As posted for public comment 2/25/2015 to 8 a.m. March 30, HERC Coverage Guidance

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1 HEALTH EVIDENCE REVIEW COMMISSION (HERC) COVERAGE GUIDANCE: PROTON BEAM THERAPY HERC Coverge Guidnce Proton em therpy (PBT) is ed for coverge for mlignnt oculr tumors (strong tion). Proton em therpy is not ed for coverge for dult mlignnt rin nd spinl tumors (wek tion). Proton em therpy is not ed for coverge for peditric mlignnt tumors (wek tion). Proton em therpy is not ed for coverge for cncer of the one, hed nd neck, esophgus, liver, lung, or prostte (wek tion). Proton em therpy is not ed for coverge for ny other cncerous or noncncerous condition (wek tion). Note: Definitions for strength of tion re provided in Appendix A GRADE Element Description RATIONALE FOR GUIDANCE DEVELOPMENT The HERC selects topics for guideline development or technology ssessment sed on the following principles: Represents significnt urden of disese Represents importnt uncertinty with regrd to efficcy or hrms Represents importnt vrition or controversy in clinicl cre Represents high costs, significnt economic impct Topic is of high pulic interest Coverge guidnce development follows to trnslte the evidence review to policy decision. Coverge guidnce my e sed on n evidence-sed guideline developed y the Evidencesed Guideline Sucommittee or helth technology ssessment developed y the Heth Technology Assessment Sucommittee. In ddition, coverge guidnce my utilize n existing evidence report produced y one of HERC s trusted sources, generlly within the lst three yers. 1

2 EVIDENCE SOURCES Trusted sources Wshington Stte Helth Cre Authority Helth Technology Assessment Progrm. (2014). Proton Bem Therpy. Olympi, WA: Helth Technology Assessment Progrm. Retrieved Jnury 22, 2015 from The summry of evidence in this document is derived directly from this evidence source, nd portions re extrcted vertim. EVIDENCE OVERVIEW Clinicl ckground Protons re positively-chrged sutomic prticles tht hve een in clinicl use s form of externl em rdiotherpy for over 60 yers. Compred to the photon X-ry energy used in conventionl rdiotherpy, proton ems hve physicl ttriutes tht re potentilly ppeling. Specificlly, protons deposit rdition energy t or round the trget, t the end of the rnge of em penetrtion, phenomenon known s the Brgg pek. The gol of ny externl em rdiotherpy is to deliver sufficient rdition to the trget tumor while mitigting the effects on djcent norml tissue. This hs een chllenge for conventionl photon therpy due to the mount of rdition deposited oth efore nd fter the trget is reched. While the mount of photon rdition t entry into the ody is much higher thn t exit, photon ems typiclly sctter to norml tissues fter leving the trget. This so-clled exit dose is sent for protons, s tissue eyond the point of pek energy deposition receives little to no rdition. Initil use of proton em therpy (PBT) focused on conditions where spring very sensitive djcent norml tissues ws felt to e of utmost importnce, such s cncers or noncncerous mlformtions of the rin stem, eye, or spinl cord. In ddition, proton em therpy ws dvocted for mny peditric tumors ecuse even lower-dose irrdition of norml tissue in peditric ptients cn result in pronounced cute nd long-term toxicity. There re lso longstnding concerns regrding rdition s potentil to cuse secondry mlignncy lter in life, prticulrly in those receiving rdition t younger ges. Finlly, rdition my produce more nunced effects in children, such s neurocognitive impirment in peditric ptients treted with rdiotherpy for rin cncers. recently, however, the use of PBT hs een expnded in mny settings to tret more common cncers such s those of the prostte, rest, liver, nd lung. With the growth in potentil ptient numers nd reimursement, the construction of proton centers hs grown sustntilly. There re now 14 operting proton centers in the U.S., including one in Settle, WA tht cme online in Mrch Eleven dditionl centers re under construction or in the plnning stges, nd mny more re proposed. The construction of cyclotrons t the hert of proton em fcilities is very expensive ($150-$200 million for multiple gntry fcility). 2 Proton Bem Therpy

3 Indictions This pprisl focuses on the use of proton em therpy (PBT) to tret ptients with multiple types of cncer s well s those with selected noncncerous conditions. Within ech condition type, two generl popultions were specified s of interest for this evlution: Ptients receiving PBT s primry tretment for their condition (i.e., curtive intent) Ptients receiving PBT for recurrent disese or for filure of initil therpy (i.e., slvge) All forms of PBT were considered for this evlution, including monotherpy, use of PBT s oost mechnism to conventionl rdition therpy, nd comintion therpy with other modlities such s chemotherpy nd surgery. All PBT studies tht met entry criteri for this review were included, regrdless of mnufcturer, tretment protocol, loction, or other such concerns. Conditions included in the evidence review re s follows: Cncers Bone tumors Brin, spinl, nd prspinl tumors Brest cncer Esophgel cncer Gstrointestinl cncers Gynecologic cncers Hed nd neck cncers (including skull se tumors) Liver cncer Lung cncer Lymphoms Oculr tumors Peditric cncers (e.g., medullolstom, retinolstom, Ewing s srcom) Prostte cncer Soft tissue srcoms Seminom Thymom Noncncerous Conditions Arteriovenous mlformtions Hemngioms Other enign tumors (e.g., coustic neuroms, pituitry denoms) Evidence review A summry of the net helth enefit of PBT vs. lterntive tretments nd the strength of ville evidence on net helth enefit, s well s n evlution of consistency of these findings with clinicl guideline sttements nd pulic/privte coverge policy, cn e found in Tle 1. The level of comprtive evidence ws extremely limited for certin conditions nd 3 Proton Bem Therpy

4 entirely sent for others. We identified totl of six RCTs nd 37 nonrndomized comprtive studies cross ll 19 condition types. Importntly, five of the six RCTs involved different tretment protocols for PBT nd hd no other comprison groups; while these re included for completeness, primry ttention ws pid to studies (RCTs nd otherwise) tht compred PBT to n lterntive form of tretment. Most of the comprtive studies identified lso hd mjor qulity concerns. For exmple, nerly ll non-rndomized comprtive studies were retrospective in nture, nd mny involved comprisons of PBT cohort to non-contemporneous group receiving lterntive therpy. Mjor differences in ptient demogrphics nd seline clinicl chrcteristics s well s durtion of follow-up were often noted etween groups. Of the 6 RCTs identified, 1, 4, nd 1 were judged to e of good, fir, nd poor qulity respectively. Corresponding figures for nonrndomized comprtive studies were 1, 20, nd 16. As noted on Tle 1, PBT ws judged to hve superior net helth enefit for oculr tumors, nd incrementl net helth enefit for dult rin/spinl tumors nd peditric cncers. PBT ws comprle to lterntive tretment options for ptients with liver, lung, nd prostte cncer s well s one noncncerous condition (hemngioms). Importntly, however, the strength of evidence ws low for ll of these conditions. The evidence se for ll other condition types ws insufficient to determine net helth enefit, including two of the four most prevlent cncers in the U.S.: rest nd gstrointestinl (lung nd prostte re the other two). As with informtion on clinicl effectiveness, dt on potentil hrms of PBT come from RCTs, comprtive cohort studies, nd cse series, lthough comprtive hrms dt re still lcking for mny condition types. Across ll condition types, totl of 25 studies reported comprtive informtion on tretment-relted hrms; differences in the types of hrms relevnt to ech condition, s well s vriility in hrms clssifiction even within conditions, precludes ny ttempt to summrily present hrms dt cross ll 19 condition ctegories. Oservtionl dt on secondry mlignncy with PBT re generlly lcking. Two studies were identified with comprtive informtion. One ws fir-qulity mtched retrospective cohort study compring 1,116 ptients in linked Medicre-SEER dtse who received either PBT or photon rdition for vriety of cncers nd were followed for medin of 6.4 yers. On n undjusted sis, the incidence rtes of ny secondry mlignncy nd mlignncies occurring in the prior rdition field were numericlly lower for PBT, ut not sttisticlly-significntly so. After djustment for ge, sex, primry tumor site, durtion of follow-up, nd yer of dignosis, PBT ws ssocited with risk of secondry mlignncy pproximtely one-hlf tht of photon therpy (HR=0.52; 95% CI: 0.32, 0.85; p=0.009). There re chllenges with these findings, however. First nd foremost, the lower rte of secondry mlignncy with PBT ppered to e mnifested lmost entirely in the first five yers fter rdiotherpy, time period in which second cncer event is not typiclly ttriuted to prior rdition (Bekelmn, 2013). In ddition, ptients were ccrued over very long time period ( ), only the very end of which included highly conforml photon techniques like IMRT. The second study ws poor-qulity retrospective cohort study compring PBT to photon rdiotherpy in 86 infnts who were treted for retinolstom nd followed for medin of 7 4 Proton Bem Therpy

5 yers (PBT) or 13 yers (photon rdiotherpy). Therpy ws received t two different US centers (PBT t MGH nd photon rdiotherpy t Children s Hospitl Boston). Kpln-Meier nlyses were conducted to control for differentil follow-up ut no djustments were mde for other differences etween groups. Ten-yer estimtes of the cumultive incidence of secondry mlignncy were numericlly lower for PBT, ut not sttisticlly significntly so (5% vs. 14% for photon, p=0.12). However, when mlignncies were restricted to those occurring in-field or thought to e rdition-induced, significnt difference in fvor of PBT ws oserved (0% vs. 14%, p=0.015). In ddition, significnt differences in fvor of PBT in oth cumultive incidence nd rdiotherpy-relted mlignncy were oserved for the sugroup of ptients with hereditry disese. Other hrms re presented in detil for ech condition type in the sections tht follow. No comprtive studies were identified for curtive therpy of: rest, esophgel, gstrointestinl, gynecologic, nd peditric cncers; lymphoms, srcoms, seminoms, nd thymoms; rteriovenous mlformtions. No comprtive studies were identified for slvge tretment of: rin/spinl/prspinl, rest, esophgel, gstrointestinl, gynecologic, peditric, nd prostte cncers; lymphoms, srcoms, seminoms, nd thymoms; rteriovenous mlformtions nd hemngioms. No comprtive studies of hrms identified for: gstrointestinl nd gynecologic cncers; lymphoms, srcoms, seminoms, nd thymoms; rteriovenous mlformtions. Cncers Bone Cncer Curtive A single poor-qulity retrospective comprtive cohort study evluted PBT for primry nd recurrent scrl chordoms in 27 ptients. Among these ptients 21 were treted with surgery nd comintion PBT /photon therpy (men rdition dose: 72.8 Gry Equivlents [GyE]), in comprison to six ptients who received PBT/photons lone (men dose: 70.6 GyE). For ptients with primry tumors, Kpln-Meier estimtes of locl control, disese-free survivl nd overll survivl exceeded 90% mong those treted y surgery nd rdition (n=14). Only two of the six ptients with primry tumors received rdition lone, one of whom hd locl filure t four yers, distnt metstses t five yers, nd died t 5.5 yers. Slvge In the sme study of 27 ptients with scrl chordoms who were treted with PBT/photon rdition lone or in comintion with surgery, seven rdition/surgery ptients nd four rdition-only ptients hd recurrent disese. Among ptients in the rdition/surgery group, four ptients died of disese 4-10 yers fter tretment; the reminder ws live with disese t lst follow-up. In the rdition-only group, two of four ptients died of disese t 4-5 yers of follow-up; the other two were live with disese t lst follow-up. 5 Proton Bem Therpy

6 Hrms In the study descried ove, multiple descriptive hrms were reported. Ptients receiving rdition lone reported numericlly lower rtes of norml owel or ldder function s well s difficulty multing in comprison to those receiving comintion therpy, ut rtes were not sttisticlly tested. PBT ptients lso reported higher rtes of return to work, lthough this ws lso not tested sttisticlly. Evidence is thus indequte to compre the potentil hrms of PBT reltive to other rdition modlities in ptients with one cncer. Brin, Spinl, nd Prspinl Tumors Curtive Two poor-qulity retrospective comprtive cohort studies investigted primry PBT for rin, spinl, nd prspinl tumors. One ws n evlution of PBT (men dose: 54.6 GyE) vs. photon therpy (men dose: 52.9 Gy) in 40 dults (men ge: 32 yers; 65% mle) who received surgicl nd rdition tretment of medullolstom t single US cncer center. PBT ptients were followed for medin of 2.2 yers, while photon ptients were followed for medin of nerly five yers. No sttisticl differences etween rdition modlities were seen in Kpln-Meier ssessment of either overll or progression-free survivl t two yers. A numeric difference ws seen in the rte of locl or regionl filure (5% for PBT vs. 14% for photon), ut this ws not ssessed sttisticlly. The second study involved 32 ptients treted for intrmedullry glioms with either PBT (n=10) or IMRT (n=22). While explicit comprisons were mde etween groups, the PBT popultion ws primrily peditric (men ge: 14 yers), while the IMRT popultion ws dult (men ge: 44 yers). Ptients in oth groups were followed for medin of 24 months; dose ws >50 GyE or Gy in pproximtely 75% of ptients. While the crude mortlity rte ws lower in the PBT group (20% vs. 32% for IMRT, not tested), in multivrite nlyses controlling for ge, tumor pthology, nd tretment modlity, PBT ws ssocited with significntly incresed mortlity risk (Hzrd Rtio [HR]: 40.0, p=0.02). The rte of rin metstsis ws numericlly higher in the PBT group (10% vs. 5% for IMRT), ut this ws not sttisticlly tested. Rtes of locl or regionl recurrence did not differ etween groups. Hrms In the first study descried ove, PBT ws ssocited with sttisticlly-significntly lower rtes of weight loss (medin % of seline: -1.2% vs. 5.8% for photon, p=0.004) s well s requirements for medicl mngement of esophgitis (5% vs. 57% respectively, p<0.001). PBT ptients lso experienced less RTOG grde 2 or greter nuse nd vomiting (26% vs. 71%, p=0.004). In the second study compring primrily 10 peditric ptients (men ge: 14 yers) receiving PBT for spinl cord glioms to 22 dults receiving IMRT for the sme condition (men ge: 44 yers) (Khn, 2011), no cses of long-term toxicity or myelopthy were reported in either group. Minor side-effect rtes were reported for the overll cohort only. In summry, limited, low-qulity evidence suggests tht PBT is ssocited with reductions in cute rdition-relted toxicity reltive to photon rdition in ptients with rin nd spinl tumors. 6 Proton Bem Therpy

7 Tle 1: Summry tle ssessing strength of evidence, direction of enefit, nd consistency with relevnt guideline sttements nd coverge policy. Condition Incidence (per 100,000) Net Helth Benefit vs. Comprtors Type of Net Helth Benefit Strength of Evidence Guideline tions Coverge Policies Cncer Bone 1.3 Insufficient M M Brin/spinl 9.6 Incrementl B: = H: + U U Brest 97.7 Insufficient --- o NM NR/NC Esophgel 7.5 Insufficient --- o NM NR/NC GI Insufficient --- o NM NR/NC Gynecologic 38.2 Insufficient --- o NM NR/NC Hed/neck 17.2 Insufficient NM M Liver 12.8 Comprle B: = H: = + NM M Lung 95.0 Comprle B: = H: = + M M Lymphoms 32.9 Insufficient --- o NR/NC NR/NC Oculr 1.2 Superior B: H: ++ U U Peditric 9.1 Incrementl B: = H: + U U Prostte 99.4 Comprle B: = H: = + M M Srcoms 4.8 Insufficient --- o NM M Seminom 4.0 Insufficient --- o NM NM Thymom 0.2 Insufficient --- o NM NM Noncncerous AVMs 1.0 Insufficient --- o NM M Hemngioms 2.0 Comprle B: = H: = + NM NM Other 2.0 Insufficient --- o NM M B: Benefits; H: Hrms Strength of Evidence: Low=+; Moderte=++; High=+++; No evidence=o Legend: U = Universlly ed or covered; M=Mixed tions or coverge policies; NM=Not mentioned in guidelines or coverge policies; NR/NC=Not ed or not covered 7 Proton Bem Therpy

8 Esophgel Cncer Hrms Two studies were identified tht exmined comprtive hrms in ptients treted with PBT for esophgel cncer. One ws reltively lrge, fir-qulity, retrospective comprtive cohort study of 444 ptients (medin ge: 61 yers; 91% mle) who were treted with chemotherpy nd rdition (PBT, IMRT, or 3D-CRT) followed y surgicl resection. Ptients were followed for up to 60 dys fter hospitl dischrge. After djustment for ptient chrcteristics nd clinicl vriles, 3D-CRT ws ssocited with significntly greter risk of postopertive pulmonry complictions vs. PBT (Odds Rtio [OR]: 9.13, 95% CI: 1.83, 45.42). No significnt differences were oserved etween PBT nd IMRT, however. No differences in the rte of gstrointestinl complictions were oserved for ny tretment comprison. In ddition, fir-qulity comprtive study ws identified tht exmined erly impct on lung inflmmtion nd irrittion in 75 ptients receiving PBT, IMRT, or 3D-CRT for esophgel cncer; ptients were followed for up to 75 dys following rdition. Nerly ll outcome nd toxicity mesures were reported for the entire cohort only. However, the rte of pneumonitis ws found to e significntly higher mong PBT ptients (33% vs. 15% for IMRT/3D-CRT, p=0.04). In summry, evidence is indequte to compre the potentil hrms of PBT reltive to other rdition modlities in ptients with esophgel cncer, prticulrly in comprison to IMRT. Hed nd Neck Cncers Curtive There were two poor-qulity retrospective comprtive cohorts of primry PBT in hed nd neck cncer. One ws n evlution of 33 ptients treted with either PBT lone or PBT+photon therpy to trget dose of 76 Gy for vriety of hed nd neck mlignncies in Jpn. Tretment groups differed sustntilly in terms of ge, gender, nd durtion of follow-up (men: 5.9 vs. 3.1 yers). Numeric differences in fvor of PBT+photon therpy were seen for locl control, recurrence, nd mortlity, ut these were not sttisticlly tested, nor were multivrite djustments mde for differences etween groups. The other study ws very smll (n=6) comprison of endoscopic resection followed y either PBT or IMRT s well s endoscopy lone in ptients with mlignnt clivl tumors. Limited description of the study suggests tht PBT ws used only in cses of residul disese, while it is uncler whether IMRT ws lso used in this mnner or s n djuvnt modlity. One of the IMRT ptients died of cuses unrelted to disese; no other deths were reported. Slvge In the first study descried ove, four ptients were identified s hving recurrent disese, three of whom received PBT lone. Two of the three PBT-only ptients were live with locl tumor control t lst follow-up (5 nd 17 yers respectively); one ptient hd their cncer recur three months fter PBT nd died in month 7 of follow-up. The one PBT+photon ptient died t 2.5 yers of follow-up, ut ws descried s hving locl tumor control. 8 Proton Bem Therpy

9 Hrms In the first study descrie ove, rtes of tongue ulcertion, osteonecrosis, nd esophgel stenosis differed somewht etween tretment groups, ut were not sttisticlly tested. Overll toxicity rtes were estimted to e 22.8% t oth three nd five yers, ut were not strtified y tretment modlity. In seprte, fir-qulity study compring rtes of vision loss from rdition-induced optic neuropthy in 75 ptients treted with PBT or cron-ion therpy for hed nd neck or skull se tumors, undjusted rtes of vision loss were similr etween modlities (8% nd 6% for PBT nd cron-ion respectively, not sttisticlly tested). In multivrite nlyses controlling for demogrphic nd clinicl chrcteristics, tretment modlity hd no effect on rtes of vision loss (p=0.42). Another comprison of PBT nd cron-ion therpy in 59 ptients with hed nd neck or skull se tumors ws of poor qulity (due to no control for differences etween ptient groups) nd focused on the incidence of rdition-induced rin chnges. The incidence of CTCAE rin injury of ny grde ws significntly (p=0.002) lower in the PBT group. MRI-sed ssessment of rin chnges showed lower rte in the PBT group (17% vs. 64% for cronion), lthough this ws not tested sttisticlly. In summry, evidence is indequte to compre the potentil hrms of PBT reltive to other rdition modlities in ptients with hed nd neck cncer. Liver Cncer Curtive Two fir-qulity prospective comprtive cohort studies provided evidence of the clinicl effectiveness of primry use of PBT in liver cncer. One ws n evlution of 35 ptients with unresectle heptocellulr crcinom (HCC) who were treted with PBT (men dose: 76.5 GyE) either lone or in comintion with chemotherpy nd were followed for up to 4 yers. While sttisticl testing ws not performed, rtes of locl tumor control nd the proportion of ptients experiencing reductions in tumor volume were nerly identicl etween groups. The other study ws lso prospective ut compred PBT to nother hevy-ion modlity not in circultion in the U.S. (cron ion). In this study, fir-qulity comprison of 350 ptients with HCC who received PBT (53-84 GyE) or cron-ion (53-76 GyE) therpy nd were followed for medin of 2.5 yers, no sttisticlly-significnt differences were oserved in 5-yer Kpln- Meier estimtes of locl control, no iologicl evidence of disese, or overll survivl etween treted groups. Slvge Two studies were identified with informtion on recurrent disese. One ws poor-qulity comprison of PBT to conventionl photon rdition in eight ptients with recurrent HCC fter heptectomy. Five ptients were treted with PBT ( GyE), nd three with photons (60-70 Gy). Seven of eight ptients died of liver filure or lung metstsis medin of 1.5 yers fter rdition; the one ptient live t the end of follow-up ws photon ptient. The rte of locl tumor control ws 78%, nd did not differ etween tretment groups. 9 Proton Bem Therpy

10 The other study ws previously-descried prospective comprison of PBT to cron-ion therpy in 350 ptients with primry or recurrent HCC. No sugroup nlyses were performed, ut prior tretment history for HCC ws found not to hve sttisticlly-significnt impct on locl tumor control (p=0.73). Prior tretment ws not exmined s risk fctor for overll survivl, however. Hrms Two comprtive studies were identified with comprtive informtion on rdition-relted hrms. In previously-descried study of eight ptients with recurrent HCC fter heptectomy, there were no instnces of one mrrow depression or gstrointestinl complictions in either group. Serum sprtte minotrnsferse (AST) level s incresed in the three photon ptients nd 4/5 PBT ptients, lthough this ws not tested sttisticlly. In the other study, previously-descried comprison of PBT to cron-ion therpy in 350 ptients with primry or recurrent HCC, rtes of toxicities s grded y the Common Terminology Criteri for Adverse Events (CTCAE) frmework were comprle etween groups, including dermtitis, GI ulcer, pneumonitis, nd ri frcture. The rte of grde 3 or higher toxicities ws similr etween groups (3% vs. 4% for PBT nd cron-ion respectively), lthough this ws not sttisticlly tested. In summry, limited, low-qulity evidence suggests tht PBT is ssocited with comprle rtes of toxicity to other rdition modlities in ptients with liver cncer. Lung Cncer Curtive Three fir-qulity comprtive cohort studies exmined the clinicl effectiveness of PBT in lung cncer. Two studies retrospectively compred outcomes with PBT to those with IMRT or older three-dimensionl conforml rdiotherpy (3D-CRT) t US cncer center. One study involved 250 ptients with non-smll-cell lung cncer (NSCLC) who were treted with 66 Gy of photons or 74 GyE of protons nd followed for up to one yer to ssess key mesure of lung function known s diffusing cpcity of lung for cron monoxide (DLCO). While this mesure did not differ etween PBT nd IMRT t 5-8 months fter tretment, DLCO declined significntly more in the 3D-CRT group s compred to PBT fter djustment for pretretment chrcteristics nd other lung function mesures (p=0.009). A second study focused on survivl in 202 ptients with loclly-dvnced, unresectle NSCLC who were followed for medin of 1.5 yers nd treted 74 GyE of PBT or 63 Gy of either IMRT or 3D-CRT. Acturil estimtes of medin overll survivl were 24.4, 17.6, nd 17.7 months for PBT, IMRT, nd 3D-CRT respectively, lthough these differences were not sttisticlly significnt (p=0.1061). A third study ws prospectively-mesured cohort ut, s with the study of liver cncer mentioned ove, compred PBT to cron ion therpy, evluting 111 Jpnese NSCLC ptients over medin of 3.5 yers. No sttisticlly-significnt differences etween groups were 10 Proton Bem Therpy

11 oserved in three-yer cturil estimtes of locl control, progression-free survivl, or overll survivl. Slvge In the second study descried ove, 22% of the study smple ws identified s hving prior mlignncy of ny type. The effects of prior mlignncy on overll survivl were not reported, however. Hrms A totl of three comprtive studies ssessed hrms in ptients with lung cncer. One ws study of severe rdition-induced esophgitis (within six months of tretment) mong 652 ptients treted for NSCLC with PBT, IMRT, or 3D-CRT t US cncer center. Rtes of grde 3 or higher esophgitis were 6%, 8%, nd 28% for PBT, 3D-CRT, nd IMRT respectively (p<.05 for PBT nd 3D-CRT vs. IMRT). In the previously-descried noncontemporneous cse series comprison of ptients with loclly-dvnced, unresectle NSCLC who were treted with PBT, IMRT, or 3D-CRT, hemtologic toxicity rtes did not differ y rdition modlity. Significnt differences in fvor of PBT were seen in rtes of grde 3 or higher esophgitis (5%, 39%, nd 18% for PBT, IMRT, nd 3D-CRT respectively, p<0.001) s well s pneumonitis (2%, 6%, nd 30%, p<0.001), while rtes of grde 3 or higher dermtitis were significntly greter in the PBT group (24% vs. 17% nd 7% for IMRT nd 3D-CRT, p<0.001). Finlly, in previously-descried comprison of PBT to cron-ion therpy in 111 ptients in Jpn, rtes of pneumonitis, dermtitis, nd ri frcture did not differ sttisticlly etween rdition modlities cross ll toxicity grdes. In summry, moderte evidence suggests tht rtes of tretment-relted toxicities with PBT re comprle to those seen with other rdition modlities in ptients with lung cncer. Oculr Tumors Curtive In comprison to other cncer types, the evidence se for oculr tumors ws reltively sustntil. A totl of seven comprtive studies were identified of the clinicl enefits of primry PBT in such cncers single RCT, four retrospective cohort studies, comprison of recent cse series to the tretment groups from the RCT, nd comprison of noncontemporneous cse series. The RCT compred PBT lone to comintion of PBT nd trnspupillry thermotherpy (TTT) in 151 ptients treted for uvel melnom nd followed for medin of 3 yers. Comintion therpy ws ssocited with sttisticlly-significntly (p=0.02) reduced likelihood of secondry enucletion; no other outcomes differed significntly etween groups. In seprte, poor-qulity comprison of these findings to seprte series of ptients undergoing PBT with endoresection of the scr, rtes of secondry enucletion did not differ etween groups, ut rtes of neovsculr glucom were significntly lower in the PBT+endoresection group vs. the groups from the RCT (7% vs. 58% nd 49% for PBT lone nd PBT+TTT respectively, p<0.0001). Of note, however, medin follow-up ws less thn two yers in the PBT+endoresection series vs. 9 yers in the RCT. 11 Proton Bem Therpy

12 Three of the cohort studies were ll fir-qulity nd involved comprisons to surgicl enucletion in ptients with uvel melnom t single centers. PBT ws ssocited with sttisticlly-significnt improvements in overll survivl rtes reltive to enucletion t 2-5 yers in two of these studies. Rtes of metstsis-relted nd ll cncer-relted deth were sttisticlly-significntly lower mong PBT ptients through two yers of follow-up in one study (n=1,051), ut were nonsignificnt t lter timepoints. The 5-yer metstsis-free survivl rte in second study (n=67) ws 50% higher mong PBT ptients in Cox regression model controlling for seline chrcteristics (59.0% vs. 39.4% for enucletion, p=0.02). In the third study, Kpln-Meier curves for ll-cuse mortlity, melnom-relted mortlity nd metstsisfree survivl did not sttisticlly differ for 132 ptients treted with PBT nd enucletion. Metstsis-free survivl lso did not differ in Cox regression djusting for ge, sex, nd tumor thickness. Another fir-qulity study ssessed the impct of PBT + chemotherpy vs. PBT lone in 88 ptients with uvel melnom who were followed for 5-8 yers. Five-yer overll survivl rtes did not sttisticlly differ etween groups on either n undjusted or Cox regression-djusted sis. Finlly, poor-qulity comprison of noncontemporneous cse series evluted tretment with PBT + lser photocogultion or PBT lone in 56 ptients with choroidl melnom. At one yer, there were no differences in visul cuity etween groups. Slvge A single comprtive study exmined PBT in recurrent oculr cncer. In this fir-qulity, comprtive cohort study, totl of 73 ptients with uvel melnom hd recurrence of disese following n initil course of PBT t US hospitl. Ptients (men ge: 58 yers) were treted with either second course of PBT (70 GyE) in five frctions or surgicl enucletion nd followed for 5-7 yers. The likelihood of overll survivl t five yers ws significntly (p=0.04) longer in the PBT group (63% vs. 36% for enucletion), s ws the proility of eing free of metstsis t this timepoint (66% vs. 31% respectively, p=0.028). Findings were similr fter Cox proportionl hzrds regression djusting for tumor volume nd yer of retretment s well s ptient ge. The likelihood of locl tumor recurrence t five yers ws 31% in the PBT group. No locl recurrences were found in the enucletion group, which is not surprising given the nture of the tretment. Hrms Two comprtive studies ssessed the hrms of PBT for oculr cncers. In the previouslydescried RCT compring PBT with thermotherpy to PBT lone in 151 ptients with uvel melnom, no sttisticlly-significnt differences were oserved etween groups in rtes of ctrcts, mculopthy, ppillopthy, glucom, or introculr pressure. The comintion therpy group hd significntly lower rte of secondry enucletion (p=0.02), lthough ctul figures were not reported. In previously-descried comprison of PBT to enucletion in 132 ptients treted for unilterl choroidl tumors, rtes of eye loss in the PBT rm were ssessed nd estimted to e 26% t 12 Proton Bem Therpy

13 five yers of follow-up. In summry, limited, low-qulity evidence suggests comprle rtes of hrm for PBT reltive to tretment lterntives in ptients with oculr tumors. Peditric Cncers Hrms PBT s theoreticl potentil to lower rdition-induced toxicity in children serves s the comprtive evidence se. Comprtive studies re lcking, most likely due to lck of clinicl equipoise. Other thn the study of secondry mlignncy descried ove, no comprtive studies of the potentil hrms of PBT in ptients with peditric cncers were identified. Prostte Cncer Curtive The lrgest evidence se ville ws for prostte cncer (10 studies). However, only 6 of these studies reported clinicl outcomes nd compred PBT to lterntive tretments. These included n RCT, prospective comprtive cohort, nd four comprisons of noncontemporneous cse series. The included RCT ws fir-qulity comprison of 202 ptients with dvnced (stges T3-T4) prostte cncer who were rndomized to receive either photon therpy with proton oost (totl dose: 75.2 GyE) or photons lone (67.2 Gy) nd were followed for medin of five yers. Kpln-Meier estimtes of locl tumor control, disese-specific survivl, nd overll survivl were similr t oth 5- nd 8-yer timepoints mong the entire intent-to-tret popultion s well s those completing the tril (n=189). However, in ptients with poorly-differentited tumors (Gleson grdes 4 or 5), locl control t 8 yers ws significntly etter in ptients receiving PBT+photons (85% vs. 40% for photons lone, p=0.0014). The prospective cohort study ws fir-qulity comprison of ptient-reported helth-relted QoL t multiple timepoints mong 185 men (men ge: 69 yers) with loclized prostte cncer who were treted with PBT, PBT+photons, photons lone, surgery, or wtchful witing. Overll QoL, generl helth sttus, nd tretment-relted symptom scles were employed. No differences in overll QoL or generl helth sttus were oserved t 18 months of follow-up, lthough men treted with PBT monotherpy reported etter physicl function in comprison to surgery (p=0.01) or photon rdition (p=0.02), nd etter emotionl functioning in reltion to photon rdition (p<0.001). Men receiving PBT+photons lso reported significntly fewer urinry symptoms t 18 months in comprison to wtchful witing (p<0.01). Outcomes were lso ssessed in three comprisons of noncontemporneous cse series. One ws fir-qulity evlution of high-dose PBT+photons (79.2 GyE) in 141 ptients enrolled in clinicl tril who were mtched on clinicl nd demogrphic criteri to 141 ptients treted with rchytherpy. Ptients were followed for medin of eight yers. Eight-yer cturil estimtes of overll survivl, freedom from metstsis, nd iochemicl filure did not sttisticlly differ etween groups. The proportion of ptients chieving ndir PSA level of Proton Bem Therpy

14 ng/ml s of their finl mesurement ws significntly higher in the rchytherpy group (92% vs. 74% for PBT, p=0.0003). Two dditionl studies were deemed to e of poor qulity due to lck of control for confounding etween study popultions. One ws comprison of cohort of 206 rchytherpy ptients compred with the sme PBT+photon group descried ove. The difference in the percentge of ptients chieving ndir PSA fter medin of 5.4 yers of follow-up ws similr to tht reported in the study ove (91% vs. 59%), lthough sttisticl results were not reported. Five-yer estimtes of disese-free survivl (using iochemicl filure definitions) did not sttisticlly differ etween groups. The other study involved comprisons of owel- nd urinry-relted QoL in three distinct cohorts receiving PBT (n=95; GyE), IMRT (n=153; Gy), or 3D-CRT (n=123; Gy). Sttisticl chnges were ssessed within (ut not etween) ech cohort immeditely following tretment s well s t 12 nd 24 months of follow-up, nd were lso ssessed for whether the chnge ws considered cliniclly meningful (>0.5 SD of seline vlues). Some differences in QoL decrements were seen t erlier timepoints. However, t 24 months, ll groups experienced sttisticlly nd cliniclly significnt decrements in owel QoL, nd none of the groups hd significnt declines in urinry QoL. A fourth, poor-qulity comprison of cse series involved n evlution of ptient-reported outcomes on the Expnded Prostte Cncer Index Composite (EPIC) questionnire mong cohort of 1,243 ptients receiving PBT for prostte cncer nd group of 204 ptients receiving IMRT from previous multicenter study. Sttisticlly-significnt differences etween tretment groups were oserved for mny seline chrcteristics, only some of which were djusted for in multivrite nlyses. No differences were oserved in summry scores for owel, urinry, nd sexul QoL t two yers, lthough more IMRT ptients reported specific owel frequency (10% vs. 4% for PBT, p=0.05) nd urgency (15% vs. 7%, p=0.02) prolems t two yers. Hrms Four comprtive studies exmined the hrms ssocited with PBT nd lterntive tretments in ptients with prostte cncer. The previously-descried RCT of PBT+photon therpy vs. photons lone exmined rtes of rectl leeding, urethrl stricture, hemturi, incontinence, nd loss of full potency; no ptients in either rm hd grde 3 or higher toxicity during rdition therpy. Acturil estimtes of rectl leeding t eight yers were significntly higher in the PBT+photon rm (32% vs. 12% for photons lone, p=0.002), lthough this ws primrily grde 2 or lower toxicity. Rtes of urethrl stricture, hemturi, incontinence, nd loss of potency did not differ etween groups. Three dditionl studies involved retrospective comprisons using ville dtses. The most recent ws mtched comprison of 314 PBT nd 628 IMRT ptients treted for erlystge prostte cncer using the linked Chronic Condition Wrehouse-Medicre dtse with focus on complictions occurring within 12 months of tretment. At six months, rtes of genitourinry toxicity were significntly lower in the PBT rm (5.9% vs. 9.5%, p=0.03). This difference ws not pprent fter 12 months of follow-up, however (18.8% vs. 17.5%, p=0.66). 14 Proton Bem Therpy

15 Rtes of gstrointestinl nd other (e.g., infection, nerve dmge) complictions did not sttisticlly differ t either timepoint. Another recent study compred mtched cohorts of men with prostte cncer in the linked Medicre-SEER dtse who were treted with PBT or IMRT (684 ptients in ech rm) nd followed for medin of four yers. IMRT ptients hd sttisticlly-significntly lower rte of gstrointestinl moridity (12.2 vs per 100 person-yers, p<0.05). No other sttisticl differences were noted in genitourinry moridity, erectile dysfunction, hip frcture, or use of dditionl cncer therpy. Finlly, there ws n nlysis of nerly 30,000 men in the Medicre-SEER dtse who were treted with PBT, IMRT, 3D-CRT, rchytherpy, or conservtive mngement (oservtion lone) nd evluted for gstrointestinl toxicity. All forms of rdition hd higher rtes of GI moridity thn conservtive mngement. In pirwise comprisons using Cox proportionl hzrds regression, PBT ws ssocited with higher rtes of GI moridity thn conservtive mngement (HR: 13.7; 95% CI: 9.1, 20.8), 3D-CRT (HR: 2.1; 95% CI: 1.5, 3.1), nd IMRT (HR: 3.3; 95% CI: 2.1, 5.2). In summry, moderte evidence suggests tht rtes of mjor hrms re comprle etween PBT nd photon rdition tretments, prticulrly IMRT. Noncncerous Conditions Hemngioms Curtive A single poor-qulity retrospective study evluted PBT s clinicl effectiveness in 44 ptients with diffuse or circumscried choroidl hemngioms who were treted with either PBT (20-23 GyE) or photon therpy (16-20 Gy) nd followed for n verge of 2.5 yers. Undjusted outcomes were reported for the entire cohort only; reduction in tumor thickness, resolution of retinl detchment, nd stiliztion of visul cuity were oserved in >90% of the overll smple. In Kpln-Meier nlysis of outcomes djusting for differentil follow-up etween tretment groups, therpeutic modlity hd no sttisticlly-significnt effects on stiliztion of visul cuity (p=0.43). Hrms A single, previously-descried retrospective comprtive cohort study ssessed outcomes in ptients with circumscried or diffuse hemngioms treted with PBT or photon rdition. Smll differences in undjusted rtes of optic nerve/disc trophy, lcrimtion (formtion of ters) nd oculr pressure s well s effects on the retin, lens, nd iris were oserved etween groups, ut most side effects were grde 1 or 2. The rte of retinopthy ws sustntilly higher in PBT ptients (40% vs. 16% for photons). However, in Cox proportionl hzrds regression djusting for etween-group differences, no effect of rdition modlity on outcomes ws oserved, including retinopthy (p=0.12). 15 Proton Bem Therpy

16 Other Benign Tumors Curtive Two comprtive studies of PBT s clinicl effectiveness in other enign tumors were oth of poor qulity. One ws retrospective cohort of consisting of 20 ptients with gint-cell one tumors who were treted with PBT+photon therpy (men: 59 GyE) or photons lone (men: 52 Gy) nd followed for medin of 9 yers. Ptients could lso hve received prtil tumor resection. Of note, the PBT popultion consisted entirely of young dults (men ge: 23 yers), while the photon-only popultion ws much older (men: 46 yers); no ttempt ws mde to control for differences etween tretment groups. Rtes of disese progression, progressionfree survivl, nd distnt metstses were numericlly similr etween groups, lthough these rtes were not sttisticlly tested. The other study ws smll cohort study compring PBT lone, photon therpy lone, or PBT + photons in 25 ptients with optic nerve sheth meningiom. On n overll sis, visul cuity improved in most ptients. Rtes did not numericlly differ etween tretment groups, lthough these were not tested sttisticlly. Slvge In the first study descried ove, five of 20 were identified s hving recurrent disese. Two of the five were treted with PBT+photon therpy, one of whom hd progression of disese t eight months ut no further progression fter retretment t five yers of follow-up. The other ptient ws free of locl progression nd metstses s of 9 yers of follow-up. In the three photon ptients, one hd locl progression t 12 months ut no further progression s of yer 19 of follow-up, one ptient ws free of progression nd metstses s of five yers of followup, nd one ptient hd unknown sttus. Hrms The previously-descried study compring PBT, PBT+photon, nd photon therpy lone in 25 ptients treted for optic nerve sheth meningioms showed numericlly lower rtes of cute oritl pin nd hedche for oth PBT groups compred to photon therpy, nd numericlly higher rtes of lte symptomtic retinopthy. None of these comprisons were tested sttisticlly, however. Evidence is limited nd indequte to compre the potentil hrms of PBT reltive to other rdition modlities in ptients with other enign tumors. Cost & Cost-Effectiveness Limited dt re ville out costs of PBT in most types of cncer. One study of rest cncer ptients in the US exmined reimursement for tretment with 3D-conforml prtil rest irrdition using protons or photons vs. trditionl whole rest irrdition. Pyments included those of tretment plnning nd delivery s well s ptient time nd trnsport. Totl per-ptient costs were sustntilly higher for PBT vs. photon prtil irrdition ($13,200 vs. $5,300) ut only modestly incresed reltive to trditionl whole rest irrdition ($10,600), s the ltter incurred higher professionl service fees nd involved greter mount of ptient time. Two dditionl studies from the sme group ssessed the cost-effectiveness of PBT vs. 16 Proton Bem Therpy

17 photon rdition mong women with left-sided rest cncer in Sweden. In the first of these, photon rdition ws ssumed to increse the risk of ischemic nd other crdiovsculr disese s well s pneumonitis reltive to PBT; clinicl effectiveness ws ssumed to e identicl. Reductions in dverse events led to gin in qulity-djusted life yers (QALYs) equivlent to pproximtely one month (12.35 vs for photon). Costs of PBT were nerly triple those of photon therpy, however ($11,124 vs. $4,950), leding to n incrementl cost-effectiveness rtio (ICER) of $65,875 per QALY gined. The other study used essentilly the sme model ut focused ttention only on women t high risk of crdic disese (43% higher thn generl popultion). In this instnce, much lower ICER ws oserved ($33,913 per QALY gined). One study evluted the economic impct of PBT in lung cncers mong ptients in the Netherlnds. A Mrkov model compred PBT to cron-ion therpy, stereotctic rdition therpy, nd conventionl rdition in ptients with stge 1 non-smll-cell lung cncer (NSCLC) over 5-yer time horizon. Effects of therpy included oth overll nd disese-relted mortlity s well s dverse events such s pneumonitis nd esophgitis. For inoperle NSCLC, PBT ws found to e oth more expensive nd less effective thn either cron-ion or stereotctic rdition nd ws therefore not included in susequent nlyses focusing on inoperle disese. While not reported in the pper, PBT s derived cost-effectiveness reltive to conventionl rdition (sed on pproximtely $5,000 in dditionl costs nd 0.35 dditionl QALYs) ws pproximtely $18,800 per QALY gined. Three decision nlyses were ville tht focused on peditric cncers, ll of which focused on lifetime time horizon in children with medullolstom who were treted t 5 yers of ge. In US-sed model tht incorported costs nd ptient preference (utility) vlues of tretment nd mngement of dverse events such s growth hormone deficiency, crdiovsculr disese, hypothyroidism, nd secondry mlignncy, PBT ws found to generte lower lifetime costs ($80,000 vs. $112,000 per ptient for conventionl rdition) nd greter numer of QALYs (17.37 vs ). Reduced risks for PBT were estimted sed on dt from dosimetric nd modeling studies. Sensitivity nlyses on the risk of certin dverse events chnged the mgnitude of PBT s cost-effectiveness, ut it remined less costly nd more effective in ll scenrios. Peditric medullolstom ws ssessed in two modeling studies. As with the nlysis ove, PBT ws ssumed to reduce oth mortlity nd nonftl dverse events reltive to conventionl photon therpy. On per-ptient sis, PBT ws ssumed to reduce lifetime costs y pproximtely $24,000 per ptient nd increse qulity-djusted life expectncy y nerly nine months (12.8 vs QALYs). On popultion sis, 25 medullolstom ptients treted y PBT would hve lifetime costs reduced y $600,000 nd generte n dditionl 17.1 QALYs reltive to conventionl photon rdition. Finlly, four studies were identified tht exmined costs nd cost-effectiveness of PBT for prostte cncer. An nlysis of the Chronic Condition Wrehouse exmined tretment costs for mtched Medicre eneficiries with prostte cncer who received PBT or IMRT. Medin Medicre reimursements were $32,428 nd $18,575 for PBT nd IMRT respectively (not sttisticlly tested). 17 Proton Bem Therpy

18 A reltively recent Mrkov decision nlysis estimted the lifetime costs nd effectiveness of PBT, IMRT, nd stereotctic ody rdition therpy (SBRT) for loclized prostte cncer. Clinicl effectiveness nd impct on mortlity were ssumed to e equivlent cross ll three groups. SBRT ws found to hve the lowest tretment costs nd shortest time in tretment of the three modlities, nd produced slightly more QALYs (8.11 vs nd 8.06 for IMRT nd PBT respectively) sed on n expected rte of sexul dysfunction pproximtely hlf tht of IMRT or PBT. SBRT ws cost-sving or cost-effective vs. PBT in 94% of proilistic simultions. An erlier decision nlysis estimted the potentil cost-effectiveness of hypotheticllyesclted PBT dose (91.8 GyE) vs. 81 Gy delivered with IMRT over 15-yer time horizon. The model focused on mortlity nd disese progression lone (i.e., toxicities were ssumed to e similr etween groups), nd ssumed 10% reduction in disese progression from PBT s higher dose. This trnslted into QALY increses of 0.42 nd 0.46 yers in 70- nd 60-yer-old men with intermedite-risk disese respectively. Costs of PBT were $25,000-$27,000 higher in these men. ICERs for PBT vs. IMRT were $63,578 nd $55,726 per QALY for 70- nd 60-yerold men respectively. Finlly, the model lso evluted costs nd outcomes for hypotheticl cohort of yerold men with prostte cncer. PBT ws ssumed to result in 20% reduction in cncer recurrence reltive to conventionl rdition s well s lower rtes of urinry nd gstrointestinl toxicities. PBT ws estimted to e pproximtely $8,000 more expensive thn conventionl rdition over lifetime ut result in QALY gin of nerly 4 months (0.297). The resulting cost-effectiveness rtio ws $26,481 per QALY gined. EVIDENCE SUMMARY Proton em therpy (PBT) hs een used for clinicl purposes for over 50 yers nd hs een delivered to tens of thousnds of ptients with vriety of cncers nd noncncerous conditions. Despite this, evidence of PBT s comprtive clinicl effectiveness nd comprtive vlue is lcking for nerly ll conditions under study in this review. As mentioned previously, it is unlikely tht significnt comprtive study will e forthcoming for childhood cncers despite uncertinty over long-term outcomes, s the potentil enefits of PBT over lterntive forms of rdition pper to e generlly ccepted in the clinicl nd pyer communities. In ddition, ptient recruitment for potentil studies my e untenle in very rre conditions (e.g., thymom, rteriovenous mlformtions). In other res, however, including common cncers such s rest nd prostte, the poor evidence se nd residul uncertinty round the effects of PBT is highly prolemtic. The net helth enefit of PBT reltive to lterntive tretments is rted Superior (modertelrge net helth enefit) in oculr tumors nd Incrementl (smll net helth enefit) in dult rin/spinl nd peditric cncers. The net helth enefit is judged Comprle (equivlent net helth enefit) in severl other cncers, including liver, lung, nd prostte cncer, s well s hemngioms. It should e noted, however, tht judgments of comprility were mde sed on limited evidence se tht provides reltively low certinty tht PBT is roughly equivlent to lterntive therpies. While further study my reduce uncertinty nd clrify differences 18 Proton Bem Therpy

19 etween tretments, it is currently the cse tht PBT is fr more expensive thn its mjor lterntives, nd evidence of its short or long-term reltive cost-effectiveness is lcking for mny of these conditions. It should lso e noted tht evidence ws exmined for 11 cncers nd noncncerous conditions not listed ove, nd it ws determined tht there ws insufficient evidence to otin even sic understnding of PBT s comprtive clinicl effectiveness nd comprtive vlue. 19 Proton Bem Therpy

20 GRADE-INFORMED FRAMEWORK The HERC develops tions y using the concepts of the Grding of tions Assessment, Development nd Evlution (GRADE) system. GRADE is trnsprent nd structured process for developing nd presenting evidence nd for crrying out the steps involved in developing tions. There re four elements tht determine the strength of tion, s listed in the tle elow. The HERC reviews the evidence nd mkes n ssessment of ech element, which in turn is used to develop the tions presented in the coverge guidnce ox. Blnce etween desirle nd undesirle effects, nd qulity of evidence, re derived from the evidence presented in this document, while estimted reltive costs, vlues nd preferences re ssessments of the HERC memers. Indiction/ Intervention Blnce etween desirle nd undesir le effects Qulity of evidence* Resource lloctio n Vriility in vlues nd preferences Coverge tion Rtionle PBT for oculr tumors Superior enefit, reduced hrms Moderte Moderte Low vriility (preference to PBT) ed for coverge (strong tion) Sufficient evidence, more effective, less risk. (IA1) PBT for dult rin/spinl tumors Comprle enefit, reduced hrms Very Low** Moderte Moderte vriility Not ed for coverge (wek tion) Insufficient evidence, lterntives ville; less risk, more cost, more risk. (IIA1) PBT for peditric tumors Comprle enefit, reduced hrms Very Low** Moderte Moderte (significnt concerns re rdition therpy) Not ed for coverge (wek tion) Insufficient evidence, lterntives ville; less risk, more cost, more risk. (IIA1) 20 Proton Bem Therpy

21 Indiction/ Intervention Blnce etween desirle nd undesir le effects Qulity of evidence* Resource lloctio n Vriility in vlues nd preferences Coverge tion Rtionle PBT for liver cncer Comprle enefit, comprle hrms Low Moderte Moderte, in prt due to limited vilility (wek tion) Sufficient evidence, similr effectiveness, similr risk, more cost. (IA2i) PBT for lung cncer Comprle enefit, comprle hrms Low Moderte Moderte (wek tion) Sufficient evidence, similr effectiveness, similr risk, more cost. (IA2i) PBT for prostte cncer Comprle enefit, comprle hrms Low Moderte Moderte (wek tion) Sufficient evidence, similr effectiveness, similr risk, more cost. (IA2i) PBT for oculr hemngioms Comprle enefit, comprle hrms Very Low Moderte Moderte to high, due to uncertinty of enefit (strong tion) Insufficient evidence, Alterntives ville, similr risk. (IIA2) PBT for one, rest, esophgel, GI, gynecologic, nd hed/neck cncer; lymphoms, srcoms, seminoms, Unknown Bone, hed/neck: Low All others: No evidence Moderte Low (most would not choose PBT due to cost, need to trvel, uncertin enefit) (wek tion) Insufficient evidence, unknown risk compred to lterntive. (IIA3) 21 Proton Bem Therpy