachytherapy: 43.2 patients University of CA, San nADT: 0% the prostate (160 or 250 mV months Francisco and • Clinical stage • Tumor stage T1b – beam) Massachusetts General T1: 61.5% T2b • Phase 2-photon Number of patients Hospital, MA, USA T2a: 25.6% • PSA <15 ng/mL Dose: 50.4 Gy, to achieve PSA ≤0.5 T2b: 12.8% • No evidence of given in 1.8 Gy ng/mL Study Objective • Gleason score metastatic disease fractions PBT + photon: 59% ≤6: 75.4% (10-23 mV beam) Brachytherapy: 91% Evaluation of efficacy of 7: 15.3% Brachytherapy brachytherapy vs. PBT + 8-10: 7.7% Inclusion Brachytherapy Number of patients photon for prostate • PSA (ng/mL): 6.2 (median) • Patients treated • Monotherapy to achieve PSA ≤0.1 cancer w/permanent 125 I: 144 Gy ng/mL 103 Brachytherapy prostate implant Pd: 125 Gy PBT + photon: 87% N=206 brachytherapy • Multimodal Brachytherapy: 96% Intervention 125 • Age: 63 (median) I: 110 Gy + 45 Gy Comparator • Additional treatment Exclusion EBRT 5-year estimate of Follow-up 103 nADT: 28% • Radiotherapy from Pd: 90 Gy + 45 bNED PBT + Photon EBRT ± nADT: 25% alternate institution Gy EBRT PBT + photon:91% • F/U (reported for entire • Clinical stage • Receipt of (95% CI, 87-95%) study population, T1: 47% adjuvant ADT Brachytherapy: 93% Zietman, 2005): 5.5 years T2a: 36% (95% CI, 88-95%) (median), (range, 1.2-8.2) T2b: 17% • Gleason score Brachytherapy ≤6: 83.5% • F/U: 5.3 years (median), 7: 16% (range, 0.3-8.3) 8-10: 0.5% • PSA (ng/mL): 6.3 (median) • Significant differences between groups including tumor stage * P-values not reported. 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 134 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Shah (2006) PBT + EBRT Inclusion PBT + EBRT NR • Gross hematuria present Poor •No significant N=7 • Patients w/new • Dose: 75 Gy in all patients difference in Retrospective onset urothelial (mean), (range, percent tobacco Comparative Cohort EBRT carcinoma after 68-80) • All patients presented users, p=0.2 N=4 receiving curative w/coexisting radiation Loma Linda doses of radiation EBRT cystitis University Medical • Mean age at diagnosis therapy for prostate (reported for 1/4 Center, CA, USA of urothelial carcinoma: cancer patients) Latency period to 72 • Dose: 75 Gy development of urothelial Study Objective carcinoma • Other baseline data • PBT + EBRT: 3.07 years Evaluation of not reported (mean) patients developing • EBRT: 5.75 years (mean) urothelial carcinoma p=0.09 following EBRT for prostate cancer Tumor Grade • PBT + EBRT Grade 1: 57% Intervention Grade 2:14% Comparator Grade 3: 29% Follow-up • EBRT: PBT + EBRT Grade 1: 25% Grade 2: 0% EBRT Grade 3: 75% •No significant differences F/U: 4.04 years in mean grade, p=0.23 (mean), (range, 0.5- 8) • No significant difference in patients requiring eventual cystectomy, p=0.6 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial Proton Beam Therapy: Final Evidence Report Page 135 WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Galbraith (2001) PBT • No age or race PBT • Multiple QoL scales NR Fair Withdrawals N=24 limitations • Dose: 74-75 Gy utilized including 6 months: 22 (12%) Prospective • Age: 68 Quality of Life Index, Comparative • Race Inclusion PBT + EBRT Southwest Oncology 12 months: 31 Cohort White:100% • Patients able to • Dose: 74-75 Gy Group Prostate (17%) Black or Hispanic: 0% speak, write, Treatment-Specific San Bernardino • PSA: 17.6 understand English EBRT Symptoms Measure, 18 months: 32 County, CA, USA • No known cognitive • Dose: 65-70 Gy and Importance of (17%) PBT + EBRT disabilities Sex-Role Identity N=47 • Able to meet basic Surgery • Multiple analyses Study Objective • Age: 69 needs independently NR 18 month - QoL available for 6, 12 Evaluation of QoL • Race No significant and 18 months following White: 81% Exclusion WW differences among different Black or Hispanic: 9% •Patients w/other NR groups treatments for • PSA: 14.1 primary comorbidities prostate cancer 18 month - Health EBRT N=25 Status • Age: 71 • PBT better physical Intervention • Race function than surgery Comparator White: 63% (p=0.01) or EBRT Follow-up Black or Hispanic: 22% (p=0.02) PBT • PSA: 22.8 • PBT better emotional functioning PBT + EBRT Surgery than WW (p=0.02) or N=59 EBRT (p=0.004) EBRT • Age: 65 • Race 18 month - Surgery White: 83% Treatment-specific Black or Hispanic: 14% Symptoms Watchful Waiting • PSA: 9.8 • WW more urinary symptoms than PBT, WW p=0.04 F/U: up to 18 N=30 months following • Age: 73 • No differences in treatment • Race masculinity noted White: 79% among groups over 18 Black or Hispanic: 14% months (p=0.49) • PSA: 11.6 • Significant differences among groups including age, PSA 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial WA – Health Technology Assessment March 28, 2014 Table 13. Prostate Cancer: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms* Quality Notes Patient Characteristics Criteria Protocol Main Findings* Study Site Shipley (1995) PBT + photon Inclusion • No concomitant/ Overall Survival PBT + photon Fair Withdrawals N=103 • Patients w/T3-T4, adjuvant endocrine •5-year N=93 PBT + photon: 10 RCT • Age: 70 (median) Nx, 0-2, M0 prostate therapy given PBT + photon: 75% Photon (9.7%) • T stage cancer Photon: 80% N=96 Photon: 3 (3.0%) Massachusetts T3: 94% • Performance status PBT + Photon General Hospital, T4: 6% ≥2 • Photon dose: • 8-year Rectal bleeding • Subgroup MA, USA • N Stage • Normal enzymatic 50.4 Gy given in PBT + Photon: 55% (incidence) analyses based on N0: 7.8% serum acid 1.8 Gy fractions Photon: 51% PBT + photon: 27% Gleason score Study Objective N+:3.9% phosphatase level • PBT dose: 25.2 Photon: 9% available for Nx: 88% • No evidence of CGE, given in 2.1 Disease-specific Survival • 91% of total events outcomes (well – Evaluation of • Gleason score metastases to bone, Gy fractions •5-year were ≤grade 2 and moderately- efficacy of a 1-2: 5.8% to retroperitoneal (160 MeV beam) PBT + photon: 86% toxicity differentiated vs. higher radiation 3: 62% lymph nodes, or to Photon: 83% poorly) dose for locally 4-5: 32% bifurcation of Photon Urethral stricture advanced common iliac vessels • Initial dose: 50.4 • 8-year (incidence) • Actuarial 8-year prostate cancer Photon Gy given in 1.8 Gy PBT + Photon: 67% PBT + photon: 13% rates calculated for N=99 Exclusion fractions Photon: 62% Photon: 5% harms w/statistical • Age: 68.6 (median) • Patients w/medical • Total tumor differences Intervention • T stage contraindications to dosing to 67.2 Gy, Local Control Hematuria Comparator T3: 96% pelvic radiation given in 2.1 Gy •5-year (incidence) • Benk (1993), Follow-up T4: 4% therapy fractions PBT + photon: 86% PBT + photon: 14% preliminary PBT + photon • N Stage • Patients w/prior (10-25 Mv beam) Photon: 81% Photon: 6% reporting on N0: 4% abdominal perineal patient population Photon N+: 5% resection • 8-year Urinary incontinence (n=191); subgroup Nx: 91% PBT + Photon: 73% PBT + photon: 1% analysis of dose F/U: 61 months • Gleason score Photon: 59% Photon: 1% volume (median), (range, 1-2: 11.1% w/incidence of 3-139) 3: 56.6% Total Tumor-free Loss of full potency rectal bleeding 4-5: 32.3% Survival PBT + photon: 24/40 •5-year (60%) PBT + photon: 39% Photon: 24/38 (63%) Photon: 41% • 8-year PBT + Photon: 20% Photon: 16% * P-values not reported. 3D-CRT: 3D conformal radiation therapy; ADT: androgen deprivation therapy; BF: biological freedom; bNED: biological no evidence of disease; CI: confidence interval; EBRT: external beam radiation therapy; F/U: follow-up; IMRT: intensity-modulated radiation therapy; N stage: describes spread of tumor to nearby lymph nodes; nADT: neoadjuvant androgen deprivation therapy; NR: not reported; PBT: proton beam therapy; PSA: prostate specific antigen; QoL: quality-of-life; RBE: relative biological effectiveness ; RCT: randomized controlled trial WA – Health Technology Assessment March 28, 2014 Table 14. Soft Tissue Sarcomas: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings No comparative studies identified Table 15. Seminomas: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Harms Quality Notes Study Design Patient Criteria Protocol Assessed Study Site Characteristics Main Findings No comparative studies identified Table 16. Thymomas: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Harms Quality Notes Study Design Patient Criteria Protocol Assessed Study Site Characteristics Main Findings No comparative studies identified Table 17. Noncancerous Conditions: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Harms Quality Notes Study Design Patient Criteria Protocol Assessed Study Site Characteristics Main Findings Arteriovenous malformations: no comparative studies identified Proton Beam Therapy: Final Evidence Report Page 138 WA – Health Technology Assessment March 28, 2014 Table 17. Noncancerous Conditions: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings* Study Site Giant cell tumors of bone Chakravarti PBT + photon Inclusion PBT + photon • Total study population NR Poor • Specific (1999) N=6 • Patients w/giant-cell • Photon (partial resection ± RT) detail • Male: 17% tumors of bone Cobalt 60 or 2-25 Progression of disease provided on Retrospective • Age: 23 treated MeV beams PBT + photon: 17% all patient Comparative • Tumor site w/megavoltage • Proton Photon: 14% cases Cohort Cervical spine: 33% radiation 160 MeV beam Sacrum: 50% • Contraindication to Distant metastases Massachusetts Temporal bone: 17% operative Mean total dose: PBT + photon: 17% General • Tumor size (cm): range, management 58.8 Gy given in Photon: 14% Hospital, MA, 2x2 – 6x7 • Use of operative fractions of 1.8-2.0 Mean duration w/lack of USA •Tumor grade management would Gy progression (months) Study 1: 50%; 2: 0%; 3: 0%; lead to major PBT + photon: 87.7 Objective Unknown: 50% morbidity or functional Photon Photon: 132.3 Evaluation of • Tumor stage impairment Cobalt 60 or 2-25 PBT in the Primary: 67% MeV beams • Radiation only population management Recurrent: 33% Exclusion Progression of disease of giant-cell Metastases: 0% • Patients w/Paget Mean total dose: PBT + photon: 0% tumors of disease 51.6 Gy given in Photon: 25% bone Photon • Patients w/brown fractions of 1.8-2.0 N=14 (15 tumors) tumors of Gy Distant metastases Intervention • Male: 43% hyperparathyroidism PBT + photon: 0% Comparator • Age: 46 Patients receiving Photon: 0% Follow-up • Tumor site radiation only Mean duration w/lack of Sacrum: 13% (n=7) progression (months) PBT + photon Femur: 20% PBT + photon: 43% PBT + photon: 114.7 Thoracic spine: 20% Photon: 57% Photon: 135 Photon Lumbar spine: 13% Sphenoid, Pubis, Lung, Patients w/partial • Partial resection + radiation F/U: 9.3 years Wrist, Tibia: each 7% resection + population (median), • Tumor size (cm): range, radiation (n=13) Progression of disease (range, 3-19) 2x2 – 12x12 PBT + photon: 23% PBT + photon: 33% •Tumor grade Photon: 77% Photon: 10% 1: 47%; 2: 33%; 3: 7%; Unknown: 13% Distant metastases • Tumor stage PBT + photon: 33% Primary: 67% Photon: 20% Recurrent: 20% Mean duration w/lack of Metastases: 13% progression (months) PBT + photon: 60.7 Photon: 131.3 * P-values not reported. CCH: circumscribed choroidal hemangioma; DCH: diffuse choroidal hemangioma; EBRT: external beam radiation therapy; F/U: follow-up; NR: not reported; PBT: proton beam therapy WA – Health Technology Assessment March 28, 2014 Table 17. Noncancerous Conditions: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Harms Quality Notes Study Design Patient Criteria Protocol Assessed Study Site Characteristics Main Findings Hemangiomas Höcht (2006) PBT Inclusion PBT Visual acuity and • Late side effects Poor • Data available N=25 • Patients • 68 MeV beam resolution of (graded using LENT/SOMA for harms related Retrospective • Male: NR w/symptomatic •Dose: 20 CGE, retinal system)* to lens and iris also Comparative • Age: 46.8 diffuse or given in 4 detachment available Cohort circumscribed fractions (1 reported for Optic nerve/optic disc Photon hemangiomas patient received entire cohort only • PBT • Cox regression Charité Campus N=19 22.5 CGE) Grade I: 48% model: no Benjamin • Male: NR • Cox regression • Photon significant impact Franklin, Germany • Age: 43.7 Photon model: no CCH, Grade I: 25% based on • 6 MV beam significant impact DCH, Grade I: 43% therapeutic Study Objective Overall cohort • Dose: 16-30 Gy, of PBT vs. photon modality seen on • Circumscribed given in 5 seen on Retina optic disc/optic Evaluation of hemangiomas: 82% fractions (2.0 Gy stabilization of • PBT nerve atrophy EBRT in the • Diffuse per fraction) vision (p=0.43) Grade I: 28% (p=0.27), or treatment of hemangiomas: 18% Grade II: 8% retinopathy choroidal Grade IV: 4% (p=0.098) hemangiomas Hemangioma size • Photon (optic disc diameters) CCH, Grade II: 17% • Mean: 6.67 DCH, Grade II: 14% Intervention • Median: 4 Comparator Ocular pressure Follow-up • PBT Mean hemangioma thickness (mm) Grade I: 4% PBT • Circumscribed • Photon F/U: 26.3 months PBT-treated: 3.3 CCH: 0% (mean), (median, Photon-treated: 4.2 DCH, Grade II: 14% 23.7) • Diffuse: 3.9 Lacrimation Photon • PBT F/U: 38.9 months • Mean visual acuity Grade III: 8% (mean), (median, of affected eye: 0.1- • Photon 29) 0.125 CCH, Grade I: 8% Grade II: 8% Grade III: 8% DCH: 0% Radiation retinopathy • PBT: 40% • Photon: 16% * P-values not reported. CCH: circumscribed choroidal hemangioma; DCH: diffuse choroidal hemangioma; EBRT: external beam radiation therapy; F/U: follow-up; NR: not reported; PBT: proton beam therapy WA – Health Technology Assessment March 28, 2014 Table 17. Noncancerous Conditions: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms* Quality Notes Patient Characteristics Criteria Protocol Main Findings* Study Site Meningiomas Arvold (2009) PBT Inclusion PBT Visual outcome Acute effects Poor N=9 • Patients w/ONSM • Mean dose • PBT (n=8) • PBT (n=8): 0% Retrospective • Male: 33% (GyE): 51 Improved:62.5% Comparative • Age: 38.9 Exclusion (range, 50.4-54) Stable: 25% • Photon (n=11): Cohort • Tumor size (mL): 3.7 • Patients Worsened: 12.5% Orbital pain: 9% • Symptoms: w/meningiomas Photon Headache: 9% Massachusetts Vision†: 89% w/only secondary • Mean dose • Photon (n=11) (same patient) General Hospital, Pain: 22% involvement of the (GyE): 50.8 Improved: 63.6% MA, USA None: 11% optic nerve sheath (range, 45-54) Stable: 36.3% • PBT + photon: 0% Study Objective Worsened: 0% Photon PBT + photon Late effects Evaluation of N=13 • Mean dose • PBT + photon (n=3) • PBT (n=8) patients w/ONSM • Male: 23% (GyE): 57 Improved: 66% Asymptomatic treated w/PBT • Age: 47.7 (range, 55.8-59.4) Stable: 33% retinopathy: 12.5% and/or photon • Tumor size (mL): 2.2 Worsened: 0% therapy • Symptoms: • Photon (n=11) Vision†: 77% • No tumor growth Asymptomatic Intervention Pain: 7.7% seen at latest follow- retinopathy: 9% Comparator None: 15% up in all patient Follow-up except 1, treated • PBT + photon (n=3) PBT PBT + Photon w/PBT + photon; Asymptomatic N=3 regrowth 11 years retinopathy: 33% Photon • Male: 100% after therapy • Age: 43 PBT + photon • Tumor size (mL): 3.6 • Symptoms: F/U: 30 months Vision†: 100% (3-168) (median, Pain: 0% range) Proptosis: 33% None: 0% * P-values not reported. † Vision symptoms included decline in visual acuity, color vision change, or visual field deficit. BCVA: best-corrected visual acuity; CI: confidence interval; F/U: follow-up; HR: hazard ratio; N: number; N/A: not available; NR: not reported; ONSM: optic nerve sheath meningioma; PBT: proton beam therapy; RCT: randomized controlled trial; RR: rate ratio; SD: standard deviation; TTT: transpupillary thermotherapy; VA: visual acuity Proton Beam Therapy: Final Evidence Report Page 141 WA – Health Technology Assessment March 28, 2014 Table 18. Mixed Cancers: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings Chung (2013) PBT Inclusion NR NR Incidence of secondary Good Pediatric patient N=558 • Patients treated malignancies analyses Non- (Pediatric, n=44) w/PBT or photon PBT: 5.2% • Second contemporaneous • Male: 70% therapy for Photon: 7.5% malignancies Case Series • Age: 59 (median) nonmetastatic p=NR PBT: 0% • Primary tumor sites cancer Photon: 0% Massachusetts CNS: 32% Median time to development of p=NR General Hospital, Head and neck: 24% Exclusion secondary malignancies MA, USA GU: 33% • Patients receiving PBT: 6.0 years •Median duration Musculoskeletal: therapy to the eye Photon: 4.75 years of f/u: 4.1 years Data source: 7.7% • Patients treated for p=0.085 Surveillance Others: 3.3% acromegaly or AVMs Epidemiology and •Patients w/history Incidence rate of secondary End Results (SEER) Photon of malignancy malignancies (per 1000 person- – Medicare linked N=558 years) database (Pediatric, n=44) PBT: 6.9 Study Objective • Male: 70% Photon: 10.3 • Age: 59 (median) p=NR Evaluation of • Primary tumor sites secondary CNS: 32% 10-year cumulative incidence malignancies in Head and neck: 24% rate for secondary malignancies patients treated GU: 33% PBT: 5.4% w/PBT and photon Musculoskeletal: Photon: 8.6% therapy 7.7% p=NR Others: 3.3% Intervention Adjusted HR of secondary Comparator malignancy • PBT vs. photon: Follow-up 0.52 (95% CI, 0.32-0.85) PBT F/U: 6.7 years Secondary malignancy occurring (median), (IQR 7.4) in prior field of radiation PBT: 10% Photon Photon: 16.7% F/U: 6.0 years p=0.20 (median), (IQR 9.3) AVM: arteriovenous malformation; CNS: central nervous system; ECOG: Eastern Cooperative Oncology Group; F/U: follow-up; GU: genitourinary; IQR: interquartile range; N: number; NR: not reported; PBT: proton beam therapy; PF: pterygopalatine fossa; PNS: paranasal sinus; PPS: parapharyngeal space; RIBC: radiation-induced brain change Proton Beam Therapy: Final Evidence Report Page 142 WA – Health Technology Assessment March 28, 2014 Table 18. Mixed Cancers: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Demizu (2009) PBT Inclusion PBT NR Vision loss caused by Fair • Patient overlap N=62 • Patients w/head • Total dose: 65 radiation-induced w/ Miyawaki Prospective • Male: 45% and neck or skull- GyE, given in 26 optic neuropathy (2009) Comparative • Age: 63 (median) base tumors adjacent fractions PBT: 9.7% Cohort • Tumor site to optic nerves Carbon: 15% Nasal/PNS: 68% Carbon p=NR Hyogo Ion Beam Skull base: 16% • Total dose: Medical Center, PF: 5% 57.6 GyE, given Incidence rate of vision Japan Nasopharynx/PPS: 8% in 16 fractions loss for all eligible Study Objective Orbita: 3% optic nerves • Treatment history PBT: 8% Evaluation of None: 74% Carbon: 6% vision loss Chemotherapy: 19% p=NR following Surgery: 7% radiation therapy • Diabetes: 3% • No significant for tumors • Hypertension: 13% difference in the adjacent to optic incident rates of vision nerves Carbon loss observed between N=13 PBT and carbon- Intervention • Male: 38% treated patients Comparator • Age: 57 (median) (p=0.4225) Follow-up • Tumor site PBT Nasal/PNS: 77% F/U: 25 months Skull base: 0% (median) PF: 15% Nasopharynx/PPS: 0% Carbon ion Orbita: 8% therapy • Treatment history F/U: 28 months None: 69% (median) Chemotherapy: 31% Surgery: 0% • Diabetes: 8% • Hypertension: 23% AVM: arteriovenous malformation; CNS: central nervous system; ECOG: Eastern Cooperative Oncology Group; F/U: follow-up; GU: genitourinary; IQR: interquartile range; N: number; NR: not reported; PBT: proton beam therapy; PF: pterygopalatine fossa; PNS: paranasal sinus; PPS: parapharyngeal space; RIBC: radiation-induced brain change Proton Beam Therapy: Final Evidence Report Page 143 WA – Health Technology Assessment March 28, 2014 Table 18. Mixed Cancers: Study Characteristics. Author (Year) Sample Size Outcomes Inclusion/Exclusion Treatment Study Design Patient Assessed Harms Quality Notes Criteria Protocol Study Site Characteristics Main Findings Miyawaki (2009) PBT Inclusion PBT Incidence of brain injury (CTCAE Poor • Patient overlap N=48 • Patients w/head • Total dose: 65 grade) w/ Demizu (2009) Prospective • Male: 42% and neck or skull- GyE, given in 26 • Grade 0 Comparative • Age: 59 (median) base tumors fractions PBT: 83% • Data provided on Cohort • Tumor site • Patients w/partial • 150 or 190 MeV Carbon: 36% patients diagnosed Skull base: 25% radiation therapy to beam • Grade 1 w/RIBC Hyogo Ion Beam Maxillary sinus: 17% the brain PBT: 13% Medical Center, Nasal cavity: 15% • No evidence of Carbon Carbon: 45% • Data provided on Japan Sphenoid sinus: 13% metastases to distant • Total dose: 57.6 • Grade 2 dose relationship Study Objective Ethmoid sinus: 4% sites GyE, given in 16 PBT: 4% with RIBC Others: 26% • ECOG performance fractions Carbon: 0% Evaluation of status of 0, 1,or 2 • 250 or 320 MeV • Grade 3 radiation-induced Carbon beam PBT: 0% brain injury N=11 Carbon: 18% following • Male: 45% • Grade 4-5 radiation therapy • Age: 58 (median) PBT: 0% in head and neck • Tumor site Carbon: 0% and skull-base Skull base: 27% p=NR tumors Maxillary sinus: 9% Nasal cavity: 9% • Incidence rate of RIBC Intervention Sphenoid sinus: 9% significantly different between Comparator Ethmoid sinus: 18% carbon and PBT (data not Follow-up Others: 27% provided) (p=0.002) PBT MRI findings of RIBC F/U: 32 months PBT: 17% (median) Carbon: 64% p=NR Carbon ion therapy Median time to development of F/U: 39 months RIBC (range) (median) PBT: 17 months (6-49) Carbon: 21 months (11-41) p=NR CTCAE grade: 0; 1: radiographic findings only; 2: symptomatic, not interfering w/activities of daily living; 3: symptomatic, interfering w/activities of daily living; 4-5: life- threatening or death AVM: arteriovenous malformation; CNS: central nervous system; ECOG: Eastern Cooperative Oncology Group; F/U: follow-up; GU: genitourinary; IQR: interquartile range; N: number; NR: not reported; PBT: proton beam therapy; PF: pterygopalatine fossa; PNS: paranasal sinus; PPS: parapharyngeal space; RIBC: radiation-induced brain change Proton Beam Therapy: Final Evidence Report Page 144 Appendix D Dose Comparison Studies WA – Health Technology Assessment March 28, 2014 Table 1. Dose Comparisons: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Treatment Protocol Harms Quality Notes Patient Characteristics Criteria Main Findings Study Site Kim (2013) Arm 1 Inclusion PBT (Arm 1) Biochemical failure • No significant differences Fair • Data on N=19 • Patients w/biopsy- 60 CGE, 20 fractions (ASTRO) among groups in acute and patient- RCT • Age: 66 (median) proven, androgen- (4x/wk) for 5 weeks Arm 1: 5.3% late toxicities reported harms Arm 2: 18.8% available • Gleason score deprivation therapy- PBT (Arm 2) Arm 3: 11.8% Acute toxicity (urinary QoL, Proton Therapy ≤6: 79%; 7: 21%; naïve prostate 54 CGE, 15 fractions Arm 4: 11.1% • Skin and GI: Grade 0 & 1 sexual function, Center, National 8-10: 0% adenocarcinoma, (3x/wk) for 5 weeks Arm 5: 25% across all arms GU and GI Cancer Center, Korea • Tumor stage stage T1-3N0M0 p=NS • GU: Grade 2 toxicity in 1 toxicities) Study Objective T1: 42%; T2: 53%; T3: PBT (Arm 3) patient from Arms 1,2, 4 & 5 Exclusion 5% 47 CGE, 10 fractions Biochemical failure (Nadir (5-8%) Evaluation of • Previous curative (2x/wk) for 5 weeks +2 ng/ml) hypofractionated Arm 2 surgery or radiation Arm 1: 5.3% Late toxicity PBT for prostate N=16 therapy PBT (Arm 4) Arm 2: 12.5% • Skin: Grade 0 & 1 across all cancer • Evidence of 35 CGE, 5 fractions Arm 3: 11.8% arms • Age: 69 (median) (2x/wk) for 2 weeks Arm 4: 5.6% • GI: Grade 2 toxicities in • Gleason score distant metastasis Intervention Arm 5: 16.7% Arms 1, 3, 4 & 5 (8-21%); ≤6: 38%; 7: 50%; • Previous ADT Comparator PBT (Arm 5) p=NS Grade 3 toxicity in Arm 1 Follow-up 8-10: 13% 35 CGE, 5 fractions (11%) • Tumor stage (1x/wk) for 2 weeks • GU: Grade 2 toxicity in PBT (Arm 1) T1: 56%; T2: 25%; T3: Arms 3 & 4 (11-24%) 60 CGE, 20 fractions 19% (4x/wk) Arm 3 PBT (Arm 2) N=17 54 CGE, 15 fractions • Age: 71 (median) (3x/wk) • Gleason score ≤6: 82%; 7: 12%; PBT (Arm 3) 8-10: 9% 47 CGE, 10 fractions • Tumor stage (2x/wk) T1: 18%; T2: 65%; T3: 18% PBT (Arm 4) Arm 5 35 CGE, 5 fractions Arm 4 N=12 (2x/wk) N=18 • Age: 70 (median) • Age: 67 (median) • Gleason score PBT (Arm 5) • Gleason score ≤6: 42%; 7: 42%; Proton Beam Therapy: Final Evidence Report Page 146 WA – Health Technology Assessment March 28, 2014 Author (Year) Sample Size Inclusion/Exclusion Outcomes Assessed Study Design Treatment Protocol Harms Quality Notes Patient Characteristics Criteria Main Findings Study Site 35 CGE, 5 fractions ≤6: 67%; 7: 28%; 8-10: 17% (1x/wk) 8-10: 6% • Tumor stage • Tumor stage T1: 33%; T2: 58%; T3: F/U: 42 months T1: 28%; T2: 67%; T3: 8% (median), (range, 11- 6% 52) ADT: androgen deprivation therapy; F/U: follow-up; GI: gastrointestinal; GU: genitourinary; N: number; PBT: proton beam therapy; PCSI: prostate cancer symptom indices; Q1-Q3: 25th – 75th percentile interquartile range; QoL: quality-of-life; RCT: randomized controlled trial; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 147 WA – Health Technology Assessment March 28, 2014 Table 1. Dose Comparisons: Study Characteristics. Author (Year) Outcomes Sample Size Inclusion/Exclusion Treatment Study Design Assessed Harms Quality Notes Patient Characteristics Criteria Protocol Study Site Main Findings Talcott (2010) PBT + photon • Surviving patients • All radiation NR • PCSI scales (mean scores) Fair • Original study Standard dose enrolled in original delivered in 1.8 findings reported Cross-sectional N=139 study Gy(E) fractions Urinary obstruction and irritation in Zietman (2005) survey of patients • Age at time of survey: 67 (median) Standard: 23.3 and Zietman enrolled in PROG • Race Inclusion PBT + photon High: 24.6 (2010) #95-09 White: 91% • Patients Standard p=0.36 African American: 7% w/clinically localized • PBT: 19.8 GyE • Multivariate Loma Linda Asian: 1% prostate • Photon: 50.4 Urinary incontinence analysis: University Medical Hispanic: 1% adenocarcinoma Gy Standard: 10.6 controlling for Center, CA, USA • PSA increase following treatment: • Tumors stage T1b High: 9.7 cancer 38% – T2b PBT + photon p=0.99 progression, no Massachusetts • Other local treatment • Serum PSA <15 High significant General Hospital, RP: 2% ng/ml • PBT: 28.8 GyE Bowel problems association MA, USA Cryotherapy: 8% • No evidence of • Photon: 50.4 Standard: 7.7 between Study Objective • Receipt of hormonal therapy: 13% metastatic disease Gy High: 7.9 treatment dose p=0.70 and any outcome Evaluation of PBT + photon variable (data not long-term, High dose Sexual dysfunction shown) patient-reported N=141 Standard: 68.2 dose-related • Age at time of survey: 67 (median) High: 65.9 • Analysis of level toxicities • Race p=0.65 of function vs. White: 95% patient-perceived Intervention African American: 1% • Utilizing numerical functional level of function Comparator Asian: 1% scales, no significant differences provided Follow-up Hispanic: 3% were found in the 4 domains PBT + photon • PSA increase following treatment: w/results based on normal, 70.2 GyE 14% intermediate and poor function Standard dose • Other local treatment between the standard and high RP: 0% dose groups PBT + photon Cryotherapy: 1% 79.2 GyE • Receipt of hormonal therapy: 6% • Perceived health and attitudes High dose toward treatment decisions: •Significant differences between Standard group less confident F/U: 9.4 years groups including PSA increase, local regarding cancer control (median), (range, treatments (p<0.001), and more regret about 7.4-12.1) treatment choice (p=0.02) ADT: androgen deprivation therapy; F/U: follow-up; GI: gastrointestinal; GU: genitourinary; N: number; PBT: proton beam therapy; PCSI: prostate cancer symptom indices; Q1- th th Q3: 25 – 75 percentile interquartile range; QoL: quality-of-life; RCT: randomized controlled trial; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 148 WA – Health Technology Assessment March 28, 2014 Table 1. Dose Comparisons: Study Characteristics. Author (Year) Sample Size Study Design Patient Inclusion/Exclusion Treatment Outcomes Assessed Study Site Characteristics Criteria Protocol Main Findings Harms Quality Notes Zietman (2010)* PBT + photon Inclusion • All radiation PSA nadir <1.0 ng/mL Acute GU Good • Conventional: 7 Conventional dose • Patients delivered in 1.8 • Conventional: 81% • Grade 2 patients (3.6%) RCT N=196 w/clinically localized Gy(E) fractions • High: 86.6% Conventional: 51% received a lower (RTOG #95-09) • Age ≥70: 32% prostate p=NS High: 60% dose; 8 patients • Race adenocarcinoma PBT + photon p=NS (4.1%) received Loma Linda White: 89% • Tumors stage T1b Conventional PSA nadir <0.5 ng/mL higher doses; 1 University Hispanic: 2% – T2b • PBT: 19.8 GyE • Conventional: •Grade 3: 3% in conv. dose; 2% patient underwent Medical Center, Black: 6% • Serum PSA <15 • Photon: 50.4 Gy 44.7% in high dose radical CA, USA • Combined Gleason ng/ml • High: 59.8% • Grade 4: 0% in conv. dose; 1% prostatectomy score • No evidence of PBT + photon p=0.003 in high dose Massachusetts 2-6: 75% metastatic disease High • High: 5 patients General Hospital, 7: 15% • PBT: 28.8 GyE 10-year ASTRO BF Acute GI (rectal) (2.6%) received a MA, USA 8-10: 9% • Photon: 50.4 Gy rate • Grade 2 higher dose; 18 • Tumor stage • Conventional: Conventional: 44% patients (9.2%) Study Objective T1b: 1% 32.3% High: 63% received lower Evaluation of T1c: 61% • High: 16.7% p=0.0006 doses high-dose T2a: 22% p=0.0001 conformal T2b: 16% • Grade 3: 1% in each arm • Analyses of radiation therapy Local failure rate • No grade 4 events factors associated for prostate PBT + photon • Men treated w/ w/ASTRO BF rate cancer High dose high dose less likely to Late GU (e.g., disease risk, N=195 have local failure than • Grade 2 tumor stage, Intervention Conventional: 22% • Age ≥70: 28% those w/conventional Gleason score) Comparator High: 27% • Race dose: HR 0.57 (95% Follow-up p=NS White: 91% CI, 0.43-0.74), PBT + photon Hispanic: 3% p<0.0001 • Grade 3: 2% in each arm 70.2 GyE Black: 3% • No grade 4 events Conventional • Combined Gleason Overall survival rate dose score • Conventional: Late GI 2-6: 75% 78.4% • Grade 2 PBT + photon 7: 15% • High: 83.4% Conventional: 13% 79.2 GyE 8-10: 8% p=0.41 High: 24% High dose • Tumor stage p=NS T1b: 0% Mortality F/U: 8.9 years T1c: 61% • Conventional: 17%% •Grade 3: 0% in conv. dose; 1% (median), (range, T2a: 26% • High: 14%% in high dose 0.8-12.5) T2b: 13% • No grade 4 events * Zietman (2005) reported on original findings with median follow-up of 5.5 years (range, 1.2-8.2). ADT: androgen deprivation therapy; F/U: follow-up; GI: gastrointestinal; GU: genitourinary; N: number; PBT: proton beam therapy; PCSI: prostate cancer symptom indices; Q1- th th Q3: 25 – 75 percentile interquartile range; QoL: quality-of-life; RCT: randomized controlled trial; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 149 WA – Health Technology Assessment March 28, 2014 Table 1. Dose Comparisons: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Gragoudas (2000) PBT, 50 CGE Inclusion • Total dose • Visual outcome was similar • No statistically Fair • Withdrawals N=94 • Patients delivered in 5 throughout study regardless significant differences in 50 CGE:15% RCT •Male: 47% w/melanoma of the fractions of PBT dose other radiation 70 CGE: 14% • Age: 62 (median) choroid and/or complications between Massachusetts • Largest tumor diameter ciliary body located 5-year visual acuity (median, groups •Visual outcome General Hospital, (mm) (median, range): 11.0 w/in 4 disc Q1-Q3) data available for MA, USA (7.0-16.0) diameters of the • 50 CGE: 20/160 (20/25 – Vitreous hemorrhage 12, 24, 36, and 48 Study Objective • Tumor height (mm) optic disc 20/900) • 50 CGE: 15% months (median, range): 3.0 (1.2- • 70 CGE: 20/100 (20/25 – • 70 CGE: 13% Evaluation of 6.3) Exclusion 20/900) reduced dose of • Macular detachment: 14% • Presence of p=0.91 Subretinal exudation in PBT and impact • Visual acuity (median, metastatic disease macula on radiation- range): 20/32 (16-800) • Prior treatment for 5-year letters read (median, • 50 CGE: 11% induced the intraocular Q1-Q3) • 70 CGE: 8% complications in PBT, 70 CGE tumor • 50 CGE: 60 (25-98) patients w/uveal N=94 • Tumors ≥15mm in • 70 CGE: 62 (25-95) Rubeosis/ neovascular melanoma •Male: 59% diameter or ≥5 mm p=0.86 glaucoma • Age: 57 (median) in height • 50 CGE: 10% Intervention • Largest tumor diameter At 5-years, number of • 70 CGE: 7% Comparator (mm) (median, range): 10.0 patients w/vision ≥20/200 Follow-up (7.0-17.0) • 50 CGE: 56% Uveitis PBT • Tumor height (mm) • 70 CGE: 54% • 50 CGE: 0% • 50 CGE (median, range): 3.0 (1.0- p=0.82 • 70 CGE: 1% 5.5) PBT • Macular detachment: 16% Local recurrence w/in 5 years Enucleation • 70 CGE • Visual acuity (median, of radiation • 50 CGE: 4% range): 20/32 (16-hand • 50 CGE: 2% • 70 CGE: 5% F/U: up to 5 years motions) • 70 CGE: 3% after radiation p>0.99 • Significant differences between groups including Metastatic death w/in 5 years gender, largest tumor of radiation diameter, tumor location • 50 CGE: 7% • 70 CGE: 8% p=0.79 ADT: androgen deprivation therapy; F/U: follow-up; GI: gastrointestinal; GU: genitourinary; N: number; PBT: proton beam therapy; PCSI: prostate cancer symptom indices; Q1- th th Q3: 25 – 75 percentile interquartile range; QoL: quality-of-life; RCT: randomized controlled trial; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 150 WA – Health Technology Assessment March 28, 2014 Table 1. Dose Comparisons: Study Characteristics. Author (Year) Sample Size Inclusion/Exclusion Treatment Outcomes Assessed Study Design Harms Quality Notes Patient Characteristics Criteria Protocol Main Findings Study Site Santoni (1998) • Data provided for Inclusion • Total dose NR Patients w/ temporal Poor •Data on status of entire patient cohort • Patients delivered in 4 lobe damage* patients RCT w/chordomas and proton fractions 66.6 CGE: 4/10 (40%) w/temporal lobe (RTOG #85-26) PBT + photon chondrosarcomas at and 1 photon 72 CGE: 6/10 (60%) damage provided 66.6 CGE the base of the skull fraction per week Massachusetts N=44 Clinical symptoms General Hospital, • Treatment (n=9)* MA, USA PBT + photon delivered as 1.8 • Grade 1 Study Objective 72 CGE CGE/fraction 66.6 CGE: 0% N=52 72 CGE: 1/6 (17%) Evaluation of PBT • Grade 2 temporal lobe • Male: 53% • Proton 66.6 CGE: 0% damage in • Age contribution to 72 CGE: 1/6 (17%) patients receiving ≤50: 67% dose ranged from • Grade 3 high-dose PBT for >50: 33& 30.6 – 66.2 CGE 66.6 CGE: 3/3 (100%) treatment of • Tumor site • Mean dose: 72 CGE: 4/6 (67%) skull-base tumors Occipital bone: 43% 55.3 Sphenoid bone: 27% • Median dose: • Prescribed radiation Intervention Temporal bone: 29% 55.8 dose not found to be Comparator Nasopharynx: 1% significantly associated Follow-up • Tumor type Photon with rate of temporal PBT + photon Chordoma: 51% • Photon lobe damage, p=0.304 • 66.6 CGE Chondrosarcoma: 49% contribution to • Presentation dose ranged from PBT + photon Primary: 78% 5.4 – 36 Gy • 72 CGE Persistent/recurrent: • Mean dose: 22% 13.9 F/U: 43.8 months • Number of surgical • Median dose: (mean), (median, procedures 12.6 range: 41, 18-126) 1: 67% >1: 33% * P-value not reported. ADT: androgen deprivation therapy; F/U: follow-up; GI: gastrointestinal; GU: genitourinary; PBT: proton beam therapy; PCSI: prostate cancer symptom indices; Q1-Q3: 25th – 75th percentile interquartile range; RCT: randomized controlled trial; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 151 Appendix E Economic Studies WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics. Author (Year) Intervention Sample Size Inclusion/ Outcomes Notes Study Design Comparator Patient and/or Study Exclusion Criteria Study Setting Follow-up Characteristics Study Objective Study Perspective Elnahal (2013) N/A Key model assumptions N/A • Facilities treating only simple • Costs (2012 levels): Medicare and private • 14 hours of daily operation cases would generate 32% less payer reimbursement rates for treatment Modeling study Patient case in treatment rooms daily revenue w/ACO assumptions • Private payer reimbursement Sensitivity analyses PBT facility in the US • Complex case or reimbursement $1.75 times • Incremental revenue values sensitive to FFS pediatric case that of Medicare/ACO • Incremental revenue gained reimbursement rates for noncomplex cases, Evaluation of w/anesthesia: 1 • Reimbursement for simple w/replacing 1 complex case modeled ACO rates and private rates debt management hour/treatment case w/1 noncomplex case lowest under different • Simple case: 30 ACO: $510/treatment for simple cases, highest for • Debt coverage for 4-room facilities sensitive reimbursement min./treatment Medicare - FFS: short prostate cases to interest rates and total capital costs scenarios • Prostate cancer $753/treatment case: 24 min./ • FFS & ACO reimbursement • ACO reimbursement reduced treatment for complex cases identical incremental revenue by 53.2% • Short prostate • Facility cost (simple cases) and 41.7% (short cancer case: 15 min./ 1-room: $30 million prostate cases) treatment 4-room: $150 million • Single-room facilities able to cover debt w/any case mix 4-room facilities, debt coverage • 52% lower w/all simple cases • 50% lower w/all prostate cases • 41% lower w/all short prostate cases Mailhot Vega (2013) PBT Base case: patients at age 5 N/A Total QALYs • Health benefits and costs tracked beginning years treated for • PBT: 17.37 at age 18 Decision analysis Photon therapy medulloblastoma • Photon: 13.91 • Difference: 3.46 • Costs (2012 levels): RT (including salaries & Outpatient treatment Time horizon: lifetime Societal perspective overhead) and management of adverse in the US Total costs events WTP threshold: • PBT: $80,210.79 Evaluation of cost $50,000 • Photon: $112,789.87 • Sensitivity analyses: risk of hearing loss, risk effectiveness of • Difference: -$32,579.08 of secondary malignant neoplasm, and risk of treatment w/PBT vs. heart failure were most influential on photon therapy in ICER: PBT dominates incremental effectiveness of PBT; PBT still pediatric dominant medulloblastoma Proton Beam Therapy: Final Evidence Report Page 153 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Study Design Patient and/or Study Inclusion/ Comparator Outcomes Notes Study Setting Characteristics Exclusion Criteria Follow-up Study Objective Study Perspective Ramaekers (2013) IMPT Base case: patients w/locally N/A ICER for IMPT vs. IMRT: • Costs (2010 levels): treatment-related advanced (stage III-IV) head €127,946/QALY ($159,421) costs of dysphagia and xerostomia Decision analysis IMRT and neck cancers (e.g., oral cavity, laryngeal, and ICER for IMPT/IMRT vs. IMRT: • Sensitivity analyses: equal disease Outpatient IMPT/IMRT* pharyngeal cancer), age 61 €60,278/QALY ($75,106) progression for patients treated w/IMRT treatment in The years w/pretreatment RTOG ICER for IMPT vs. IMRT: and IMPT relaxed, and IMRT dominated for Netherlands Time horizon: grade <2 dysphagia and €7,936/DTFLY ($9,888) all patients compared to IMPT for all lifetime xerostomia patients Evaluation of ICER for IMPT/IMRT vs. IMRT: swallow-sparing WTP threshold: Health care perspective €3,854/DTFLY ($4,802) treatment following €80,000 ($99,680) (DTFLY: disease and toxicity radiation therapy free life year) Yu (2013) PBT PBT Inclusion Treatment reimbursement • Costs (2008-2009 levels): Medicare N=314 • Patients w/early- (median, IQR) reimbursement for treatment planning, CC (database study) IMRT •Age ≥70: 63.7% stage, treated • PBT: $32,428 ($31,265- management, and delivery based on 6- •Race prostate cancer $34,189) month costs Outpatient F/U: 3 months White: 93% • PBT or IMRT as • IMRT: $18,575 ($14,911- treatment in the US following initiation Black: <3.5% primary treatment $23,022) of RT Other: >3.5% Evaluation of • Comorbidities Exclusion treatment costs of 0:73.6% • Patients without radiation therapy 1-2: >22.9% Medicare A & B, 9 ≥3: <3.5% months prior to • Receipt of ADT: 20.7% treatment through 3 months after IMRT N=628 •Age ≥70: 63.7% •Race White: 93% Black: 2.9% Other: 4.1% • Comorbidities 0: 73.4% 1-2: 23.2% ≥3: 3.3% • Receipt of ADT: 21% Proton Beam Therapy: Final Evidence Report Page 154 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Study Design Patient and/or Study Inclusion/ Comparator Outcomes Notes Study Setting Characteristics Exclusion Criteria Follow-up Study Objective Study Perspective Johnstone (2012) N/A Key model assumptions N/A • Number of patients treated • Costs (year of levels not reported): • Unit of analysis: per room per day per room is Medicare and private payer reimbursement Modeling study Patient case w/14 hours of daily maximized w/greater rates per treatment assumptions operation percentages of simple and PBT facility in the US • Complex case or • Private payer prostate cancer cases pediatric case reimbursement $1.75 times Evaluation of w/anesthesia: 1 that of Medicare • 1-room facility: 12 hours of practical case hour/treatment • Facility cost complex/pediatric cases to distribution • Simple case: 30 1-room: $25 million service debt necessary to min./treatment 4-room: $150 million facilitate debt • Prostate cancer: • 1-room facility: 4 hours of management 24 min./treatment prostate cancer/simple cases to service debt • 3- and 4-room facilities: cannot service debt without inclusion of simple cases Proton Beam Therapy: Final Evidence Report Page 155 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Study Design Patient and/or Study Inclusion/ Comparator Outcomes Notes Study Setting Characteristics Exclusion Criteria Follow-up Study Objective Study Perspective Parthan (2012) PBT Base case: 65-year old men N/A • Localized prostate cancer • Costs (2011 levels): with localized prostate Medicare payments for Decision analysis IMRT cancer who are unwilling or PAYER PERSPECTIVE treatment, follow-up and ineligible for surgery Lifetime healthcare costs management of Outpatient SBRT • PBT: $69,412 gastrointestinal, treatment in the Payer and societal • IMRT: $33,068 genitourinary and sexual U.S. Time horizon: perspectives • SBRT: $24,873 dysfunction toxicities; lifetime societal perspective includes Evaluation of the QALYs work-time lost (cost/hour) cost effectiveness of WTP threshold: • PBT: 8.06 different external $50,000/QALY • IMRT: 8.05 • Sensitivity analyses with beam radiation • SBRT: 8.11 varying toxicities (using therapies in the confidence intervals) and treatment of ICER costs/QALY gained costs (±25%) resulted in prostate cancer • IMRT, PBT dominated by SBRT as the dominant SBRT strategy SOCIETAL PERSPECTIVE • Sensitivity analyses Lifetime healthcare costs equating toxicity of PBT to • PBT: $71,657 that of SBRT (in place of • IMRT: $35,088 IMRT) resulted in SBRT • SBRT: $25,097 weakly dominating IMRT and no longer dominating PBT QALYs • PBT: 8.06 • IMRT: 8.05 • SBRT: 8.11 ICER costs/QALY gained • IMRT, PBT dominated by SBRT Proton Beam Therapy: Final Evidence Report Page 156 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Study Design Patient and/or Study Inclusion/ Comparator Outcomes Notes Study Setting Characteristics Exclusion Criteria Follow-up Study Objective Study Perspective Grutters (2011) ROA: Base case N/A For a trial of 200 patients, • Sensitivity analyses • “Adopt and trial” • Time horizon: 5 years expected net gain demonstrated that the Real Options vs. “delay and trial” • Study design: single-arm • Adopt & trial: €1,592,586 model was sensitive to Analysis (ROA) in the adoption of cohort of PBT ($1,984,362)† increased treatment costs PBT as preferred • Costs include fixed & • Delay & trial: -€744,306 abroad and costs of reversal Outpatient therapy over SBRT variable trial costs, extra (-$927,405)† treatment in The costs of treatment abroad, Netherlands WTP threshold: cost of health benefits • Expected net gain of adopt €80,000 ($99,680)† forgone due to suboptimal & trial higher than that of Evaluation of treatment delay & trial for study sample adoption of PBT in • Benefits: value of reduced size <950 patients the treatment of uncertainty after trial stage I NSCLC Dvorak (2010) PBT Key model assumptions N/A Highly conformal EBRT • Costs (2008 levels): • EBRT techniques used as a utilization Medicare reimbursement Cost utilization EBRT (including proxy for PBT • Number of courses: 431 rates per fraction of model IMRT, SBRT, and • Average PBT time slot: 30 (38% of total courses) radiation therapy delivered Gamma Knife minutes • Number of fractions: 6,151 (other technical and Hospital- or clinic- radiosurgery) • 9 hours of daily operation (31% of total fractions) professional charges based PBT in the US • Identical fractionation excluded) Timeline: 1 year schedules used • Baseline annual cost: Evaluation of the approximately $6 million costs associated w/cancer treatment • Use of PBT in place of EBRT utilizing PBT in place would increase annual cost to of other EBRTs $7.3 million (22% above baseline) Proton Beam Therapy: Final Evidence Report Page 157 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Inclusion/ Study Design Patient and/or Study Comparator Exclusion Outcomes Notes Study Setting Characteristics Follow-up Criteria Study Objective Study Perspective Grutters (2010) PBT Base case: Patients N/A • Inoperable stage I NSCLC • Costs (2007 levels): treatment, follow-up and w/inoperable and operable management of pneumonitis and esophagitis Decision analysis Carbon ion stage I NSCLC Total healthcare costs over 5 therapy years • For operable stage I NSCLC, SBRT and carbon Outpatient Health care perspective • PBT: €27,567 evaluated treatment in The SBRT • Carbon: €19,215 Netherlands • SBRT: €13,871 • Sensitivity analysis for inoperable stage I CRT • CRT: €22,696 NSCLC utilizing data published after 2004 (as Evaluation of the QALYs CRT data were generally older): cost effectiveness of Time horizon: 5 • PBT: 2.33 ICER for PBT vs. carbon: €81,479 ($110,160) particle therapies in years • Carbon: 2.67 ICER for carbon vs. SBRT: €36,017 ($48,695) the treatment of • SBRT: 2.59 CRT dominated by carbon NSCLC WTP threshold: • CRT: 1.98 €80,000 ($108,160) ICER for carbon vs. SBRT: €67,257/QALY ($90,931) • PBT, CRT dominated by carbon and SBRT Peeters (2010) PBT-only Key model assumptions N/A Total costs/year (million) • Total costs (2007 levels): Capital and • Lifetime of facility = 30 years • PBT: €24,964,716 ($33,752,296) operational costs Cost analysis PBT + carbon ion • 3-room facility for PBT+carbon • PBT+carbon: €36,758,027 and PBT; 2 rooms for photon ($49,696,852) • Sensitivity analyses indicate that the Facilities in The Photon • 14 hours of daily operation • Photon: €9,581,850 cost/fraction of PBT and PBT+carbon compared Netherlands • Average time per radiation ($12,954,661) to photon is most sensitive to a shorter lifecycle fraction of the facility, increased average time per Comparative PBT: 18 minutes Cost/fraction fraction and increased number of special (e.g., evaluation of capital PBT+carbon: 18 minutes • PBT: €743 ($1,004) stereotactic radiotherapy or IMRT) cases and operational Photon: 10 minutes • PBT+carbon: €1,128 ($1,525) costs associated • Number of fractions per year • Photon: €233 ($315) • For specific kinds of tumors, the cost with radiation PBT: 33,614 difference among the different therapies was therapy facilities PBT+carbon: 32,585 Cost/fraction ratio to photon small for lung and prostate tumors, and larger Photon: 41,160 • PBT: 3.2 for skull-base chordomas and head & neck Hospital perspective • PBT+carbon: 4.8 tumors Proton Beam Therapy: Final Evidence Report Page 158 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Inclusion/ Study Design Patient and/or Study Comparator Exclusion Outcomes Notes Study Setting Characteristics Follow-up Criteria Study Objective Study Perspective Konski (2007) PBT Base case: a 70-year-old man N/A Mean cost of treatment • Costs (2005 levels): Hospital and diagnosed w/intermediate- • PBT: $63,511 physician reimbursement rates, Decision analysis IMRT risk prostate • IMRT: $36,808 treatment costs (including hormone adenocarcinoma therapy and chemotherapy) Outpatient treatment Time horizon: 15 QALYs in the US years Payer’s (Medicare) • PBT: 9.91 • Sensitivity analyses evaluated perspective • IMRT: 9.45 effect on the net monetary benefit Evaluation of the cost WTP threshold: where PBT would be favored if cost effectiveness of PBT vs. $50,000 ICER: $63,578/QALY of IMRT >$45,000, cost of PBT IMRT for prostate <$39,000 or utility associated cancer w/IMRT <0.85 • Secondary analysis w/base case of a 60-year-old man resulted in marginal cost effectiveness of PBT (ICER=$55,726/QALY) Taghian (2006) 3D-CPBI proton Base case: 60-year old woman N/A Overall cost of a treatment • Costs (2006 levels): Professional and w/stage I breast cancer regimen technical direct costs of treatment, Cost analysis 3D-CPBI photon • 3D-CPBI proton: $13,200 including patient time and transport Hospital-based Societal perspective • 3D-CPBI photon: $5,300 based on Medicare reimbursement outpatient treatment in WBI-B • WBI-B: $10,600 the US Comparative evaluation of treatment utilizing alternative radiation modalities Proton Beam Therapy: Final Evidence Report Page 159 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Study Design Patient and/or Study Inclusion/ Comparator Outcomes Notes Study Setting Characteristics Exclusion Criteria Follow-up Study Objective Study Perspective Lundkvist (2005c) PBT Breast cancer, base case: 55- N/A Number of patients treated per • Model results from Lundkvist (2005a) and year-old women w/left-sided year: 300 each for breast, Lundkvist (2005b) utilized Decision analysis Conventional radiation breast cancer, at high risk of prostate and head and neck (photon) cardiac disease cancers, 25 for medulloblastoma • Costs (2002 levels): RT (including operation & Outpatient treatment in capital costs, and travel/hotel costs) and Sweden Time horizon: lifetime Prostate cancer, base case: ICER management of adverse events 65-year-old-men • Breast: €34,290/QALY ($33,913) Evaluation of the cost WTP threshold: NR • Prostate: €26,776/QALY • Average ICER for all 4 cancers: €10,130 effectiveness of PBT vs. Head and neck cancer, base ($26,481) ($10,019) photon therapy in the case: 65-year-old patients • Head and neck: €3,811/QALY treatment of 4 different ($3,769) • For a WTP of €55,000 ($54,395), total yearly cancers Pediatric, base case: patients • Pediatric: cost saving net benefit of treating 925 patients (w/specific at age 5 years treated for cancer types and patient profiles): medulloblastoma Total cost difference, for all approximately €20.8 million ($20.6 million) treated patients in 1 year (M€) Societal perspective • Breast: 1.8 ($1.78) • Prostate: 2.4 ($2.37) • Head and neck: 1.2 ($1.19) • Pediatric: -0.6 (-$0.59) Total difference in QALYs, for all treated patients in 1 year • Breast: 51.8 • Prostate: 89.1 • Head and neck: 306.0 • Pediatric: 17.1 Lundkvist (2005a) PBT Base case: 55-year-old women N/A Total costs • Costs (2002 levels): treatment, follow-up and w/left-sided breast cancer • PBT: €11,248 ($11,124) management of adverse events (cardiac and Decision analysis Conventional radiation • Photon: €5,005 ($4,950) pulmonary) (photon) Societal perspective • Difference: €6,243 ($6,174) Outpatient treatment in • Sensitivity analyses demonstrated substantial Sweden Time horizon: lifetime QALYs decreases in ICER when treating a high-risk • PBT: 12.3460 population w/doubled risk of cardiac disease: Evaluation of cost WTP threshold: NR • Photon: 12.2523 base case = €34,290/QALY ($33,913) effectiveness of PBT vs. • Difference: 0.0937 conventional radiation in the treatment of ICER: €66,608/QALY ($65,875) breast cancer Proton Beam Therapy: Final Evidence Report Page 160 WA – Health Technology Assessment March 28, 2014 Table 1. Economic Evaluations: Study Characteristics, continued. Author (Year) Sample Size Intervention Study Design Patient and/or Study Inclusion/ Exclusion Comparator Outcomes Notes Study Setting Characteristics Criteria Follow-up Study Objective Study Perspective Lundkvist (2005b) PBT Base case: patients at age 5 N/A Total costs • Costs (2002) levels: treatment, follow-up and years treated for • PBT: €14,450 ($14,291) management of adverse events Decision analysis Conventional radiation medulloblastoma • Photon: €38,096 ($37,677) (photon) • Difference: -€23,647 • Sensitivity analyses: PBT remained dominant Outpatient treatment Societal perspective (-23,387) with reductions in IQ loss and growth hormone in Sweden Time horizon: lifetime deficiency being key factors in cost effectiveness QALYs evaluation Evaluation of cost WTP threshold: NR • PBT: 12.778 effectiveness of • Photon: 12.095 treatment w/PBT vs. • Difference: 0.683 photon therapy in pediatric ICER: PBT dominates medulloblastoma Goitein (2003) PBT Key model assumptions N/A Construction costs (k€) • Total costs (2002 levels): Capital and • Lifetime of facility = 30 • PBT: 62,500 ($61,813) operational costs Cost analysis Photon therapy years • Photon: 16,800 ($16,615) • 2-room facilities • Alternate scenarios Hospital-integrated • Daily hours of operation Operation costs (k€) Facilities in 5-10 years: decrease in equipment facility PBT: 13 • PBT: 15,300 ($15,132) costs for PBT, increase in number of fractions (US & Switzerland Photon: 8 • Photon: 6,400 ($6,330) delivered/year for both types of facilities data) • Average time per (18,900) radiation fraction Cost per fraction (k€) • Cost per fraction (k€) Comparative PBT: 22 minutes • PBT: 1.025 ($1.014) PBT: 0.65 ($0.64) evaluation of capital Photon: 14 minutes • Photon: 0.425 ($0.420) Photon: 0.31 ($0.31) and operational costs • Mean number of fractions • Ratio of costs: 2.1 associated with per patient: 25 Cost per treatment (k€) radiation therapy • Number of fractions • PBT: 25.6 ($25.3) Initial capital investment forgiven: facilities delivered per year: 15,000 • Photon: 10.6 ($10.5) • Cost per fraction (k€) PBT: 0.37 ($0.37) Ratio of costs Photon: 0.23 ($0.23) • PBT: 2.4 • Ratio of costs: 1.6 • Photon: 1 * IMPT given to patients when expected to be cost-effective; all other patients receive IMRT. † Converted to US$ utilizing 2010 exchange rate. 3D-CPBI: 3D conformal, external-beam accelerated partial breast irradiation; ACO: accountable care organization; ADT: androgen deprivation therapy; FFS: fee-for-service; ICER: incremental cost effectiveness ratio; IMPT: intensity-modulated proton therapy; IMRT: intensity-modulated radiation (photon) therapy; k€: thousand euro; M€: million euro; NR: not reported; N/A: not applicable; NR: not reported; NSCLC: non-small cell lung cancer; PBT: proton beam therapy; QALY: quality-adjusted life-year; RT: radiation therapy; RTOG: Radiation Therapy Oncology Group; SBRT: stereotactic body radiotherapy; WBI-B: whole-breast irradiation w/a boost; WTP: willingness-to-pay Proton Beam Therapy: Final Evidence Report Page 161 Appendix F Single-arm Case Series WA – Health Technology Assessment March 28, 2014 Table 1. Single-arm Case Series: Bone Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Chen (2013) Chordoma of N=24 • Dose: 75 or 77.4 • Median: 56 3-year • CTCAE & RTOG/EORTC • All patients the mobile or Gy RBE (range, months (range, • Overall survival: 92% scoring w/primary disease Massachusetts saccrococcygeal 71.6-79.2) 18-172) • Local progression-free General Hospital, spine survival: 90% • Acute effects • Subgroup data MA, USA ≥ Grade 3: 0% reported 5-year • Overall survival: 78% • Late effects • Local progression-free ≥ Grade 3: 0% survival: 80% Ciernik (2011) Unresectable or N=55 • PBT ± photon, • Median: 27 2-year • Scoring methodology: NR • 17/55 (31%) incompletely mean: 68.4 Gy months (range, • Overall survival: 84% w/recurrent Massachusetts resected 0-196) • Disease-free survival: 68% • Acute effects: NR disease General Hospital, osteosarcoma MA, USA 5-year • Late effects • Subgroup data • Overall survival: 67% Grade 3: 15% reported • Disease-free survival: 65% Grade 4: 16% Staab (2011) Extracranial N=40 • PBT ± photon, • Median: 43 5-year • CTCAE scoring • 8/40 (20%) chordoma mean: 72.5 months (range, • Overall survival: 80% w/recurrent Paul Scherrer Gy(RBE) (range, 24-91) • Disease-free survival: 57% • Acute effects disease Institute, 59.4-75.2) ≥ Grade 3: 0% Switzerland • Subgroup data • Late effects reported Grade 3 (osteonecrosis, fistula): 5% Hug (1995) Osteo- and N=47 • PBT + photon, • Mean: 38 5-year overall survival • Severity of acute/late • Patients chondrogenic mean CGE months (range, • Chordoma: 50% effects: NR w/primary and Massachusetts tumors of the 6-136) • Chondrosarcoma: 100% recurrent disease, General Hospital, axial skeleton • Chordoma: 74.6 • Osteogenic sarcoma: 44% number NR MA, USA • • Mixed: NR Chondrosarcoma: • No skull-base 72.2 tumors included in • Osteogenic analysis sarcoma: 69.8 • Mixed: 61.8 • Subgroup data reported * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; N: number; NR: not reported; PBT: proton beam therapy; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 163 WA – Health Technology Assessment March 28, 2014 Table 2. Single-arm Case Series: Brain, Spinal, and Paraspinal Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Hauswald (2012) Low-grade glioma N=19 • Median: 54 GyE • Median: 5 • Overall survival: 100% • CTCAE scoring (WHO I/II) (range, 48.6-54) months (range, University of 0-22) • Acute effects Heidelberg, ≥ Grade 3: 0% Germany • Late effects: NR Mizumoto (2010) Supratentorial N=20 • PBT + photon NR Overall survival • CTCAE & RTOG/EORTC glioblastoma Photon dose: 50.4 Gy • 1-year: 71% scoring University of multiforme PBT dose: 46.2 GyE • 2-year: 45% Tsukuba, Japan • Acute effects Grade 3 hematologic: 65% Grade 4 hematologic: 30% • Late effects Grade 3 leukoencephalopathy: 10% Fitzek (2006)* Craniopharyngiom N=5 • PBT ± photon, • Median: 186 Overall survival • Severity of acute/late • 6/15 (40%) a (median age: median: 55.6 CGE months (range, • 5-year: 93% effects: NR w/recurrent Massachusetts 15.9 years) 122-212) • 10-year: 72% disease General Hospital, MA, USA Fitzek (2006)* Craniopharyngiom N=10 • PBT ± photon, a (median age: median: 62.7 CGE Massachusetts 36.2 years) General Hospital, MA, USA Fitzek (2001)† Grade 2/4 N=7 • PBT + photon, • Median: 61 • 5-year survival: 71% • Severity of harms: NR • Subgroup data malignant glioma dose: 68.2 CGE months reported Massachusetts General Hospital, MA, USA Fitzek (2001)† Grade 3/4 N=13 • PBT + photon, • Median: 55 • 5-year survival: 23% malignant glioma dose: 79.7 CGE months Massachusetts General Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 164 WA – Health Technology Assessment March 28, 2014 Table 2. Single-arm Case Series: Brain, Spinal, and Paraspinal Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Hug (2000) Atypical/malignant N=31 • PBT + photon (52%) • Mean: 59 5- and 8-year overall • Severity of acute/late • 15/31 (48%) meningioma or photon alone months survival effects: NR w/recurrent Massachusetts (48%), dose: ranging (range, 7-155) • Atypical: 89% disease General Hospital, from 40-72 CGE • Malignant: 51% MA, USA (PBT) • Subgroup data reported Fitzek (1999) Glioblastoma N=23 • PBT + photon, NR Overall survival • Severity of harms: NR • Subgroup data multiforme median: 93.5 CGE • 1-year: 78% reported Massachusetts (range, 81.6-94.2) • 2-year: 34% General Hospital, • 3-year: 18% MA, USA * Fitzek (2006) reported on 2 patient populations. Separate results are reported where available. † Fitzek (2001) reported on 2 dosing protocols, based on tumor grade. Separate results are reported where available. CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; N: number; NR: not reported; PBT: proton beam therapy; RTOG: Radiation Therapy Oncology Group; WHO: World Health Organization Proton Beam Therapy: Final Evidence Report Page 165 WA – Health Technology Assessment March 28, 2014 Table 3. Single-arm Case Series: Breast Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Chang (2013) Early stage breast N=30 • Dose: 30 CGE • Median: 59 • Overall survival: 100% • Severity of harms: NR* cancer w/primary months (range, Proton Therapy tumors ≤3cm 43-70) Center, Korea MacDonald (2013) Invasive breast N=12 • Dose • Up to 2 • Overall survival: 100% • CTCAE scoring† cancer Chest wall: 50.4 months Massachusetts Gy(RBE) • Acute effects General Hospital, Regional lymphatics Grade 3 fatigue: 8% MA, USA at risk: 45-50.4 Gy(RBE) Bush (2011) Invasive nonlobular N=50 • Dose: 40 Gy • Median: 48 5-year • CTCAE scoring† breast carcinoma months • Overall survival: 96% Loma Linda ≤3cm • Disease-free survival: 92% • Acute effects University Medical ≥ Grade 3: 0% Center, CA, USA • Late effects ≥ Grade 3: 0% Kozak (2006) Stage I breast N=20 • Dose: 32 CGE • Median: 12 • Overall survival: 100% • Severity of harms: NR* cancer w/tumor- months (range, Massachusetts free margin ≥2mm 8-22) General Hospital, MA, USA * Proposed grading scale does not follow standardized scales. † Different versions of the CTCAE are utilized in the listed studies. CTCAE: Common Terminology Criteria for Adverse Events; N: number; NR: not reported; PBT: proton beam therapy; Proton Beam Therapy: Final Evidence Report Page 166 WA – Health Technology Assessment March 28, 2014 Table 4. Single-arm Case Series: Esophageal Cancer. Author (Year) Sample Survival Condition Type Total PBT Dose Follow-up Harms Notes Study Site Size Outcomes Echeverria (2013) Esophageal cancer N=100 • Median: 50.4 CGE • Median: 1 NR • CTCAE scoring • Potential patient (range, 45-60.6) month (0.7-3) overlap w/Lin MD Anderson • Acute effects (2012) Cancer Center, TX, Grade 3 pneumonitis: 7% USA Other acute effects: NR Lin (2012) Esophageal cancer N=62 • Dose: 50.4 Gy(RBE) • Median • 3-year overall • Scoring: NR • Potential patient (among survival: 52% overlap MD Anderson survivors): 20 • Acute/late effects w/Echeverria Cancer Center, TX, months Grade 3 esophagitis: 10% (2013) USA Grade 3 dysphagia: 10% Grade 3 nausea/vomiting: 8% • Subgroup data Grade 3 dermatitis: 3% reported Grade 3 fatigue: 8% Grade 3 anorexia: 5% Grade 3 pneumonitis: 2% Grade 5: 5% Mizumoto (2011)* Esophageal cancer N=19 • PBT + photon, • Median Overall survival • RTOG/EORTC scoring • Subgroup data median: 78 GyE (range, (among • 1-year: 79% reported University of 70-83) survivors): 111 • 5-year: 43% • Acute effects Tsukuba, Japan months (range, Grade 3 esophagitis: 5% 11-121) • Late effects Grade 3 esophagitis: 5% Mizumoto (2010)* Esophageal cancer, N=51 • PBT + photon (n=33), • Median • 5-year overall • RTOG/EORTC scoring • All patients stage T1N1M0 or median: 80 GyE (range, (among survival: 21% w/primary disease University of T2-4N0/1 70-90) survivors): 23 • Acute effects Tsukuba, Japan months Grade 3 esophagitis: 12% • Subgroup data • PBT (n=18), median: reported 79 GyE (range, 62-98) • Late effects Grade 5: 2% Sugahara (2005)* Esophageal cancer N=46 • PBT + photon (n=40), • Median: 35 • 5-year overall • RTOG/EORTC scoring • All patients median: 76 GyE (range, months survival: 34% w/primary disease University of 69.1-87.4) • Acute effects Tsukuba, Japan Grade 3 esophagitis: 11% • Subgroup data • PBT (n=6), median: 82 reported GyE (range, 75-89.5) • Late effects Grade 3: 7% Grade 5: 4% Proton Beam Therapy: Final Evidence Report Page 167 WA – Health Technology Assessment March 28, 2014 Table 4. Single-arm Case Series: Esophageal Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Koyama (2003)*† Superficial N=13 • PBT + photon, • Median: 48 Overall survival • Severity of • Subgroup esophageal cancer mean: 77.7 Gy (2 months (range, • 5-year: 100% harms: NR data reported University of patients w/PBT 5-132) • 10-year: 88% Tsukuba, Japan alone) Koyama (2003)*† Advanced N=17 • PBT + photon, Overall survival esophageal cancer mean: 80.7 Gy (4 • 5-year: 49% University of patients w/PBT • 10-year: 38% Tsukuba, Japan alone) * Potential patient overlap among patients in these studies. † Koyama (2003) reported on 2 patient populations, based on level of disease. Separate results are reported where available. CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NR: not reported; PBT: proton beam therapy; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 168 WA – Health Technology Assessment March 28, 2014 Table 5. Single-arm Case Series: Gastrointestinal Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Makita (2014) Advanced N=28 • Median dose: • 12 months 1-year • CTCAE scoring • 10/28 (36%) cholangiocarcinoma 68.2 Gy (RBE) (range, 3-29) • Overall survival: 49% w/recurrent Hyogo Ion Beam (range, 50.6-80) • Progression-free • Acute effects disease Medical Center, survival: 30% Grade 3 cholangitis: 4% Japan • Subgroup data • Late effects reported Grade 3 cholangitis: 7% Grade 3 bile duct stenosis: 4% Grade 3 duodenal ulcer: 4% Grade 3 duodenal hemorrhage: 7% Grade 3 duodenal stenosis:4% Nichols (2013) Pancreatic or N=22 • Dose: ranging • Median: 11 • Overall survival: 36% • CTCAE scoring ampullary from 50.4 – 59.4 months University of adenocarcinoma CGE (range, 5-36) • Acute/late effects Florida Proton ≥ Grade 3: 0% Therapy Institute, FL, USA Takatori (2013)† Locally advanced N=91 • Dose: 67.5 GyE • Up to 10 NR • CTCAE scoring • Subgroup data pancreatic cancer months reported Hyogo Ion Beam • Acute effects Medical Center, ≥ Grade 3: 0% Japan • Late effects Grade 4 GI: 1% Grade 5 GI: 2% Tseng (2013) Resectable N=47 • Dose: 25 GyE • 1 week NR • CTCAE scoring • Patient overlap adenocarcinoma of (3 patients w/Hong (2011) Massachusetts the pancreatic head received 30 GyE) • Acute effects General or neck ≥ Grade 3: 0% • Subgroup data Hospital, MA, reported USA Proton Beam Therapy: Final Evidence Report Page 169 WA – Health Technology Assessment March 28, 2014 Table 5. Single-arm Case Series: Gastrointestinal Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Terashima (2012)†‡ Locally advanced N=5 • P-1 • Median: 12 1-year • CTCAE scoring • All patients pancreatic cancer, Dose: 50 GyE months • Overall survival: w/primary Hyogo Ion Beam adjacent to the GI (range, 8-19) 77% • Acute effects disease Medical Center, Japan • Progression-free Grade 3 hematologic: 40% survival: 64% Grade 3 GI: 40% Grade 3 fatigue: 20% P-3 protocol • Late effects • 1-year ≥ Grade 3: 0% Terashima (2012)†‡ Locally advanced N=5 • P-2 • Median: 20 Overall survival: • CTCAE scoring pancreatic cancer, Dose: 70.2 GyE months 79% Hyogo Ion Beam non-adjacent to the (range, 18- Progression-free • Acute effects Medical Center, Japan GI 22) survival: 61% Grade 3 hematologic: 100% Grade 3 GI: 20% • Late effects Grade 3 GI: 20% Terashima (2012)†‡ Locally advanced N=40 • P-3 • Median: 12 • CTCAE scoring pancreatic cancer Dose: 67.5 GyE months Hyogo Ion Beam (range, 3-22) • Acute effects Medical Center, Japan Grade 3 hematologic: 65% Grade 4 hematologic: 8% Grade 3 GI: 20% Grade 3 weight loss: 8% Grade 3 fatigue: 3% • Late effects Grade 3 GI: 10% Grade 3 fatigue: 3% Grade 5 GI:3% Hong (2011)§ Resectable N=3 • Dose: 30 GyE • Median: 12 • 1-year overall • Scoring protocol: NR adenocarcinoma of months survival: 75% Massachusetts General the pancreatic head • Acute effects Hospital, MA, USA or neck Grade 3 GI: 67% • Late effects: NR Hong (2011)§ Resectable N=12 • Dose: 25 GyE • Scoring protocol: NR adenocarcinoma of Massachusetts General the pancreatic head • Acute effects Hospital, MA, USA or neck Grade 3 GI: 8% Grade 3 pain: 8% • Late effects: NR WA – Health Technology Assessment March 28, 2014 Table 5. Single-arm Case Series: Gastrointestinal Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Fukumoto (2010) Advanced N=2 • Mean: 75.2 (GyE) • Up to 14 months NR • RTOG/EORTC scoring abdominal Hyogo Ion Beam leiomyosarcoma • Acute/late effects Medical Center, ≥ Grade 3: 0% Japan * Different versions of the CTCAE are utilized in the listed studies. † Potential patient overlap among patients in these studies. ‡ Terashima (2012) reported on 3 dosing protocols based on disease. Separate results are reported where available. § Hong (2011) reported on 2 dosing levels. Separate results are reported where available. Proton Beam Therapy: Final Evidence Report Page 171 WA – Health Technology Assessment March 28, 2014 Table 6. Single-arm Case Series: Gynecologic Cancers. Author (Year) Condition Sample Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Type Size Kagei (2003) Stage IIB-IVA N=25 • PBT + photon, • Median: 139 • 10-year overall • RTOG/EORTC scoring • Subgroup carcinoma of median: 86 Gy months (range, survival: 59% data reported University of the uterine (range, 71-101) 11-184) • Severity of acute effects: Tsukuba, Japan cervix NR • Late effects Grade 3 GI/GU: 0% Grade 4 GI: 4% Grade 4 GU: 4% Arimoto (1991) Uterine N=15 • PBT ± photon • Ranging from • 2-year overall • Severity of harms: NR • Subgroup cervical or PBT: ranging from 15-57 months survival: 93% data reported University of vaginal 74.5 – 86 cGy Tsukuba, Japan carcinoma, Photon: ranging from ≤stage IIIB 14.4-37.8 cGy disease EORTC: European Organization for Research and the Treatment of Cancer; GI: gastrointestinal; GU: genitourinary; N: number; NR: not reported; PBT: proton beam therapy; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 172 WA – Health Technology Assessment March 28, 2014 Table 7. Single-arm Case Series: Head and Neck Cancers (including skull-base tumors). Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size McDonald (2013) Progressive or N=16 • Median: 75.2 Gy • Median: 24 • 2-year overall • CTCAE scoring • All patients with recurrent chordoma (range, 40-79.2) months survival: 80% recurrent disease Indiana University (range, 6-63) • Acute effects Health Proton Grade 3 laryngeal edema: • Subgroup data Therapy Center, IN, 6% reported USA Grade 4 ventricular obstruction: 6% • Late effects Grade 3 radiation necrosis: 6% Grade 4 stroke: 6% Grade 4 CSF leak: 6% Fukumitsu (2012) Unresectable stage N=17 • Median: 78 GyE • Median: 23 Overall survival • RTOG scoring • 2/17 (12%) IV and local (range, 72.4-89.6) months • 2-year: 47% w/recurrent University of recurrent carcinoma (3 patients • 5-year: 16% •Acute effects disease Tsukuba, Japan of the nasal cavity w/additional Grade 3 mucositis: 6% and paranasal photon therapy) Grade 3 dermatitis: 6% • Subgroup data sinuses reported • Late effects Grade 3 brain necrosis: 6% Grade 4 fracture: 6% Grade 4 visual: 6% Hojo (2012) Nasal cavity or N=65 • Median: 65 GyE • Median: 52 3-year NR • 52/65 (80%) of paranasal (range, 60-70) months • Overall survival: patients received National Cancer malignancies (range, 25- 72% PBT Center Hospital 125) • Progression-free East, Japan survival: 44% Okano (2012) T4b nasal and N=13 • Dose: 65 CGE • Median: 57 5-year • CTCAE scoring sinonasal months • Overall survival: National Cancer malignancies (range, 1-64) 76% • Acute effects Center Hospital • Progression-free Grade 3 mucositis: 15% East, Japan survival: 34% • No reported late effects Proton Beam Therapy: Final Evidence Report Page 173 WA – Health Technology Assessment March 28, 2014 Table 7. Single-arm Case Series: Head and Neck Cancers (including skull-base tumors). Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Pehlivan (2012) Chordoma and N=62 • Chordoma, mean: • Median: 38 Chordoma • CTCAE scoring • 17/62 (27%) chondrosarcom 73.5 Gy (RBE) (range, months (range, • 5-year overall survival: 62% w/recurrent Paul Scherrer a of the skull 67-74) 14-92) • 5-year disease-free • Acute effects: NR disease Institute, base survival: 81% Switzerland • Chondrosarcoma, • Late effects • Subgroup of mean: 68.4 Gy (RBE) Chondrosarcoma Grade 3 temporal lobe patients in Ares (range, 63-74) • 5-year overall survival: 91% damage: 3% (2009) • 5-year disease-free survival: 100% Moore (2011) Stage II-IV N=70 • PBT ± photon, • Median: 65 5-year NR • All patients sinonasal median: 69 Gy months • Overall survival: 59% w/primary disease Massachusetts malignancies (range, 59.4-77.8) • Disease-free survival: 55% General Hospital, MA, US Zenda (2011a) Mucosal N=14 • Dose: 60 GyE • Median: 37 • 3-year overall survival: 58% • CTCAE scoring melanoma of months National Cancer the head and • 2-year progression-free • Acute effects Center Hospital neck survival: 44% Grade 3 mucositis: 21% East, Japan • Late effects Grade 3 neuropathy: 14% Zenda (2011b) Unresectable N=39 • Dose: ranging from • Median: 45 3-year • CTCAE scoring • Subgroup data malignancies of 60-70 GyE months (range, • Overall survival: 59% reported National Cancer the nasal cavity 1-91) • Progress-free survival: 49% • Acute effects Center Hospital and paranasal ≥ Grade 3: 0% East, Japan sinuses 5-year • Overall survival: 55% • Late effects Grade 3 cataract: 3% Grade 3 neuropathy: 3% Grade 3 bone necrosis: 3% Grade 4 neuropathy: 3% Grade 5 CSF leakage: 3% Proton Beam Therapy: Final Evidence Report Page 174 WA – Health Technology Assessment March 28, 2014 Table 7. Single-arm Case Series: Head and Neck Cancers (including skull-base tumors). Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Ares (2009) Chordoma and N=64 • Chordoma, mean: • Median: 34 5-year overall survival • CTCAE scoring • 17/64 (27%) chondrosarcoma of 73.5 Gy (RBE) (range, months (range, • Chordoma: 62% w/recurrent Paul Scherrer Institute, the skull base 67-74) 14-92) • Chondrosarcoma: • Acute effects: NR disease Switzerland 91% • Chondrosarcoma, • Late effects • Subgroup data mean: 68.4 Gy (RBE) Grade 3 neuropathy: 2% reported (range, 63-74) Grade 4 neuropathy: 2% Grade 3 temporal lobe damage: 3% Roda (2009) Skull-base neoplasm N=3 • Dose: ranging from • Mean: 24 •Overall survival: • Acute effects: NR 6,600 - 7,200 cGy, 15 months (range, 6- 100% NR CGE 48) • Severity of late effects: NR Truong (2009) Primary sphenoid N=20 • PBT + photon, • Median: 21 2-year • CTCAE scoring • All patients sinus malignancy median: 76 Gy (range, months • Overall survival: 53% w/primary disease Massachusetts 66-78) • Disease-free • Acute effects General Hospital, MA, survival: 31% Grade 3 mucositis: 30% • Subgroup data US Grade 3 skin: 10% reported • Late effects Grade 3 nasal: 5% Grade 5 CSF leak: 5% Grade 4 pituitary dysfunction: 5% Nichols (2008) Esthesio- N=10 • PBT + photon, • Median: 53 5-year • CTCAE scoring • All patients neuroblastoma median: 62.7 CGE months • Overall survival: 86% w/primary disease Massachusetts (range, 54-70) (3 • Disease-free • Acute/late effects General Hospital, MA, patients with PBT survival: 90% ≥ Grade 3: 0% • Subgroup data US alone) reported Resto (2008) Locally advanced N=102 • PBT + photon, • Median: 43 • Overall survival, NR • Subgroup data sinonasal malignancies median: 71.6 Gy (range, months (range, 1- disease-free survival reported Massachusetts 55.4-79.4) 157) reported based on General Hospital, MA, surgical procedure US Nishimura (2007) Olfactory N=14 • Dose: 65 GyE • Median: 40 5-year • RTOG/EORTC scoring • 1/14 (7%) neuroblastoma months (range, • Overall survival: 93% w/recurrent National Cancer 11-74) • Local progression- • Acute/late effects disease Center Hospital East, free survival: 84% ≥ Grade 3: 0% Japan Proton Beam Therapy: Final Evidence Report Page 175 WA – Health Technology Assessment March 28, 2014 Table 7. Single-arm Case Series: Head and Neck Cancers (including skull-base tumors). Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Pommier (2006) Adenoid cystic N=23 • PBT + photon, • Median: 62 5-year • CTCAE scoring • All patients carcinoma of median: 76.4 months • Overall survival: 77% w/primary Massachusetts the skull base CGE (range, 70- • Disease-free survival: 56% • Acute effects disease General Hospital, 79.1) ≥ Grade 3: 0% MA, US 8-year • Subgroup data • Overall survival: 59% • Late effects reported • Disease-free survival: 31% Grade 4 retinopathy: 4% Grade 3 (cataract, ectropion, dacryocystorrhinostomy): 13% Grade 3 neurologic: 43% Grade 5 CSF leak: 4% Weber (2006) Advanced nasal N=36 • PBT + photon, • Median: 52 3-year • LENT/SOMA and CTCAE • 3/36 (8%) cavity and median: 69.6 months • Overall survival: 90% scoring w/recurrent Massachusetts paranasal sinus CGE (range, (range, 17- • Disease-free survival: 77% disease General Hospital, cancer 60.8-77) 123) • Severity of acute effects: NR MA, US 5-year • Late effects • Subgroup data • Overall survival: 81% Grade 3 cataract: 3% reported • Disease-free survival: 73% Grade 3 nasolacrimal duct blockage: 3% Feuvret (2005) Chondromyxoid N=2 • PBT + photon: • Ranging • Overall survival: 100% • Severity of harms: NR fibroma of the 59 CGE from 1 - 4 Centre de skull base years Protonthérapie d’Orsay, France Noël (2005) Chordoma of N=100 • PBT + photon, • Median: 31 Overall survival • Severity of acute/late • 30/100 (30%) the skull base or median: 67 CGE months • 2-year: 94% effects: NR w/recurrent Centre de upper cervical (range, 60-71) (range, 0-87) • 4-year: 90%% disease Protonthérapie spine • 5-year: 81% d’Orsay, France • Subgroup data reported Slater (2005) Localized stage N=29 • PBT + photon, • Median: 28 Disease-free survival • RTOG scoring • All patients II-IV dose: 75.9 GyE months • 2-year: 81% w/primary Loma Linda oropharyngeal (range, 2-96) • 5-year: 65% • Severity of acute effects: NR disease University cancer • Late effects Medical Center Grade 3 (fibrosis, trismus, vocal cord paralysis): 11% Proton Beam Therapy: Final Evidence Report Page 176 WA – Health Technology Assessment March 28, 2014 Table 7. Single-arm Case Series: Head and Neck Cancers (including skull-base tumors). Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Marucci (2004) Chordoma or N=85 • PBT + photon, • Median: 41 NR • RTOG/EORTC scoring • Subgroup data reported chondrosarcoma of mean: 76.3 CGE months (range, Massachusetts the cervical spine (range, 68.6-83.5) 2-117) • Acute effects: NR General Hospital, and cervico- • Late effects MA, USA occipital junction ≥ Grade 3: 5% Noël (2004) Chordoma or N=90 • PBT + photon, • Median: 34 Overall survival • LENT/SOMA & RTOG scoring • 30/90 (33%) w/recurrent chondrosarcoma of median: 67 CGE months (range, • 2-year: 93% disease Centre de the cranial base (range, 22-70) 3-74) • 3-year: 92% • Severity of acute effects: NR Protonthérapie and cervical spine • 4-year: 86% • Late effects • Subgroup data reported d’Orsay, France Grade 3 oculomotor: 2% Grade 3 hearing loss: 1% Grade 4 visual: 1% Bowyer (2003) Clival chordoma N=4 • PBT + photon, • Mean: 34 • Overall survival: 100% • Severity of acute/late effects: mean: 76.7 CGE months (range, NR Walton Hospital, (range, 72-83.5) 17-60) Liverpool , UK Fitzek (2002) Olfactory N=19 • PBT + photon, • Median: 45 • 5-year overall survival: 74% • CTCAE & LENT/SOMA scoring • All patients w/primary neuroblastoma or median: 69.2 CGE months (range, disease Massachusetts neuroendocrine (range, 67.2-72.6) 20-92) • Severity of acute effects: NR General Hospital, carcinoma • Subgroup data reported MA, USA • Late effects Grade 3 temporal lobe damage: 5% Grade 3 xerostomia: 11% Hug (1999) Chordoma and N=58 • Mean: 70.7 CGE • Mean: 33 3-year overall survival • LENT/SOMA scoring • 14/58 (24%) w/recurrent chondrosarcoma of (range, 64.8-79.2) months (7-75) • Chordoma: 87% disease Loma Linda the skull base (6 patients received • Chondrosarcoma: 100% •Severity of acute effects: NR University Medical additional photon • Subgroup data reported Center, CA, USA therapy) 5-year overall survival • Late effects • Chordoma: 79% Grade 3-4: 7% • Chondrosarcoma: 100% Lin (1999) Recurrent or N=16 • Mean: 62.8 CGE • Mean: 24 2-year • Severity of harms: NR • All patients w/recurrent persistent (range, 59.4-70.2) months (range, • Overall survival: 50% or persistent disease Loma Linda nasopharyngeal 4-47) • Disease-free survival: 50% University Medical carcinoma • Subgroup data reported Center, CA, USA Proton Beam Therapy: Final Evidence Report Page 177 WA – Health Technology Assessment March 28, 2014 Table 7. Single-arm Case Series: Head and Neck Cancers (including skull-base tumors). Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Rosenberg (1999) Chondrosarcom N=200 • Median: 72.1 CGE • Mean: 65 NR NR a of the skull (range, 64.2-79.6) months (range, Massachusetts base 2-222) General Hospital, MA, USA Terahara (1999) Skull-base N=115 • PBT + photon, • Median: 41 NR NR • Subgroup data chordoma median: 68.9 CGE months (range, reported Massachusetts (range, 66.6-79.2) 5-174) General Hospital, (2 patients received MA, USA PBT alone) Debus (1997) Chordoma and N=367 • PBT + photon, • Mean: 43 Overall survival • Scoring consistent • Subgroup data low-grade mean: 67.8 CGE months (range, • 5-year: 94% w/LENT/SOMA reported Massachusetts chondrosarcom (range, 63-79.2) 6-257) • 10-year: 86% General Hospital, a of the skull • Acute effects: NR MA, USA base • Late effects (brainstem toxicity only) Grade 3: 1% Grade 4: 1% Grade 5: 0.8% Fagundes (1995) Relapsed N=63 • PBT + photon, • Median: 54 Overall survival NR • Subgroup data chordoma of the median: 70.1 CGE months (range, • 3-year: 43% reported Massachusetts skull base or (range, 66.6-77.4) 8-158) • 5-year: 7% General Hospital, cervical spine MA, USA O’Connell (1994) Skull-base N=62 • PBT + photon • Median: 69 • Overall survival: 66% NR • Patient overlap chordoma dose: ranging from months (range, w/Terahara (1999) Massachusetts 64.9-73.5 CGE 20-158) General Hospital, • Subgroup data MA, USA reported * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. CSF: cerebrospinal fluid; CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NR: not reported; PBT: proton beam therapy; RBE: relative biological effectiveness; RTOG: Radiation Therapy Oncology Group Table 8. Single-arm Case Series: Liver Cancer. Proton Beam Therapy: Final Evidence Report Page 178 WA – Health Technology Assessment March 28, 2014 Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Abei (2013) Locally N=9 • Mean: 72.2 GyE NR • Overall survival: • CTCAE scoring • All patients advanced (range, 52.8-87.6) 33% w/recurrent University of recurrent HCC • Acute effects disease Tsukuba, Japan ≥ Grade 3: 0% • Late effects: NR Kanemoto (2013) HCC N=67 • Dose: 66 Gy • Median: 28 NR • Severity of harms: NR • Subgroup data (RBE) months reported University of (range, 7-81) Tsukuba, Japan Kanemoto (2012) Liver metastases N=5 • Dose: 66 or 72.6 • Median: 33 • Overall survival: • CTCAE scoring from breast GyE months 100% University of cancer (range, 20- • No acute/late effects ≥ Tsukuba, Japan 102) Grade 3 Mizumoto (2012) HCC N=259 • Dose: ranging • Up to 24 NR NR • Patients from 66 – 77 GyE months evaluated in University of based on tumor following PBT Mizumoto (2011) Tsukuba, Japan location as described in • Subgroup data Mizumoto (2011) reported Bush (2011) HCC N=76 • Dose: 63 CGE NR • Overall survival, • Common Toxicity Criteria • Subgroup data progression-free reported Loma Linda survival in figures • No acute/late effects ≥ University only Grade 3 Medical Center, CA, USA Proton Beam Therapy: Final Evidence Report Page 179 WA – Health Technology Assessment March 28, 2014 Table 8. Single-arm Case Series: Liver Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Kawashima (2011) HCC ≤10 cm N=60 • Dose: ranging NR 3-year • CTCAE scoring • 10/60 (17%) from 60-76 CGE • Overall survival: 56% w/recurrent National Cancer • Disease-free survival: 18% • Proton-induced hepatic disease Center Hospital insufficiency: 18% East, Japan 5-year • Subgroup data • Overall survival: 25% •Acute effects reported • Disease-free survival: 4% Grade 3 elevation of bilirubin: 2% Grade 3 elevation of transaminases: 13% Grade 3 hematologic: 23% ≥Grade 3 GI: 2% • Late effects Grade 3 GI: 2% Mizumoto (2011)† HCC >2cm from N=104 • Protocol A: 66 NR 1-year • CTCAE & RTOG/EORTC • Patients from the GI tract or GyE • Overall survival: 87% scoring Mizumoto University of porta hepatis • Progression-free survival: (2008) included Tsukuba, Japan 56% • Acute effects in analysis Mizumoto (2011)† HCC ≤2cm from N=95 • Protocol B: 72.6 Grade 3 dermatitis: 0.8% the porta hepatis GyE 3-year • Subgroup data University of • Overall survival: 61% • Late effects reported Tsukuba, Japan • Progression-free survival: Grade 3 dermatitis: 0.8% Mizumoto (2011)† HCC ≤2cm from N=60 •Protocol C: 77 21% Grade 3 GI: 1% the GI tract GyE University of 5-year Tsukuba, Japan • Overall survival: 48% • Progression-free survival: 12% Proton Beam Therapy: Final Evidence Report Page 180 WA – Health Technology Assessment March 28, 2014 Table 8. Single-arm Case Series: Liver Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Nakayama HCC located ≤2cm N=47 • Dose: ranging • Median: 23 1-year • CTCAE scoring • Subgroup data (2011) to the alimentary from 72.6 – 77 months • Overall survival: 70% reported tract GyE (range, 3-52) • Local progression-free • Acute effects University of survival: 92% ≥ Grade 3: 0% Tsukuba, Japan 3-year • Late effects • Overall survival: 50% Grade 3 hemorrhage: 2% • Local progression-free survival: 88% 4-year • Overall survival: 34% • Local progression-free survival: 88% Sugahara (2010) HCC >10cm N=22 • Median: 72.6 • Median: 13 1-year • CTCAE & RTOG/EORTC CGE (range, months • Overall survival: 64% scoring University of 47.3-89.1) (range, 2-85) • Progression-free Tsukuba, Japan survival: 62% • Acute effects ≥ Grade 3: 0% 2-year • Overall survival: 36% • No reported late effects • Progression-free survival: 24% Fukumitsu HCC located ≥2cm N=51 • Dose: 66 GyE • Ranged from Overall survival • RTOG/EORTC scoring • 33/51 (65%) (2009) from porta 19-60 months • 3-year: 49% w/recurrent hepatis or • 5-year: 39% • Acute effects disease University of digestive tract ≥ Grade 3: 0% Tsukuba, Japan • Subgroup data • Late effects reported Grade 3 radiation pneumonitis: 2% Nakayama HCC N=318 • Median: 72.6 • Median: 19 Overall survival • CTCAE scoring (2009) GyE (range, 55- months • 1-year: 90% 79.2) (range, 1-64) • 3-year: 65% • Overall effects University of • 5-year: 45% Grade 3 skin: 1% Tsukuba, Japan Grade 3 GI: 0.3% Proton Beam Therapy: Final Evidence Report Page 181 WA – Health Technology Assessment March 28, 2014 Table 8. Single-arm Case Series: Liver Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Sugahara (2009) Advanced HCC N=35 • Median: 72.6 • Median: 21 2-year • RTOG/EORTC scoring • 14/35 (40%) of w/portal vein GyE (range, 55- months (range, • Overall survival: 48% patients University of tumor thrombosis 77) 2-88) • Local progression-free • Acute effects w/recurrent PVTT Tsukuba, Japan (PVTT) survival: 46% Grade 3 hematologic: 6% Grade 4 hematologic: 3% • Subgroup data 5-year reported • Overall survival: 21% • Late effects • Local progression-free ≥ Grade 3: 0% survival: 20% Mizumoto (2008) HCC located ≤2cm N=53 • Dose: 72.6 GyE NR 2-year • NCI Common Toxicity • Patients of the main portal • Overall survival: 57% Criteria & RTOG/EORTC included in University of vein • Progression-free survival: scoring Mizumoto (2011) Tsukuba, Japan 38% • Acute effects • Subgroup data 3-year ≥ Grade 3: 0% reported • Overall survival: 45% • Progression-free survival: • Late effects 25% ≥ Grade 3: 0% Hata (2007a) HCC N=3 • Dose: 24 Gy • Up to 30 • Overall survival: 67% • CTCAE scoring w/uncontrollable months University of ascites • No reported acute effects Tsukuba, Japan • Late effects ≥ Grade 3: 0% Hata (2007b) Patients ≥80 years N=21 • Dose: ranging • Median: 16 1-year • RTOG/EORTC scoring • 10/21 (48%) of w/HCC from 60 – 70 Gy months (range, • Overall survival: 84% patients University of 6-49) • Disease-free survival: 70% • Acute effects w/recurrent Tsukuba, Japan Grade 3 hematologic: 10% disease 3-year • Overall survival: 62% • No reported late effects • Disease-free survival: 51% Mizumoto (2007) HCC w/inferior N=3 • Dose: ranging • Up until death • All patients died, 13-55 • No toxicities ≥ Grade 3 vena cava tumor from 50 – 70 Gy months following PBT observed University of thrombus Tsukuba, Japan Proton Beam Therapy: Final Evidence Report Page 182 WA – Health Technology Assessment March 28, 2014 Table 8. Single-arm Case Series: Liver Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Hashimoto (2006) Patients w/HCC N=27 • Dose: ranging • Median: 62 5-year survival • CTCAE & RTOG/EORTC w/ ≥2 courses of from 40-83 months (range, • From the first course: 56% scoring University of PBT 9-149) • From the second course: 26% Tsukuba, Japan • Acute effects Grade 4 hepatic failure: 7% • Late effects Grade 4 rib fracture: 4% Grade 4 bile duct stenosis: 7% Hata (2006a) HCC in patients N=21 • Median: 73 Gy • Median: 40 Overall Survival • RTOG/EORTC scoring w/limited (range, 63-84) months (range, • 2-year: 62% University of treatment 4-128) • 5-year: 33% • Acute effects Tsukuba, Japan options ≥ Grade 3: 0% (contraindicatio Disease-free rate • 1-year: 72% • Late effects ns) ≥ Grade 3: 0% • 2-year: 33% Hata (2006b) HCC w/Child- N=19 • Median: 72 Gy • Median: 17 1-year • RTOG/EORTC scoring • Subgroup Pugh class C (range, 50-84) months • Overall survival: 53% data University of cirrhosis (range,3-63) • Progression-free survival: 47% • Acute effects reported Tsukuba, Japan ≥ Grade 3: 0% 2-year • Overall survival: 42% • No reported late effects • Progression-free survival: 42% Chiba (2005) HCC in patients N=162 • Median: 72 Gy • Ranged from • 5-year overall survival: 24% • RTOG/EORTC scoring • Subgroup unsuitable for (range, 50-88) 32 – 133 data University of surgery months • Acute effects reported Tsukuba, Japan ≥ Grade 3: 0% • Late effects: reported for ≥ Grade 2 Hata (2005) HCC w/tumor N=12 • Median: 55 Gy • Median: 28 2-year • RTOG/EORTC scoring • 3/12 (25%) thrombus in (range, 50-72) months (range, • Overall survival: 88% w/recurrent University of main trunk 4-88) • Progression-free survival: 67% • Acute effects disease Tsukuba, Japan branches of the ≥ Grade 3: 0% portal vein 5-year • Overall survival: 58% • Late effects • Progression-free survival: 24% ≥ Grade 3: 0% Proton Beam Therapy: Final Evidence Report Page 183 WA – Health Technology Assessment March 28, 2014 Table 8. Single-arm Case Series: Liver Cancer. Author (Year) Condition Sample Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Type Size Niizawa (2005) HCC N=22 • Mean: 65.8 Gy • Mean: 12 NR NR (TACE in 6 months (range, University of patients, 27%) 6-15) Tsukuba, Japan Ahmadi (1999a) HCC N=46 • Mean: 70.4 Gy • Ranging from Overall survival • Severity of harms: NR • Subgroup data (range, 50-84) 12-76 months • 3-year: 76% reported University of • 5-year: 49% Tsukuba, Japan Ahmadi (1999b) Unresectable N=4 • Mean: 70 Gy • Mean: 14 • Overall survival: 100% NR hypervascular (range, 55-82) months (range, University of HCC 9-22) Tsukuba, Japan Ohara (1997) HCC N=26 • Dose: ranging • Ranging from NR • Severity of harms: NR from 55 – 84 Gy 12-27 months University of Tsukuba, Japan Ohara (1996) HCC N=18 • Dose: ranging • Ranging from NR NR • All patients from 50.5 – 82 Gy 7-33 months w/primary disease University of Tsukuba, Japan * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. † Mizumoto (2011) reported on different dosing protocols for PBT, determined by tumor location, delivered to patients w/HCC tumors. Results for each arm are listed separately. CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; GI: gastrointestinal; HCC: hepatocellular carcinoma; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NCI: National Cancer Institute; NR: not reported; PBT: proton beam therapy; PVTT: portal vein tumor thrombosis; RBE: relative biological effectiveness; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 184 WA – Health Technology Assessment March 28, 2014 Table 9. Single-arm Case Series: Lung Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Kanemoto (2014) Stage I NSCLC N=74 • Dose: 66 or • Median: 31 3-year • CTCAE & RTOG/EORTC • Patient (central & 72.6 GyE months (range, • Overall survival: 77% scoring overlap University of peripheral sites) 7-104) • Progression-free survival: 59% w/Nakayama Tsukuba, Japan • Acute effects (2010) 5-year Grade 3 pneumonitis: 1% • Overall survival: 66% • Subgroup • Progression-free survival: 53% • Late effects data reported Grade 3 pneumonitis: 1% Grade 3 skin ulcer: 1% Grade 4 rib fracture: 15% Bush (2013) Stage I NSCLC N=111 • Dose: 51, 60 • Median: 48 4-year overall survival • CTCAE scoring • Subgroup or 70 Gy months • Dose, 51 Gy: 18% data reported Loma Linda • Dose, 60 Gy: 32% • No acute/late effects ≥ University Medical • Dose, 70 Gy: 51% Grade 3 Center, CA, USA (p=0.006) Colaco (2013) Limited stage- N=6 • Dose: • Median: 12 1-year • CTCAE scoring SCLC ranging from months (range, • Overall survival: 83% University of Florida 45 CGE in 1 8-41) • Progression-free survival: 66% • No acute/late effects ≥ Proton Therapy patient to 60- Grade 3 Institute, FL, USA 66 CGE Gomez (2013) NSCLC N=25 • Dose: 45, • Median (in NR • CTCAE scoring 52.5, or 60 patients alive at MD Anderson Gy(RBE) analysis): 13 •Acute effects Cancer Center, TX, months (range, ≥ Grade 3: 0% USA 8-28) • Late effects Grade 3 (pneumonitis, esophagitis): 8% McAvoy (2013) Locoregionally N=33 • Median: 66 • Median: 11 1-year • CTCAE scoring • All patients recurrent NSCLC Gy(RBE) months (range, • Overall survival: 47% w/recurrent MD Anderson 1-32) • Progression-free survival: 28% • Acute/late effects disease Cancer Center, TX, ≥ Grade 3 esophageal: 9% USA 2-year ≥ Grade 3 pulmonary: 21% • Subgroup • Overall survival: 33% ≥ Grade 3 cardiac: 3% data reported • Progression-free survival: 14% Table 9. Single-arm Case Series: Lung Cancer. Proton Beam Therapy: Final Evidence Report Page 185 WA – Health Technology Assessment March 28, 2014 Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Hoppe (2012) Regionally N=19 • Median: 74 CGE • Median: 15 • Overall survival: 42% • CTCAE scoring advanced NSCLC (range, 62-80) (12 months University of patients also (range, 7-26) • Acute effects Florida Proton received adjacent Grade 3 hematologic: 37% Therapy Institute, nodal PBT, Grade 3 hypoxia/dyspnea: FL, USA median 40 CGE) 11% Grade 3 weight loss: 5% Grade 4/5 (PS, fatigue, esophagitis): 16% • Late effects Grade 3 PS: 6% Grade 3 fatigue: 6% Grade 3 pulmonary: 18% Grade 4/5 pulmonary: 13% Grade 4/5 hematologic: 13% Westover (2012) Medically N=15 • Median: 45 • Median: 24 • 2-year overall survival: • CTCAE scoring • All patients inoperable stage Gy(RBE) (range, months 64% w/primary disease Massachusetts I NSCLC 42-50) • Acute/late effects General Hospital, Grade 3 pneumonitis: 7% MA, USA Xiang (2012) Unresectable N=84 • Dose: 74 • Median: 19 3-year NR • Patients from 2 stage III NSCLC Gy(RBE) months • Overall survival: 37% prospective trials MD Anderson (range, 6-52) • Progression-free survival: Cancer Center, TX, 31% • Subgroup data USA reported Chang (2011a) Unresectable N=44 • Dose: 74 • Median: 20 1-year • CTCAE scoring stage III NSCLC Gy(RBE) months • Overall survival: 86% MD Anderson (range, 6-44) • Progression-free survival: • Acute effects Cancer Center, TX, 63% Grade 3 dermatitis: 11% USA Grade 3 esophagitis: 11% Grade 3 dehydration: 7% Grade 3 fatigue: 2% • Late effects Grade 3 pulmonary: 5% Proton Beam Therapy: Final Evidence Report Page 186 WA – Health Technology Assessment March 28, 2014 Table 9. Single-arm Case Series: Lung Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Chang (2011b) Inoperable stage N=18 • Dose: 87.5 • Median: 16 1-year • CTCAE scoring IA, IB or II NSCLC Gy(RBE) months (range, • Overall survival: 93% MD Anderson 5-36) • Disease-free survival: 53% • Acute effects Cancer Center, Grade 3 dermatitis: 17% TX, USA 2-year • Overall survival: 55% • Late effects • Disease-free survival: 46% ≥ Grade 3: 0% Nakayama Stage II & III N=35 • Median: 78.3 • Median: 17 1-year • CTCAE scoring (2011) NSCLC Gy(RBE) (range, months • Overall survival: 82% 67.1-91.3) • Progression-free survival: 60% • No acute/late effects ≥ University of Grade 3 Tsukuba, 2-year Japan • Overall survival: 59% • Progression-free survival: 29% Nakayama Stage I NSCLC N=55 • Dose: 66 or • Median: 18 2-year • CTCAE scoring • Subgroup (2010) 72.6 GyE months (range, • Overall survival: 98% data 1-53) • Progression-free survival: 89% • Acute/late effects reported University of Grade 3 pneumonitis: 4% Tsukuba, 3-year Japan • Progression-free survival: 79% • Severity of other effects: NR Hata (2007) Stage I NSCLC N=21 • Dose: 50 or 60 • Median: 25 2-year • RTOG/EORTC scoring • Subgroup Gy months • Overall survival: 74% data University of • Disease-free survival: 79% • No acute/late effects ≥ reported Tsukuba, Grade 3 Japan Nihei (2006) Stage I NSCLC, N=37 • Dose: ranging • Median: 24 1-year • CTCAE & RTOG/EORTC • Subgroup tumor ≤5cm from 70-94 GyE months (range, • Disease progression-free scoring data National 3-62) survival: 73% reported Cancer Center • Acute effects East, Chiba, 2-year ≥ Grade 3: 0% Japan • Overall survival: 84% • Disease progression-free •Late effects survival: 58% Grade 3 pulmonary: 8% Proton Beam Therapy: Final Evidence Report Page 187 WA – Health Technology Assessment March 28, 2014 Table 9. Single-arm Case Series: Lung Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Shioyama (2003) NSCLC N=51 • Median: 76 Gy • Median: 30 5-year • Common Toxicity Criteria • 5/51 (10%) (range, 49-93) months (range, • Overall survival: 29% w/recurrent University of 18-153) • Disease-free survival: • Acute effects disease Tsukuba, Japan 37% Grade 3 pulmonary: 2% • Subgroup data • Late effects reported ≥ Grade 3: 0% Bonnet (2001)† Stage I-II NSCLC N=10 • Dose: 51 CGE • Up to 12 NR • Severity of acute/late • Overlapping w/FEV1≤ 1L months effects: NR patient population Loma Linda w/Bush (1999a & University Medical 1999b) Center, CA, USA Bonnet (2001)† Stage I-IIIA NSCLC N=15 • PBT + photon, w/FEV1> 1L dose: 73.8 Gy Loma Linda University Medical Center, CA, USA Bush (1999b)‡ Stage I-IIIa NSCLC in N=19 • Dose: 51 CGE • Median: 14 • 2-year overall • Pulmonary injury • Overlapping patients w/poor months (range, survival: 31% reported in Bush (1999a) patient population Loma Linda cardiopulmonary 3-45) w/Bonnet (2001) University Medical function • Severity of acute/late Center, CA, USA effects: NR Bush (1999b)‡ Stage I-IIIa NSCLC in N=18 • PBT + photon, patients dose: 73.8 Gy Loma Linda w/adequate University Medical cardiopulmonary Center, CA, USA function (FEV1> 1L) * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. † Bonnet (2001) reported on different dosing protocols for PBT, determined by disease stage, delivered to patients w/NSCLC. Results for each arm are listed separately. ‡ Bush (1999) reported on patients treated w/different dosing protocols. Overall findings are listed. CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; FEV1: forced expiratory volume in 1 second; N: number; NR: not reported; NSCLC: non-small-cell lung cancer; PBT: proton beam therapy; RBE: relative biological effectiveness; RTOG: Radiation Therapy Oncology Group; SCLC: small-cell lung cancer Proton Beam Therapy: Final Evidence Report Page 188 WA – Health Technology Assessment March 28, 2014 Table 10. Single-arm Case Series: Lymphomas. Author (Year) Condition Sample Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Type Size Li (2011) Mediastinal N=10 • Mean: 39.1 CGE NR NR • Scoring protocol: NR • 2/10 (20%) masses from (range, 28-50.4) w/recurrent MD Anderson lymphoma • Acute effects disease Cancer Center, TX, ≥ Grade 3: 0% USA • Late effects: NR N: number; NR: not reported Proton Beam Therapy: Final Evidence Report Page 189 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Condition Type Sample Size Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Petrovic (2014) Uveal melanoma N=129 • Dose: 60 Gy • Mean: 79 NR • Severity of harms: NR • Subgroup data (RBE) months (range, 4- reported Paul Scherrer 281) • Secondary enucleation: 16% Institute, Switzerland Sandinha (2014) Iris melanoma N=150 • Dose: 53.1 Gy • Median: 66 NR NR • Patient months (range, overlap w/ Clatterbridge Cancer 12-108) Konstantinidis Centre, UK (2013) Konstantinidis Diffuse or N=12 • Dose: 53.1 Gy • Median: 3.5 • Overall survival: • Acute effects: NR • All patients w/ (2013) multifocal primary years (range, 1- 92% primary disease iris melanoma 12) • Severity of late effects: NR Clatterbridge Cancer Centre, UK Mishra (2013) Uveal melanoma N=704 • Dose: 56 GyE • Median: 58.3 NR • Acute effects: NR • Subgroup data months (range, 6- reported University of San 194) Late effects Francisco, CA, USA • Secondary enucleation: 4% • Other late effects: NR Caujolle (2012) Uveal melanoma N=1102 • Dose: 60 CGE Median 10-year overall NR • Subgroup data • Patients survival reported Centre Antoine w/recurrence: 5 • Patients w/local Lacassagne, Nice, years recurrence: 43% France • Patients w/out • Patients free of recurrence: 4 recurrence: 69% years Chappell (2012) Uveal melanoma N=197 NR • Median: 22 NR NR • Subgroup data months (range, 2- reported University of San 112) Francisco, CA, USA Tran (2012) Peripapillary N=59 • Mean: 57 CGE • Median: 63 • 5-year overall • Acute effects: NR • Subgroup data choroidal (32% w/54 CGE, months (range, 4- survival: 85% reported Vancouver Hospital melanoma (≤2mm 68% w/60 CGE) 131) Late effects Eye Care Centre, from optic disc) • Secondary enucleation:14% Canada • Severity of other late effects not reported Proton Beam Therapy: Final Evidence Report Page 190 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Lane (2011)† Peripapillary and N=573 NR • Median: 96 • Overall survival: • Severity of harms: NR parapapillary months (range, 69% Massachusetts melanomas located 10-173) • Secondary enucleation: 10% General Hospital, MA, within 1 disc diameter USA of the optic nerve Macdonald (2011) Ciliary body and N=147 NR • Median: 3.1 • Overall survival: • Acute effects: NR • All patients w/ choroidal melanomas years (3 months- 75% primary disease NR 15 years) Late effects • Secondary enucleation: 12% • Other late effects: NR Caujolle (2010) Uveal melanoma N=886 • Dose: 60 CGE • Median: 63.7 • 15-year overall • Severity of harms: NR • Subgroup data months (range, 6- survival: 54% reported Centre Antoine 185) • Secondary enucleation: 4% Lacassagne, Nice, France Kim (2010)† Parapapillary N=93 • Dose: 70 CGE • Mean: 5.5 years NR • Severity of harms: NR • Subgroup data choroidal melanoma (range, 6 months- reported Massachusetts within 1 disc diameter 13 years) General Hospital, MA, of the optic nerve USA Mizumoto (2010) Tumors proximal to N=3 • Patient 1: 55.4 • Median: 10 • Overall survival: • CTCAE scores the optic nerve GyE months (range, 7- 100% NR • Patient 2 12) • Acute effects Photon: 50.4 Gy ≥ Grade 3: 0% PBT: 46.2 GyE • Patient 3: 67.3 • No reported late effects GyE Vavvas (2010)† Posterior unilateral N=50 NR • Median: 16.7 • Overall survival: NR choroidal or ciliary years (range, 2.7- 84% Massachusetts melanoma 24.5) General Hospital, MA, USA Aziz (2009) Uveal melanoma N=76 • Dose: 58 CGE • Mean: 39 NR • Severity of harms: NR • 9/76 (12%) months (range, 3- w/recurrent Clatterbridge Centre 122) • Secondary enucleation: 17% disease for Oncology, UK • Subgroup data reported Proton Beam Therapy: Final Evidence Report Page 191 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Mosci (2009) Intraocular melanoma N=368 • Dose: 60 GyE • Median: 3.9 • 6-year overall survival rate: • Acute effects: NR • All patients w/ years 90% primary disease Centre Lacassagne • Late effects Cyclotron Biomedical Secondary enucleation: 4% • Subgroup data of Nice, France reported Rundle (2007) Unresectable iris N=15 • Dose: 5,310 cGy • Median: 40 • Overall survival: 100% • Severity of harms: NR • 2/15 (13%) melanoma months (range, 6- w/recurrent disease Royal Hallamshire 65) • Secondary enucleation: 13% Hospital, Sheffield, UK Conway (2006) Extra-large uveal N=21 • Dose: 5600 cGy • Median: 28 • Overall survival: 86% • Severity of harms: NR • Severity described melanoma (≥10mm months (range, for subset of adverse University of San max thickness, 20mm 13-85) • Secondary enucleation: 29% effects only Francisco, CA, USA in max basal diameter, or ≤3mm of optic • Subgroup data nerve and w/≥8mm reported max thickness or 16mm in max basal diameter Dendale (2006) Uveal melanoma N=1406 • Dose: 60 CGE • Median (of • Overall survival: 79% • Severity of harms: NR • All patients w/ surviving primary disease Institut Curie, France patients): 73 • Secondary enucleation: 7% months (range, • No patients w/iris 24-142) melanoma • Subgroup data reported Lumbroso-Le Rouic Iris melanoma N=21 • Dose: 60 CGE • Median: 33 • Overall survival: 100% • Severity of harms: NR • 15/21 (71%) (2006) months (range, 8- w/recurrent disease 72) • Secondary enucleation: 0% Institut Curie, France • Subgroup data reported Marucci (2006) Locally recurrent uveal N=31 • Dose: 70 CGE • Median: 36 • Overall survival: 74% • Severity of harms: NR • All patients melanoma (1 patient received months (range, 6- w/recurrent disease Massachusetts 48 CGE) 164) • Secondary enucleation: 13% General Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 192 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Wuestmeyer (2006) Conjunctival N=20 • Primary target • Median: 34 • Overall survival: 95% • Severity of harms: NR • 16/20 (80%) melanoma dose: 45 Gy months (range, w/recurrent disease Cyclotron Biomedical of 13-117) the Centre • Secondary target Antoine-Lacassagne, dose: 31 Gy France Damato (2005a) Choroidal N=349 • Dose: 53.1 Gy • Median: 3.1 NR • Severity of harms: NR • All patients w/ melanoma (RBE) years (range, primary disease Clatterbridge Centre for 0.01-11.5) • Secondary enucleation: 4% Oncology, UK • Subgroup data reported Damato (2005b) Iris melanoma N=88 • Dose: 58.4 CGE • Median: 2.7 • Overall survival: 97% • Severity of harms: NR • All patients w/ years primary disease Clatterbridge Centre for • Secondary enucleation: 0% Oncology, UK • Subgroup data reported Tsina (2005) Choroidal N=63 • Dose: 28 CGE • Median (among • Overall survival: 22% • Severity of harms: NR • Unknown if metastatic disease survivors): 8 patients w/recurrent Massachusetts General months (range, 1- • Secondary enucleation: 0% disease Hospital, MA, USA 34) Höcht (2004) Primary uveal N=245 • Dose: 60 CGE • Median: 18.4 NR • Severity of harms: NR • Subgroup data melanoma months reported Hahn-Meitner Institute, Germany Kodjikian (2004) Posterior uveal N=224 • Dose: 60 CGE • Median (among • 5-year overall survival: • Severity of harms: NR • Subgroup data melanoma survivors): 41 78% reported Lacassagne Cyclotron months • Secondary enucleation: 8% Biomedical Centre, France Egger (2003) Uveal melanoma N=2645 • Dose: 60 CGE • Median: 44 • Overall survival: 84% • Acute effects: NR • Subgroup data months (range, 0- reported Paul Scherrer Institute, 187) Late effects Switzerland • Secondary enucleation: unable to determine • Other late effects: NR Proton Beam Therapy: Final Evidence Report Page 193 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Sample Survival Condition Type Total PBT Dose Follow-up Harms* Notes Study Site Size Outcomes Hadden (2003) Bilateral uveal N=2 NR • Variable: 4 – • Overall survival: • Acute effects: NR melanoma 22 months 100% Ocular Oncology Late effects Centre, Liverpool, UK • Secondary enucleation: 50% • Severity of other late effects: NR Li (2003)† Primary N=1204 • Dose: 70 CGE • Median: 95 • Overall survival: NR • All patients w/ choroidal months 70% primary disease Massachusetts melanoma General Hospital, MA, USA Zografos (2003) Intraocular N=6 • Mean: 48 Gy • Mean: 11 • Overall survival: • Severity of harms: NR metastatic (range, 25-60) months 0% Paul Scherrer melanoma (range, 1-42) Institute, Switzerland Gragoudas (2002a)† Choroidal/ciliary N=1922 • Dose: 70 CGE • Median: 62 NR NR • All patients w/ body melanoma (95% of years primary disease Massachusetts patients) General Hospital, MA, (5% received 50 • Subgroup data USA CGE) reported Gragoudas (2002b)† Unilateral N=2069 • Dose: 70 CGE • Median NR • Acute effects: NR choroidal or (among Massachusetts ciliary survivors) : 9.4 • Late effects General Hospital, MA, melanoma years (range, Secondary enucleation: 7% USA 10 months – 24 years) Fuss (2001) Medium and N=78 • Dose: 70.2 • Median: 34 • 5-year overall • Acute effects: NR large choroidal CGE months survival: 70% Loma Linda University melanomas (range, 6-102) Late effects Medical Center, CA, • Secondary enucleation: 9% USA • Severity of other late effects: NR Lumbroso (2001) Uveal N=480 • Dose: 60 CGE • Median: up NR • Severity of harms: NR • Subgroup data melanoma to 62 months reported Institut Curie, France Proton Beam Therapy: Final Evidence Report Page 194 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Li (2000)† Uveal melanoma N=1848 • Dose: 70 CGE • Median NR NR • Subgroup data (range, 54-100) (among reported Massachusetts survivors): 9.5 General Hospital, years MA, USA Courdi (1999) Uveal melanoma N=538 • Dose: 57.2 CGE • Up to 78 • Overall survival: 73.8% • Acute effects: NR • 5 patients months w/secondary Centre A. • Late effects enucleation w/out Lacassagne, Secondary enucleation: attributable cause France 3% • Subgroup data reported Egan (1999)† Choroidal N=1818 • Dose: 70 CGE • Median f/u • 10-year overall survival NR • All patients w/ melanoma among Men: 61% primary disease Massachusetts survivors: 8.5 Nulliparous women: 59% General Hospital, years Parous women: 66% • Subgroup data MA, USA reported Gragoudas Choroidal tumors, N=558 • Dose: 70 CGE • Median: 4 NR • Severity of harms: NR • Subgroup data (1999)† <5mm in height and years reported <15mm in diameter, Massachusetts located within 4 General Hospital, disc diameters of MA, USA macula or optic nerve Wilson (1999) Choroidal N=267 • Dose: 60 GyE • Mean: 43 NR NR melanoma months (range, St. Bartholomew’s 4-85) Hospital and Moorfields Eye Hospital, London, England Egan (1998)† Unilateral choroidal N=1541 • Dose: 70 CGE • Median • 10-year overall survival: • Acute effects: NR • All patients w/ or ciliary body (among 63% primary disease Massachusetts melanoma survivors): 8 • Late effects General Hospital, years (range, 6 Secondary enucleation: • Subgroup data MA, USA months-18.3 7% reported years) Proton Beam Therapy: Final Evidence Report Page 195 WA – Health Technology Assessment March 28, 2014 Table 11. Single-arm Case Series: Ocular Tumors. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Kent (1998) Uveal melanoma N=17 • Dose: 53 Gy (Reported for entire • Overall survival: • Severity of harms: NR study population) 94% Ocular Oncology • Median: 268 days Service, UK (range, 0-892) Naeser (1998) Uveal melanoma N=20 • Dose: 54.6 Gy • Up to 5 years • Overall survival: • Severity of harms: NR 85% Uppsala University, • Late effects Sweden Secondary enucleation: 35% Foss (1997) Primary uveal N=127 • Dose: 52 CGE • Median: 36 months NR • Acute effects: NR • Subgroup melanoma data reported St. Bartholomew’s Late effects Hospital and • Secondary nucleation: Moorfields Eye 13% Hospital, London, • Other late effects: NR England Thuomas (1997) Choroidal N=18 NR • Up to 6 years NR NR melanoma Uppsala University, Sweden Park (1996) Parapapillary N=59 NR • Mean: 53 months NR • Severity of harms: NR • Subgroup choroidal (range, 29-94) data reported Massachusetts melanoma General Hospital, MA, USA * Secondary enucleation rates reported for adverse effects not related to tumor recurrence. † Potential patient overlap among studies. CTCAE: Common Terminology Criteria for Adverse Events; N: number; NR: not reported; PBT: proton beam therapy Proton Beam Therapy: Final Evidence Report Page 196 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Survival Condition Type Total PBT Dose Follow-up Harms* Notes Study Site Size Outcomes Petrovic (2014) Uveal N=43 • Dose: 60 Gy (RBE) • Mean: 155 months NR • Severity of harms: • Subgroup melanoma (range, 6-336) NR data reported Paul Scherrer Institute, • Secondary Switzerland enucleation†: 9% Walcott (2014) Cerebral N=44 • Median: 15.5 Gy • Median: 52 months • Overall survival: • Severity of harms: • Subgroup arteriovenous (RBE) (range, 14-17) (range, 9-111) 100% NR data reported Massachusetts malformations General Hospital, MA, USA Bian (2013) Pliocytic N=6 • Mean initial dose: • Median: 24 months • Overall survival: • Severity of harms: astrocytoma 37.8 CGE (range, (range, 5-95) 83% NR MD Anderson 30.6-48.6) Cancer Center, TX, USA • 4 patients received boost doses, ranging from 45-104.4 CGE De Amorim Atypical teratoid N=10 • Median: 50.4 Gy • Median: 27.3 • Overall survival: • Severity of harms: Bernstein (2013) rhabdoid tumors (RBE) (range, 50.4- months (11.3-99.4) 90% NR 55.8) Massachusetts General Hospital, MA, USA Hill-Kayser (2013) High-risk N=13 • Mean: 2,271 cGy • Median: 16 months • Overall survival: • Severity of harms: neuroblastoma (RBE) (range, 2,160- (5-27) 85% NR Children’s 3,600) Hospital of (2 patients Philadelphia, PA, w/photon therapy) USA Proton Beam Therapy: Final Evidence Report Page 197 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Jimenez (2013) Medulloblastoma or N=15 • Median: 54.0 Gy • Median: 39 • 3-year overall survival: • CTCAE scoring • Subgroup data supratentorial (RBE) (range, 39.6- months (range, 3- 86% reported Massachusetts primitive 54.0) 102) • Ototoxicity General Hospital, MA, neuroectodermal Grade 3: 2/13 (15%) USA tumor (patients received concurrent chemotherapy) • No significant changes from baseline in neuropsychological testing • Excluding patients w/endocrine dysfunction, no significant changes from baseline in vertical height impairment MacDonald (2013) Intracranial N=70 • Median: 55.8 Gy • Median: 46 3-year • Median height loss was • Subgroup data ependymoma (range, 50.4-60) months (range, • Overall survival: 95% not significant (p=.142) reported Massachusetts 12-140) • Progression-free survival: General Hospital, MA, 76% • Changes in Mental USA Development Index and IQ were not significant across comparisons • Severity of other harms: NR Oshiro (2013) Neuroblastoma N=14 • Median: 30.6 GyE • Median: 40 • Overall survival: 57% • CTCAE scoring • 6/14 (43%) (range, 19.8-45.5) months (range, w/recurrent University of Tsukuba, 17 months-30 • Overall progression-free • No toxicities ≥ Grade 3 disease Japan years) survival: 50% Ray (2013) Leptomeningeal N=22 • Median: 37.8 Gy • Median: 14 • 12-month overall survival: NR • 5/22 (23%) spinal metastases (range, 21.6-54) months (range, 4- 68% w/recurrent Indiana University 33) disease Health Proton Therapy Center, IN, USA • Subgroup data reported Proton Beam Therapy: Final Evidence Report Page 198 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Condition Type Sample Size Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Rombi (2013) Chordoma and N=26 • Chordoma, mean • Mean: 46 5-year overall survival • CTCAE scoring • Subgroup data chondrosarcoma dose: 74 Gy (RBE) months (range, • Chordoma: 89% reported Paul Scherrer Institute, (range, 73.8-75.6) 4.5-126.5) • Chondrosarcoma: 75% • Acute effects Switzerland ≥ Grade 3: 0% • Chondrosarcoma, mean dose: 66 Gy(RBE) (range, 54-72) • Late effects ≥ Grade 3: 0% Sabin (2013) CNS embryonal N=8 • Total dose: 54 Gy • Median: 3.9 • Overall survival: 75% • Severity of harms: tumors months (mean, NR NR 4.2) Suneja (2013) CNS malignancies N=48 • Median dose: 5,400 NR NR • CTCAE scoring • Subgroup data involving the brain cGy (RBE) (range, reported Roberts Proton Center, 4,500-6,300) • Fatigue University of ≥ Grade 3: 0% Pennsylvania • Headache Grade 3: 2% • Insomnia ≥ Grade 3: 0% • Anorexia Grade 3: 4% • Nausea ≥ Grade 3: 0% • Vomiting ≥ Grade 3: 0% • Alopecia ≥ Grade 3: 0% Yonekawa (2013) Diffuse choroidal N=2 • Dose: 20 Gy (RBE) • Mean: 18.5 • Overall survival: 100% • No severe harms hemangioma in months (range, reported Massachusetts General Sturge-Weber 16-19) Hospital, MA, USA syndrome Childs (2012) Parameningeal N=17 • Median: 50.4 CGE • Median: 5.0 • 5-year overall survival: • Severity of harms: • Subgroup data rhabdomyosarcom (range, 50.4-56) years (range, 2- 64% NR reported Massachusetts General a 10.8) Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 199 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Hattangadi (2012a) Ewing sarcoma N=2 • Mean: 56.7 CGE • Mean: 4.8 • Overall survival: 50% • Severity of harms: NR (range, 55.8-57.6) years (range, 2- Massachusetts 7.5) General Hospital, MA, USA Hattangadi (2012b) High-risk N=9 • Mean: 26.9 • Median: 38 • Overall survival: 78% • CTCAE scoring neuroblastoma Gy(RBE) (range, months (11-70) Massachusetts 18-36) • Acute effects General Hospital, ≥ Grade 3: 0% MA, USA • Severity of late effects: NR Kuhlthau (2012) Brain tumors N=142 • PBT Dose • Up to 5 years NR NR • Subgroup data (including <45 GyRBE: 4.2% reported Massachusetts medulloblastoma, ≥45 GyRBE: 95.8% General Hospital, ependymoma and MA, USA glioma) Laffond (2012) Benign N=29 • Postoperative • Mean: 6.2 NR NR • 13/29 (45%) craniopharyngioma PBT: range, 54- months (range, w/recurrent Institut Curie, 55.2 Gy 1.7 months – 19 disease France years) • Subgroup data reported Rombi (2012) Ewing sarcoma N=30 • Median total • Median: 38.4 • 3-year event-free • Scoring methodology: NR • Subgroup data dose: 54 Gy (RBE) months (range, survival: 60% reported Massachusetts (range, 45-59.4) 17.4 months-7.4 • Grade 3 skin reactions: General Hospital, years) • 3-year overall survival: 17% MA, USA • Fraction: 1.8 Gy 89% • Grade 3 fatigue: 3% (RBE) daily • Severity of other effects: NR Amsbaugh (2011) Ependymoma of N=8 • Mean: 51.1 CGE • Mean: 26 • Overall survival: 100% • CTCAE scores • 3/8 (38%) the spine (range, 45-54) months (7-51) w/recurrent MD Anderson • Acute effects disease Cancer Center, TX, ≥ Grade 3: 0% USA • No late effects identified Proton Beam Therapy: Final Evidence Report Page 200 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Chang (2011) Retinoblastoma N=3 • Mean: 47 CGE • Median: 24 • Overall survival: 100% • Secondary • 2/3 (67%) (range, 46-50.4) weeks (range, enucleation: 66% w/recurrent National Cancer Center, 3-32) disease Korea Cotter (2011) Bladder/prostate N=7 • Mean: 42.9 CGE • Median: 27 • Overall survival: 100% • Severity of harms: rhabdomyosarcoma (range, 36-50.4) months (range NR Massachusetts General 10-90) Hospital, MA, USA MacDonald (2011) CNS germinoma or N=22 • Mean total dose • Median: 28 • Overall survival: 100% • Acute effects: NR nongerminomatous (3D-CPT + other months (range, Massachusetts General germ cell tumor modalities): 44.0 13-97) • Overall progression- • No severe late Hospital, MA, USA Gy(RBE) (range, free survival: 95% effects 30.6-57.6) Moeller (2011) Medulloblastoma N=19 • Adjuvant PBT, • Mean: 11 NR • Brock ototoxicity • Subgroup data total dose: 54.0 months (range, scale reported MD Anderson Cancer CGE 8-16) Center, TX, USA • High grade (grade 3-4) ototoxicity: 5% Oshiro (2011) Nasopharyngeal N=2 • Mean: 65.3 GyE • Mean: 5.3 • Overall survival: 100% • Scoring carcinoma (range, 59.4-71.3) years (4.5-6) methodology: NR University of Tsukuba, Japan • Acute effects Grade 3, mucositis: 1 patient (50%) • Late effects ≥ Grade 3: 0% Vavvas (2010) Posterior unilateral N=17 NR • Median: 16 • Overall survival: 100% • Acute effects: NR • Subgroup data choroidal or ciliary years (5-25) reported Massachusetts General melanoma • Late effects Hospital, MA, USA Secondary enucleation: 0% Gray (2009) Sinonasal Ewing N=2 • Mean: 57.6 GyE NR • Overall survival: 100% • Severity of harms: • All patients sarcoma (range, 55.8-59.4) NR w/primary Massachusetts General disease Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 201 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Winkfield (2009) Benign N=24 • Total dose: range, • Median: 40.5 NR NR • 8/24 (33%) craniopharyngioma 52.2 – 54 GyE months (range, w/recurrent Massachusetts 6-78) disease General Hospital, MA, USA Habrand (2008) Skull base and N=30 • Postoperative PBT • Mean: 26.5 5-year overall survival: • CTCAE scores • 1/30 (3%) cervical canal + photon (3% months (range, • Chondrosarcoma: 100% w/recurrent Institut Curie, primary bony w/PBT only) 5-102) • Chordoma: 100% • Auditory (unilateral disease France malignancies hypoacousia) • Mean total dose: 5-year progression-free Grade 3: 9% • Subgroup data 68.3 CGE (range, survival: reported 54.6 – 71) • Chondrosarcoma: 81% • Visual (unilateral • Chordoma: 77% blindness) Grade 3-4: 17% MacDonald (2008) Intracranial N=17 • Median: 55.8 CGE • Median: 26 • Overall survival: 89% • No acute effects reported • 1/17 (6%) ependymoma (range, 52.2-59.4) months (range, w/recurrent Massachusetts 43 days-78 • Progression-free • Too early to report late disease General Hospital, months) survival: 80% effects MA, USA • Subgroup data reported Rutz (2008) Chordoma and N=10 • Chordoma, dose: • Median: 36 • All patients alive at last • CTCAE scores • 2/10 (20%) chondrosarcoma 74.0 CGE months (range, follow-up w/recurrent Paul Scherrer 8-77) • Acute effects disease Institute, • Chondrosarcoma, ≥ Grade 3: 0% Switzerland mean dose: 66 CGE (range, 63.2-68) • Late effects ≥ Grade 3: 0% Timmermann Sarcomas of the N=16 • Median: 50 CGE • Median: 18.6 • 2-year overall survival: • RTOG/EORTC criteria • 2/16 (13%) (2007) head, neck, (range, 46-61.2) months (4.3- 69% w/recurrent parameningeal, (2 patients received 70.8) • Acute effects disease Paul Scherrer paraspinal or pelvic additional photon • Progression-free Bone marrow (seen in Institute, region therapy) survival: 72% patients w/parallel Switzerland chemotherapy) Grade 3: 4/13 (31%) Grade 4: 3/13 (23%) • Severity of late effects: NR Proton Beam Therapy: Final Evidence Report Page 202 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Hoch (2006) Skull-base chordoma N=73 NR • Mean: 7.25 years • Overall survival: 81% NR (range, 1-21) Massachusetts General Hospital, MA, USA Luu (2006) Benign N=16 • Dose: range, 50.4- • Mean: 60.2 • Overall survival: 80% • Severity of harms: • 7/16 (44%) craniopharyngioma 59.4 CGE months (range, 12- NR w/recurrent disease Loma Linda University 121) Medical Center, CA, USA • Subgroup data reported Noël (2003) Intracranial tumors N=17 • PBT + photon • Mean: 27 • 36-month overall • LENT/SOMA scoring • 7/17 (41%) (benign & malignant) Median PBT dose: 20 months (3-81) survival: 83% w/recurrent disease Centre de Protonthérapie CGE (range, 9-31) • Severity of harms: d’Orsay, France Median photon dose: NR 40 Gy (24-54) Hug (2002a) Giant cell tumors of N=4 • PBT + photon • Mean: 52 • Overall survival: 100% • Severity of harms: • 2/4 (50%) the skull base Mean dose: 59.0 CGE months (37-69) NR w/recurrent disease Massachusetts General (range, 57.6-61.2) Hospital, MA, USA Hug (2002c) Skull-base N=29 • Patients received PBT • Mean: 40 • 5-year overall survival: • Severity of harms: • 14/29 (48%) mesenchymal alone (45%) or months (range, 13- 56% NR w/recurrent disease Massachusetts General neoplasms PBT+photon (55%) 92) Hospital, MA, USA • Subgroup data • Total dose: range, 45- reported Loma Linda University 78.6 CGE Medical Center, CA, USA Hug (2002b) Low-grade N=27 • Mean: 55.2 CGE • Mean: 39 • Overall survival: 85% • LENT/SOMA scoring • 15/27 (56%) astrocytoma (range, 50.4-63) months (range, 7- w/recurrent disease Loma Linda University (1 patient received 81) • Progression-free Acute effects Medical Center, CA, USA PBT+photon) survival: 78% • All were Grade 1-2 • Subgroup data • Severity of late reported effects: NR Hug (2000) Orbital N=2 • Mean: 53 CGE (range, • Mean: 36 • Overall survival: 100% • Severity of harms: rhabdomyosarcoma 50-55) months (range, 30- NR Massachusetts General 41) Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 203 WA – Health Technology Assessment March 28, 2014 Table 12. Single-arm Case Series: Pediatric Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Tumors in the N=28 • Patients received • Median: 25 • Overall survival: 100% • Severity of harms: McAllister (1997) cranium, skull base or PBT alone (71%) or months (range, NR in the orbit PBT+photon (29%) 7-49) • Progression-free survival: Loma Linda 61% University Medical • PBT only, median: Center, CA, USA 54 CGE (range, 40- 70.2) • PBT + photon Median photon: 36 Gy (range, 18-45) Median PBT: 18 CGE (range, 12.6-31.6) Benk (1995) Skull-base or cervical N=18 • Median: 69 CGE • Median: 72 • 5-year overall survival: • Severity of harms: • Subgroup spine chordomas (range, 55.8-75.6) months (range, 68% NR data reported Massachusetts 19-120) General Hospital, • 5-year disease-free MA, USA survival: 63% * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. † Secondary enucleation rates reported for adverse effects not related to tumor recurrence. CNS: central nervous system; CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NR: not reported; PBT: proton beam therapy; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 204 WA – Health Technology Assessment March 28, 2014 Table 13. Single-arm Case Series: Prostate Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Henderson (2013) Low- and intermediate- N=171 PR-01 • Median: 60 • Overall survival: • CTCAE scoring • Patients enrolled in PR- risk disease • Dose: 78 CGE months (range, 0- 91% 01 and PR-02 University of Florida 71) • Acute/late effects Proton Therapy PR-02 Grade 3 GU: 3% Institute, FL, USA • Dose: 78-82 CGE Kil (2013) Low- and intermediate- N=228 • Low-risk dose: 70 CGE • Median: 24 NR NR • Patient overlap risk disease months w/Hoppe (2012) University of Florida • Intermediate-risk dose: Proton Therapy 70-72.5 CGE • Subgroup data reported Institute, FL, USA McGee (2013) Disease in patients N=186 • Median: 78 CGE (range, • Median: 24 NR • CTCAE scoring • Patient overlap w/large prostates (≥60 58-82) months w/Mendenhall (2012) 3 University of Florida cm ) • Acute effects Proton Therapy Grade 3 GU: 2% • Subgroup data reported Institute, FL, USA • Late effects Grade 3 GU: 6% Grade 3 GI: 0.5% Pugh (2013) Localized, non- N=291 • Dose: 76 Gy (RBE) • At least 24 NR • modified RTOG scoring • All patients w/primary metastatic disease months disease MD Anderson Cancer • Acute/late effects Center, TX, USA ≥ Grade 3 GU: 0% • Subgroup data reported Grade 3 GI: 0.3% Valery (2013) Low-, intermediate- and N=382 • Dose: ranging from 70- • Median: 48 • Overall survival: • Severity of harms: NR • Patients enrolled in PR- high-risk disease 82 CGE months (range, 8- 94% 01, PR-02, and PR-03 University of Florida 66) Proton Therapy Institute, FL, USA Coen (2012) Clinical stage T1c-T2b N=95 • Dose: ranging from 74- • Median: 37 NR NR • Patient overlap w/Coen disease 79 GyE to 82 GyE months (range, 12- (2011) Massachusetts General 64) Hospital, MA, USA Hoppe (2012) Patients ≤60 years N=262 • Dose: ranging from 70- • Median: 24 NR NR • Patient overlap 80 CGE months (range, 6- w/Mendenhall (2012) University of Florida 53) Proton Therapy • Subgroup data reported Institute, FL, USA Proton Beam Therapy: Final Evidence Report Page 205 WA – Health Technology Assessment March 28, 2014 Table 13. Single-arm Case Series: Prostate Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Johansson (2012) Clinical stage T1b- N=265 • PBT + EBRT • Median: 57 Overall survival • RTOG scoring • Subgroup data T4N0M0 disease EBRT dose: 50 Gy months (range, 6- • 5-year: 89% reported The Svedberg Laboratory, PBT dose: 20 Gy 109) • 8-year: 71% • Acute effects: NR Uppsala, Sweden • Late effects Grade 3 GU: 7% Grade 4 GU: 2% Grade 3-4 GI: NR Mendenhall (2012)† Low-risk disease N=89 PR-01 • ≥ 24 months 2-year • CTCAE scoring • All patients • Dose: 78 CGE • Overall survival: 96% w/primary disease University of Florida Proton • Progression-free survival: • Acute/late effects Therapy Institute, FL, USA 99% Grade 3 GU: 2% • Subgroup data Mendenhall (2012)† Intermediate-risk N=82 PR-02 Grade 3 GI: 0.4% reported disease • Dose: 78-82 CGE 2-year progression-free University of Florida Proton survival by protocol Therapy Institute, FL, USA • PR-01: 100% Mendenhall (2012)† High-risk disease N=40 PR-03 • PR-02: 99% • Dose: 78 CGE • PR-03: 94% University of Florida Proton (w/concomitant Therapy Institute, FL, USA therapy) Nichols (2012) Low- and N=171 PR-01 • Up to 24 NR NR • Patients enrolled intermediate-risk • Dose: 78 CGE months in PR-01 and PR-02 University of Florida Proton disease Therapy Institute, FL, USA PR-02 • Subgroup data • Dose: 78-82 CGE reported Coen (2011) Clinical stage T1c- N=85 • Dose: 82 GyE • Median: 32 NR • CTCAE & RTOG/EORTC • All patients T2b disease months (range, 2- scoring w/primary disease Loma Linda University 51) Medical Center, CA, USA • Acute effects Grade 3 (GU, pain): 4% Massachusetts General Hospital, MA, USA • Late effects Grade 3 GU: 8% Grade 3 GI: 1% Grade 4 GI: 1% Proton Beam Therapy: Final Evidence Report Page 206 WA – Health Technology Assessment March 28, 2014 Table 13. Single-arm Case Series: Prostate Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Nihei (2011) Stage II disease N=151 • Dose: 74 GyE • Median: 43 • Overall survival: • CTCAE scoring (clinical stage months (range, 99% Multi-institutional T1-T2N0M0) 3-62) • Acute effects (n=3), Japan ≥ Grade 3: 0% • Late effects Grade 3 bladder: 1% Mayahara (2007) Any clinical N=287 • Dose: 74 GyE • At least 3 NR • Common Toxicity Criteria • Subgroup data stage of disease months reported Hyogo Ion Beam • Acute effects Medical Center, Grade 3 GU: 1% Japan Nihei (2005) Clinical stage N=30 • PBT + photon • Median: 30 • Overall survival: • Common Toxicity Criteria & • Subgroup data T1-3N0M0 Photon dose: 50 Gy months (range, 100% RTOG/EORTC reported National Cancer disease PBT dose: 26 GyE 20-45) Center East, Chiba, • No acute/late effects ≥ Grade 3 Japan Rossi (2004) Clinical stage N=1038 • PBT + photon, dose: • Median: 62 NR NR • Patient overlap T1-T2c disease 75 CGE months (range, w/Slater (2004), Loma Linda University (38% of patients 1-128) Slater (1999), Medical Center, CA, received PBT alone) Yonemoto (1997) USA Photon dose:45 Gy • Subgroup data PBT dose: 30 CGE reported Slater (2004) Stage Ia-III N=1255 • PBT + photon, dose: • Median: 62 NR • RTOG scoring • Patient overlap disease (clinical 75 CGE months (range, w/ Rossi (2004), Loma Linda University stage T1-T3) (42% of patients 1-132) • Acute effects Slater (1999), Medical Center, CA, received PBT alone) Grade 3 GI/GU: <1% Yonemoto (1997) USA Photon dose:45 Gy • Late effects • Subgroup data PBT dose: 30 CGE Grade 3 GU: 1% reported Grade 3 GI: 0.2% Gardner (2002) Clinical stage N=39 • PBT + photon, dose: • Median: 157 NR • RTOG/EORTC scoring T3-T4 disease 77.4 Gy months (range, w/incorporated measure for Massachusetts 84-276) urinary incontinence (SOMA) General Hospital, MA, Photon dose: 50.4 Gy USA PBT dose: 27 Gy • Acute effects: NR • Late effects Grade 3-4 GU: 21% WA – Health Technology Assessment March 28, 2014 Table 13. Single-arm Case Series: Prostate Cancer. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Slater (1999) Stage T1-T2B N=319 • PBT + photon, • Median: 43 5-year • RTOG scoring • Patient overlap disease dose: 75 CGE months (range, • Overall survival: 100% w/Rossi (2004), Loma Linda (71% of patients 12-74) • Disease-free survival: • No acute/late effects Slater (2004), University received PBT alone) 95% ≥ Grade 3 Yonemoto (1997) Medical Center, CA, USA Photon dose:45 Gy PBT dose: 30 CGE Yonemoto (1997) Locally N=106 • PBT + photon, • Median: 20 • Overall survival: 96% • RTOG scoring • Patient overlap advanced dose: 75 CGE months (range, w/Rossi (2004), Loma Linda disease, clinical 10-30) • Acute effects: NR Slater (2004), University stage T2b-T4 Photon dose:45 Gy Slater (1999) Medical Center, PBT dose: 30 CGE • Late effects CA, USA ≥ Grade 3: 0% * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. † Mendenhall (2012) reported on 3 dosing protocols, based on level of disease risk. Separate results are reported where available. CTCAE: Common Terminology Criteria for Adverse Events; EBRT: external-beam radiation therapy; EORTC: European Organization for Research and the Treatment of Cancer; GI: gastrointestinal; GU: genitourinary; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NCI: National Cancer Institute; NR: not reported; PBT: proton beam therapy; RBE: relative biological effectiveness; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 208 WA – Health Technology Assessment March 28, 2014 Table 14. Single-arm Case Series: Soft Tissue Sarcomas. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Yoon (2010) Retroperitoneal or N=28 • PBT ± IMRT, median: • Median: 33 • 3-year overall • Severity of harms: NR • 8/28 (29%) pelvic soft-tissue 50 Gy (range, 37.5- months survival: 87% w/recurrent disease Massachusetts sarcoma 66.6) General Hospital, (12 patients received • Subgroup data MA, USA IOERT) reported Weber (2007) Nonmetastatic soft- N=13 • PBT ± photon, • Median: 48 • 4-year overall • CTCAE scoring • 4/13 (31%) tissue sarcoma median: 69.4 CGE months (range, survival: 83% w/recurrent disease Paul Scherrer (range, 50.4-76) 19-101) • Acute effects: NR Institute, Switzerland • Late effects Grade 3 brain necrosis: 8% CTCAE: Common Terminology Criteria for Adverse Events; IMRT: intensity-modulated radiation therapy; IOERT: intraoperative electron radiation therapy; N: number; NR: not reported; PBT: proton beam therapy Proton Beam Therapy: Final Evidence Report Page 209 WA – Health Technology Assessment March 28, 2014 Table 15. Single-arm Case Series: Noncancerous Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Nakai (2012) Cerebral N=8 • Mean: 37.5 GyE • Mean: 39 • Overall survival: 88% • No reported acute arteriovenous (range, 24-46.2) months (range, effects University of malformations 18-84) Tsukuba, Japan • Severity of late effects: NR Slater (2012) Benign cavernous N=72 • Median: 57 or 59 • Median: 74 • 5-year overall • Severity of acute/late • Subgroup data sinus malignancies Gy months (range, survival: 72% effects: NR reported Loma Linda 3-183) University Medical Center, CA, USA Halasz (2011) Benign N=50 • Median: 13 Gy • Median: 32 NR • Severity of acute/late • Subgroup data meningiomas (RBE) (range, 10- months (range, effects: NR reported Massachusetts 15.5) 6-133) General Hospital, MA, USA Hattangadi (2011) High-risk inoperable N=59 • Median: 16 • Median: 56 • Overall survival: 81% • CTCAE scoring cerebral Gy(RBE) (range, 12- months (range, Massachusetts arteriovenous 28) 7-173) • Acute effects General Hospital, malformations ≥ Grade 3: 0% MA, USA • Late effects ≥ Grade 3: 0% Ito (2011) Arteriovenous N=11 • Mean: 25.3 GyE • Median: 138 • Overall survival: 91% • Severity of acute/late malformation (range, 22-27.5) months (range, effects: NR University of ≥30mm in diameter 81-198) Tsukuba, Japan Levy-Gabriel (2009) Circumscribed N=71 • Dose: 20 CGE • Median: 52 • Overall survival: 100% • Severity of acute/late • 9/71 (13%) choroidal months (8-133) effects: NR w/failed previous Institut Curie, hemangioma laser therapy France Petit (2008) Refractory ACTH- N=38 • Median: 20 CGE • Median: 62 • Overall survival: 100% • Severity of acute/late producing pituitary (range, 15-20) months (range, effects: NR Massachusetts adenoma 20-136) General Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 210 WA – Health Technology Assessment March 28, 2014 Table 15. Single-arm Case Series: Noncancerous Conditions. Author (Year) Condition Sample Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Type Size Ronson (2006) Pituitary N=47 • Median: 54 CGE • Median: 47 • Overall survival: • Severity of acute/late • 10/47 (21%) adenoma (range, 50.4-55.9) months (range, 87% effects: NR w/recurrent Loma Linda 6-139) disease University Medical Center, CA, USA • Subgroup data reported Noël (2005) Intracranial N=51 • PBT + photon, • Median: 21 • 4-year overall • LENT/SOMA scoring • 16/51 (31%) meningioma median: 60.6 CGE months (range, survival: 100% w/recurrent Institut Curie, (range, 54-64) 1-90) • Acute effects: NR disease France • Late effects Grade 3 (hypophysis insufficiency, hearing loss): 4% Vernimmen (2005) Intracranial N=64 • Mean: 27.5 Gy • Median: 62 NR • RTOG/EORTC scoring arteriovenous (range, 16.1-38.4) months iThemba LABS, malformations • Acute effects South Africa Grade 4 epilepsy: 3% • Late effects Grade 3-4 (epilepsy, neurologic deficits): 6% Silander (2004) Cerebral N=26 • Dose: ranging from • Median: 40 NR • Severity of acute/late arteriovenous 16-25 Gy months (range, effects: NR University Hospital, malformations 33-62) Uppsala, Sweden Barker (2003) Cerebral N=1250 • Median: 10.5 Gy • Median: 78 NR • Severity of acute/late • Subgroup data arteriovenous (range, 4-65) months (range, effects: NR reported Massachusetts malformations 1-302) General Hospital, MA, USA Proton Beam Therapy: Final Evidence Report Page 211 WA – Health Technology Assessment March 28, 2014 Table 15. Single-arm Case Series: Noncancerous Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Weber (2003) Vestibular N=88 • Median: 12 CGE • Median: 39 NR • Hearing function, • Subgroup data schwannoma (range, 10-18) months (range, Gardner-Robertson scale reported Massachusetts 12-103) • Facial nerve function, General Hospital, MA, House-Brackmann scale USA • 7/21 (33%) retained functional hearing • Grade 4-5 facial nerve dysfunction: 6% • Severity of other late effects: NR Vernimmen (2001)* Intracranial N=18 • Mean: 20.3 CGE • Mean: 40 • Overall survival: 100% • Severity of acute/late meningioma months (range, effects: NR National Accelerator 13-69) Center, South Africa Vernimmen (2001)* Intracranial N=5 • Dose: ranging • Overall survival: 100% • No reported acute meningioma from 54-61.6 CGE effects National Accelerator Center, South Africa • Severity of late effects: NR Wenkel (2000) Recurrent, biopsied, N=46 • PBT + photon, • Median: 53 Overall survival • RTOG scoring • 29/46 (63%) or subtotally median: 59 CGE months (range, • 5-year: 93% w/recurrent disease Massachusetts resected meningioma (range, 53.1-74.1) 12-207) • 10-year: 77% • Acute effects General Hospital, MA, Severe: 11% USA • Late effects Grade 3-4: 17% Gudjonsson (1999) Skull-base N=19 • Dose: 24 Gy • ≥ 36 months • Overall survival: 100% • Severity of acute/late meningioma effects: NR University Hospital, • Progression-free Uppsala, Sweden survival: 100% Proton Beam Therapy: Final Evidence Report Page 212 WA – Health Technology Assessment March 28, 2014 Table 15. Single-arm Case Series: Noncancerous Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Zografos (1998) Choroidal N=53 • Dose: ranging • Up to 108 NR • Severity of acute/late hemangioma from 16.4 – 27.3 Gy months effects: NR Paul Scherrer Institute, Switzerland Hannouche (1997) Circumscribed N=13 • Dose: 30 CGE • Mean: 26 • Overall survival: 100% • No reported acute/late • 4/13 (31%) choroidal months (range, effects w/failed previous Institut Curie, France hemangioma 9-48) laser therapy * Vernimmen (2001) reported on patients receiving different dosing protocols depending on meningioma location. Separate results reported where available. ACTH: adrenocorticotropic hormone; CTCAE: Common Terminology Criteria for Adverse Events; EORTC: European Organization for Research and the Treatment of Cancer; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NCI: National Cancer Institute; NR: not reported; PBT: proton beam therapy; RTOG: Radiation Therapy Oncology Group Proton Beam Therapy: Final Evidence Report Page 213 WA – Health Technology Assessment March 28, 2014 Table 16. Single-arm Case Series: Mixed Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms* Notes Study Site Size Barney (2014) Medulloblastoma N=50 • Median: 54 Gy (RBE) • Median: 20.1 2-year • RTOG scoring (38%); germ cell (range, 24-58.6) months (range, • Overall survival: 96% MD Anderson Cancer tumor (30%); 0.3-59) • Progression-free survival: • Acute effects Center, TX, USA pineoblastoma (14%) 82% Grade 3 ototoxicity: 4% Grade 3 leukopenia: 9% 5-year Grade 3 thrombocytopenia: 2% • Overall survival: 84% Grade 4 thrombocytopenia: 2% • Progression-free survival: 68% Combs (2013a) Low-grade N=260 NR • Median: 12 NR • CTCAE scoring meningioma (27%); months (range, 2- Heidelberg Ion atypical/anaplastic • Patients received PBT 39) • No acute/late effects ≥ Grade 3 Therapy Center, meningioma (14%); (67%) or carbon ± Germany low-grade glioma photon therapy (33%) (12%); glioblastoma (11%) Combs (2013b) Benign, atypical, and N=70 • PBT (54%) or carbon ± • Median: 6 • Overall survival: 100% • Severity of harms: NR • Some patients anaplastic photon (46%) months (range, 2- w/recurrent disease, Heidelberg Ion meningiomas 22) % not reported Therapy Center, • PBT dose: ranging Germany from 52.2-57.6 GyE Schneider (2013) Mixed paraspinal and N=31 • Mean: 72.3 Gy (RBE) • Mean: 59 • 3-year overall survival: 84% • CTCAE scoring retroperitoneal (range, 64-76) months (range, Paul Scherrer Institute, neoplasms 19-125) • 5-year overall survival: 72% • Acute effects Switzerland Grade 3 skin: 13% • Late effects Grade 3 non-GI: 6% Grade 3 skin: 3% Grade 3 bone necrosis: 3% Tuan (2013) Chordoma and N=21 • Median: 74 GyE • Mean: 5 NR • CTCAE scoring • Preliminary data, chondrosarcoma of (range, 70-74) months (range, 1- including quality-of- Italian National the skull base and 12) • Acute effects life outcomes, Hadrontherapy Center sacral/ paraspinal sites ≥ Grade 3: 0% reported in for Cancer, Italy Srivastava (2013) MMSE scoring • No significant changes occurred • 5/21 (24%) from start to finish of PBT w/recurrent disease Proton Beam Therapy: Final Evidence Report Page 214 WA – Health Technology Assessment March 28, 2014 Table 16. Single-arm Case Series: Mixed Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Weber (2012) Benign, atypical, and N=39 • Median: 56 • Median: 55 • 5-year overall survival: • CTCAE & RTOG scoring • Subgroup anaplastic Gy(RBE) (range, months (range, 82% data reported Paul Scherrer meningiomas 52.2-66.6) 6-147) • Acute effects Institute, ≥ Grade 3: 0% Switzerland • Late effects Grade 3 brain necrosis: 8% Grade 4 optic neuropathy: 5% Boskos (2009) Atypical and N=24 • PBT + photon, • Median: 32 Overall survival • No reported acute effects • Potential malignant median: 68 CGE months (range, • 1-year: 100% patient overlap Centre de meningiomas 1-72) • 2-year: 96% • Severity of late effects: NR w/Noël (2002) Protonthérapie • 4-year: 65% d’Orsay, France • 8-year: 43% • Subgroup data reported DeLaney (2009) Skull-base and N=50 • Median: 76.6 • Median: 48 Overall survival • CTCAE scoring • Subgroup paraspinal tumors (range, 59.4-77.4) months (range, • 1-year: 98% data reported Massachusetts (chordoma, 58%; 37-124) • 3-year: 87% • Acute effects General Hospital, chondrosarcoma, • 5-year: 87% Grade 3 fracture: 2% MA, USA 28%) • Late effects Grade 3 neuropathy: 4% Grade 3 fracture: 2% Grade 3 GU: 2% Grade 3 GI: 2% Pieters (2006) Tumors of the N=62 • Median: 65.8 CGE • Median: 87 Disease-free survival • LENT scoring • Subgroup retroperitoneum, (range, 31.9-85.1) months • 5-year: 66% data reported Massachusetts paravertebral areas, (range,14-217) • 10-year: 53% •Acute effects: NR General Hospital, lumbar and sacral MA, USA vertebral bodies • Late effects Grade 3 neurologic toxicity: 3% Grade 4 neurologic toxicity: 6% Noël (2002) Atypical/malignant N=17 • PBT + photon, • Median: 37 • 4-year overall survival: • Severity of harms: NR and benign median: 61 CGE months (range, 89% Centre de meningiomas (range, 25-69) (1 17-60) Protonthérapie patient w/PBT d’Orsay, France alone) Proton Beam Therapy: Final Evidence Report Page 215 WA – Health Technology Assessment March 28, 2014 Table 16. Single-arm Case Series: Mixed Conditions. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Pai (2001) Neoplasms of the N=107 • Median: 68.4 CGE • Median: 66 Overall survival • Severity of harms: NR • Subgroup skull base, not (range, 55.8-79) months • 5-year: 96% data reported Massachusetts associated w/the • 10-year 87% General Hospital, pituitary gland or MA, USA hypothalamus (chondrosarcoma, 50%, chordoma, 43%, benign meningioma, 4%) * Different versions of the CTCAE/Common Toxicity Criteria are utilized in the listed studies. CTCAE: Common Terminology Criteria for Adverse Events; GI: gastrointestinal; GU: genitourinary; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; MMSE: Mini Mental Status Exam; N: number; NCI: National Cancer Institute; NR: not reported; PBT: proton beam therapy; RBE: relative biological effectiveness; RTOG: Radiation Therapy Oncology Group Table 17. Single-arm Case Series: Bladder Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Hata (2006) Invasive bladder N=23 • Dose: 33 Gy NR 5-year • CTCAE & LENT/SOMA scoring • Subgroup cancer, T2-T3N0M0 • Overall survival: 61% data reported University of • Disease-free survival: 50% • Harms reported for entire Tsukuba, patient population, including Japan those without PBT CTCAE: Common Terminology Criteria for Adverse Events; LENT/SOMA: Late Effects of Normal Tissue – subjective, objective, management, analytic; N: number; NR: not reported; PBT: proton beam therapy Proton Beam Therapy: Final Evidence Report Page 216 WA – Health Technology Assessment March 28, 2014 Table 18. Single-arm Case Series: Skin Cancers. Author (Year) Sample Condition Type Total PBT Dose Follow-up Survival Outcomes Harms Notes Study Site Size Umebayashi (1994) Skin carcinomas n=12 • Mean: 71.1 Gy • Up to 84 • Overall survival: 75% • Severity of harms: (range, 51-99.2) months NR University of Tsukuba, Japan N: number; NR: not reported Proton Beam Therapy: Final Evidence Report Page 217