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Review
Proton
beam
and
prostate
cancer:
An
evolving
debate
Anthony
Zietman
∗DepartmentofRadiationOncology,MassachusettsGeneralHospital,FruitStreet,Boston,MA02114,USA
a
r
t
i
c
l
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f
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Articlehistory: Received18April2013 Accepted3June2013 Keywords: Prostatecancer Protonbeama
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Thispaperevaluatesthereasonsbehindtheriseintheuseofprotonbeamforprostate can-cer,theeconomicsdriversbehindit,andtheevidencethatexiststosupportit.Itconcludes thatclinicaloutcomedataunderlyingthenotionthatthisisasuperiortreatmentremains sparseanddiscusseswhatisneededtofillinthegaps.
©2013GreaterPolandCancerCentre.PublishedbyElsevierUrban&PartnerSp.zo.o.All rightsreserved.
1.
Introduction
and
rationale
Thepropertiesoftheprotonbeamhavebeenlongrecognized ashavingtherapeuticpotential.Inparticular,theirsingular property of slowing rapidly in tissue, depositing energy at depth,and withoutany dosebeyondthetarget,were envi-sionedtohavegreatclinicaladvantage.Thiswasfirst recog-nizedinthe1940sandhasbeenthebasisofitsuseeversince.1
Earlytherapeuticfacilitiesweremerelyphysicslaboratoriesat universitiescleverlyadaptedtoallowpatienttreatment.The beamenergiesweregenerallylowandsotreatmentwas lim-itedtotumorsatrelativelyshallowdepthsuchastheeye,the spine,orthebaseofskull.Intherealmofpediatricswhere lowdose,orindeedanydose,radiationtonormaltissuescan havedisastrousconsequencesproton beamwasused with enthusiasm.Luckilythe lowerenergybeamsthenavailable hadsufficientpenetrationtoreachmostpediatricsarcomas orCNStumorsandindeedtumorsalmostanywhereinababy. Inthe1990spatient-dedicatedprotonfacilitieswere devel-opedandsincethentheiruseandestablishmenthasgreatly
∗ Tel.:+16177241160;fax:+16177263603.
E-mailaddress:azietman@partners.org
accelerated. Dozens of facilities now exist globally, ten of which are fully functional in the Unites States. Contracts havebeensignedonmanymorefacilitiesandconstructionis underway.Itisthewaveofthefutureand,atcurrentcosts, a very expensive wave. The enthusiasm, based upon sim-pledosimetricstudies,hasactuallyprecededthe resultsof prospectiveclinicalstudiesdesignedtoassesstheoutcomesof thistherapyand,insomecases,hasactuallyreplacedit.Data isstartingtoemergedemonstratingclearadvantagesinterms of organ function and areduction insecond malignancies amongthe pediatricpopulation.2–4 Thishasretrospectively
justifieditsuseinanareawhereitwaslongpresumedtobe advantageous.Theproblemisthat,intheUSAatleast,80% ofpatientstreatedwithprotonbeamhaveprostatecancer.5
Thereasons are simple.Between3and5prostate patients canbetreatedinthetimeittakestotreatasinglecomplex pediatriccase.Theinstallationofaprotonfacilityisso expen-sive that,atcurrent ratesofUSreimbursement, ahospital can onlybegintocover itsdebtwitha highthroughputof prostate cancercases.Thishasleadtoadangerous distor-tionofpatternsofcare.Manycentersthatshouldbetreating
1507-1367/$–seefrontmatter©2013GreaterPolandCancerCentre.PublishedbyElsevierUrban&PartnerSp.zo.o.Allrightsreserved.
childrentreatprostatecancercases,andmanyelderlypatients withprostatecancerwhoshouldbehavingnotreatmentat allreceive itunnecessarily.An“armsrace”hasbegunwith manycenterstakingahugefinancialandmoralrisk invest-inginprotontherapytokeepupwiththeircompetitors.6As
prostatecanceristheUSeconomicengineforproton ther-apyitisworthspendingsometimeassessingtheevidence supportingitsuse.
2.
Uncertainties
in
the
physics
and
biology
The Bragg Peak has a tremendous therapeutic appeal but invivothedistributionoftheprotonbeamissubjecttomany perturbationsanduncertainties.Thedeeperthebeamin tis-suethelesscertainoneisofitsstoppingpoint.This“endof rangeuncertainty”meansthatthebeamhastobeplanned toovershootthetargettoguaranteegoodcoverage.In addi-tion,atgreaterdepthsthereisconsiderablelateralscattering resultinginasignificantpenumbramakingthelateral mar-ginsofthebeamlesssharp.7Protonbeam,likeotherformsofparticletherapy,ishighlysubjecttotissueinhomogeneities. Trofimovetal.havedemonstratedthedifferencethatsmall movementsofthehipscanmaketoalateralbeamdelivered totheprostate.8
TheRadio-BiologicEffectoftheprotonbeamhasbeen mea-suredat1.1relativetoX-raysyetthisnumbermaynotbeso precise.JustbeyondtheBraggPeakitmaybealittlehigher. FurthermoretheRBEmaydifferslightlyfordifferenttissues. Whilethiswouldnotmatteratlowerdoseswhenoneisgiving closeto80Gytoaprostate,forexample,smalldifferencesin RBEcanbecritical.Apassivelyscatteredprotonbeam,andthis remainstheprevalentdeliverytechniquein2013,also gen-eratesneutronsinthecollimatorwithaveryhighRBEand acompletelyunknowncontributiontotheeffectonnormal tissues.
Manyoftheseissueswilleitherbeclarifiedbyfuture exper-imentationormodeling(RBE)orbymovingtospotscanned beamtechniques(neutrons)but,fornow theymayor they maynotcontributetothemorbidityofprotontherapyor,at least,dilutethebenefits.9,10
3.
The
clinical
evidence
Themanagementoflocalizedprostatecancerhasbeen con-troversialfordecades.Ithasbeendifficulttodecidewhether ornotanytreatmentisbetterthansimpleobservationand,if so,whichofthecurativetherapiesissuperior:surgery, exter-nalradiation,orbrachytherapy.Amongtheradiationoptions newtechnologieshavebeenreadilyadoptedalthoughthereis remarkablylittleevidenceofthebenefittheybring.3-D exter-nalradiationwasshowntoreduceratesofradiationproctitis oversimple2-Dtherapy.11 Intheearly 2000sIMRT became
extremelypopularandisnowalmostexclusivelytheexternal beamstrategyofchoiceintheUS.ArecentanalysisofRTOG datasuggeststhattheadvantageofIMRTover3-Dinterms ofmorbidityandqualityoflifemayberemarkablysmall.12
Itisimpossible toturn backthe clockbut if this datahad beenavailableover adecade agoit ispossiblethatthe big
switch toIMRT may have been slowed or,had there been no financialdrivers,stoppedaltogether.Newtechniquesof image-guidancemayultimatelyprovetobemoresignificant thaneithertheplanningorbeamdeliverytechnique.
Convincingdatanow existsintheformoffive random-izedtrialsdemonstratingthathigherradiationdosesaremore likelytoreducetherisk ofprostate cancerrecurrenceand, inthecaseofhigh-risk tumors,the rateofmetastases.13,14 Thisnow drivesthe useofhigh-doses inpracticewiththe presumptionthatonlyIMRTorprotonbeamareadequateto safely them.Highqualityevidencedemonstratingthatthat isthecaseisindeedrare.Attheendofthedaythehighest radiationdosesaredeliveredbybrachytherapy,alowcostand thushigh-valuealternative.Qualityoflifestudieshavefailed toshowthatpatientsreceivingbrachytherapyfareanyworse than those receiving any formof high-tech externalbeam treatment.15
Onerandomizedtrialhascomparedprotonbeamwith con-ventionalradiationandshowednodifferenceinanyoutcome. Interpretationofthisstudyis,however,greatlylimitedbythe factthatittreatedadvancedcaseswhowouldhavebeen bet-terservedbytheadditionofhormonaltherapyandbecauseit tookplaceinthepre-PSAerawhenmanypatientswouldhave hadoccultmetastaticdiseaseatthetimeofpresentation.16
TheworkoftheMassachusettsGeneralHospitalhastested anumberofhypotheses:
DoesprotonbeamproducesuperiordosedistributionsoverIMRT forprostate cancer?Theanswerismixed. Thereis undoubt-edlylessofa“dosebath”totheanteriorandposteriortissues but moreradiation passes throughthe femoralheadsand, becauseofbeamuncertainty,thehigh-dosevolumeis actu-allyalittlelargerwithprotonsthanIMRT17Fig.1.Inaddition,
tworegionsassociatedwithmorbidities(theprostaticurethra andperi-prostaticnervebundles)aretreatedequallywiththe twotechniques.Thevolumeofrectumtreatedlikelydepends moreonimageguidance,choiceofmargins,andtheuseor notofarectalballoonthanitdoesthedeliverytechnique.
Doesprotonbeamcurepatientswithprostatecancer?Indeed itdoes,asdoallformsofradiationdeliveredinhighdose.A prospectivephaseIIIstudyclearlyshowsthatdosesof79Gy canbedeliveredsafelywithprotonsandthatover90%of low-riskpatientsmaybecuredthisway.Theproblemisthat79Gy canalsoeasilybedeliveredbyIMRTandprobablyby3-D ther-apyalso.18Acase-controlledstudyhasalsoshownthatthe
cureratesat10yearsfromprotonbeamandbrachytherapy appeartobeidentical19Fig.2.
Canprotonbeambeusedtodoseescalatefurther?Thishasbeen testedinaphaseIIstudyof90patients.82Gywasdeliveredbut unacceptablelevelsofrectaltoxicitywerereachedimplying that,forwholeglandtreatmentusingcurrenttechniquesat least,79Gyisclosetothepracticallimit.20
Can protonbeambe usedto escalatethedosefurtherto part oftheprostategland?Itiscertainlyappealingtoimaginethe entireglandbeingtreatedtoonedoseandadominantnodule beingtreatedtoahigherdose.Thiscouldrepresentintelligent doseescalationwithoutmorbidityescalationandis theoret-icallypossibleusingscannedbeamtechniques.Theproblem isthatourimaging,althoughimproving,rapidly,iscurrently insufficienttopickoutatargetwithintheprostatewithgreat reliability.Inadditionourtechniquesofimage-guidanceand
Fig.1–Comparativeplanningstudyshowingthedifferenceindosedistributionbetweenopposedlateral,passively scatteredprotonbeamsandanintensitymodulatedphotonplan.
prostateimmobilizationmaynotyetbesufficientlyreliableto allowustosharpshootinthismanner.
Doesprotonbeamreducethemorbidityofprostatetreatment? This is, perhaps, the most important question ofall. If it doesthenthesizeoftheeffectcanbemeasuredagainstthe costofthe therapyand policydecisionsabout its valuebe made. Talcottet al. have performedsome prospectiveand othercross-sectionalqualityoflifestudiesonprostatecancer patientsreceivingprotonbeamtherapyaswellasIMRTand 3-D.Thefirstitemofnoteisthatthereisindeedsignificant sexual,bladder,andrectaldysfunctionamongpatientsafter proton beam.While any treatmentthat covers the nerves, prostaticurethra,bladderneck,andanteriorrectumwouldbe expectedtohavetheseconsequencessomehowthe“internet hype”aroundprotonbeamsuggeststhatthisisneverthecase. Whenthelateeffects(5–10years)aremeasuredagainst3-D andIMRTfewdifferencescanbeseen.21Arecentstudyby
Efs-tathiouetal.suggeststhattheremaybeasmallreductionin
Fig.2–Case-controlledstudyfromtheMassachusetts GeneralHospitalcomparingpatientstreatedwitheither high-doseprotonbeamradiationorlowdose-rate brachytherapy.Figureshowscumulativebiochemical recurrencerates.19
proctitisduringthefirstpost-treatmentyearbutthisisa sin-glestudyandtheeffectwassmallandtemporary.22Newdata
emergingfromotherUSprotoncenterscertainlyshow excel-lent (though non-comparative) quality of life-outcomes.23
Whetherthisistheresultoftheprotonbeamorthetechniques ofimage-guidanceadoptedinparallelremainsunclear.
Ahighlycontroversialstudywasrecentlypublishedwhich usedthe SEERdatabase toassessthe lateconsequencesof differenttypesofexternalradiation therapymeasuringthe outcomes usingbillingcodes forinterventionssuchas cys-toscopy,colonoscopy,orargonplasmacoagulation.24Thedata appearedtoshowthat,forthetimeintervalstudied,therectal morbidityofprotonbeamwasactuallyhigherthanphotons. There aremanyweaknessesinthiskind ofstudy,onethat doesnotuseinformationgathereddirectlyfrompatientsand which precededthe eraofimage-guidance, but itcertainly doesmakethecasethatthesuperiorityofprotonbeam can-notbepresumedineverysituation.Itispossiblethatsomeof thecurrentphysicalandbiologicaluncertaintiesareindeed limiting.
4.
Cost
considerations
Itisthecostofproton beamtherapythatmakesitsusein prostatecancer,whentherearemanyalternatives,so contro-versial.IntheUSAthepricechargedandthereimbursement deliveredvarygreatlyfromoneinsurertoanotherandfrom onestatetothenextandsothereimbursementforalmost allformsoftreatmentfluctuateconsiderably.Itis,however, generallyagreedthatthecostofprotontreatmentisgreater thanthatofIMRT,whichis,inturn,greaterthan brachyther-apy,surgery,oractivesurveillance.Brachytherapyandactive surveillance are generallyagreed tobethe“bestbargains”. Manymodelingstudieshavebeenperformedwhichattempt to determine the value ofproton therapy but most make assumptionsaboutbenefitwhichare,aswasseeninthe previ-oussections,somewhatshaky.Oneparticularmodelingstudy madetheassumptionthatanadditional10Gycouldbesafely deliveredbyprotonbeampushingthedelivereddoseto91Gy and thatthis wouldleadtoasmallbut detectablesurvival advantageforintermediate-riskmen.25Eventhenthecostper
lifesaved(qualityadjustedlifeyears)wasprohibitivelyhigh. Ashasbeen shownboththeseassumptionswere incorrect anyhow.
Thecostofprotonbeamremainsveryfluidespeciallyin anera ofcost control and health carereform and no-one is yet clear what direction prices are heading. There are, however,twochangesonthehorizonthatwilllikelychange the cost equation insome fashion. The first isthat hypo-fractionatedradiationisemergingasaconvenientlower-cost methodofadministeringexternalbeamwithhigh-levelphase IIIsupport. Itispossible thatthe homogeneity ofthe pro-tonbeam isbetter suited to large doses per fraction than thelesshomogeneousIMRT.Evenso,otherphotonplatforms fordeliveringthesefractionswithhighaccuracynowexist.If hypo-fractionationbecomesthenormthenprotonbeamwill alsobecomemorecompetitiveintermsofprice.
Asecondtrendisthedevelopmentofsmallersingle-gantry protonfacilties.Johnstoneetal.havecalculatedthatthedebt incurrediseasiertorecuperatewithasmallerproportionof prostatecases.5Withfurthertechnologicaladvancesitislikely
thatthecostdifferentialbetweenprotonsandphotonswill,in time,diminish.
5.
Proton
treatment
for
prostate
cancer
in
the
future
Prostatecancertreatments have,to date,largely employed opposedlateralbeamsbecausetheend-of-rangeuncertainty hasmade overshooting ofthe target necessary. Any beam angledtowardtheanteriorwouldthusentertherectuminan undesirableway.Unfortunately,lateralbeamshavetotakethe longestroutetotheprostatepossibleandmustpassthrough theinhomogeneousand mobilehips.Ithasbeen saidthat inthisscenariowearetakinganadvancedtechnologyand, frankly,gettingthe leastout ofit.Itisclearthat the tech-nologywillnotstandstillandthedevelopmentofscanned protonbeamswiththeirabilitytobemodulatedshould fur-therincreasetheconformalityoftheprotonbeaminthenear futureallowingmorecreativebeamanglesandtarget shap-ing.TheadvantageofIMRTinthatitcanscoopoutahollowed volumeontherectalsideoftheprostatewillbemimicked andperhapsexceeded,byintensitymodulatedprotons. Par-tialprostateboostingmaybecomemoreofatechnicalreality withscannedbeamsifimagingcanimprovecorrespondingly. Muchofthecontroversyoverprostatecancercomesfrom itshighpricetagandmuchwouldevaporateifthecostcame downsubstantially.Thisislikelytohappenbutthe installa-tioncostsofevenasinglegantryfacilitywillbegreaterthan linear acceleratorsfor the forseeablefuture and treatment costswillalwaysgreaterthansimplebrachytherapyoractive surveillancebecauseofthehighstaffingandmaintenance lev-elsrequired.Thus,thedebatewillcontinuetoturnuponthe advantagepatients(orpayers)arereceivingfortheadditional cost.AsIhaveshowntheevidencesofardoesnotsuggestthat thisadvantageisgreatbutitmaystillbepresentatalevelthat hasbeendifficultforrecentstudiestodetect.Formanyyears thecallhasbeenheardfortheestablishmentofa random-izedtrial.Thestrongargumentsagainstcomefromthosewho feelthatthedosimetryspeaksforitself,thatprotonscannot
beinferior,andthusanRCTisethicallyunjustifiable.Italso comesfromthosewhofeelthatRCTsaresimplynottheway tosolvetechnologyquestions.AnRCTforeverynew technol-ogywouldslowdowntheengineoftechnologicalinnovation, indeedbringittoahalt.Mosttechnologiesaresimplysharper knivesandwherewouldonedrawthelineofRCTnecessity? Others feelthattheRCTshouldbeusedfortechnologybut rarelyandselectively.26Thiswillbefor:newtechnologiesthat arevastlyexpensiveandpotentiallydisrupttheflowofhealth caredollarselsewhere;fortechnologiesthatpotentially intro-ducenewbiologyandthusmayhaveunpredictableoutcomes; and fortechnologies thatrequire agreatdealofretraining and recertification.Protonbeamfitsthebill.No-one would argueforatrialineveryclinicalscenario.Forexample,most wouldbeveryuncomfortablerandomizingchildrentoproton beamorIMRTwhentheIMRTdosecarriessuchrisk.Equally therewouldbelittlevaluerandomizingskincancerswhere nobenefitcouldbeanticipated,orperhapsdiseasessuchas localizedlymphomasorplasmacytomaswheretheradiation dosesarerelativelylow.Prostatecancerfitsintoagrayzoneof highuseandhighcostbutunpredictableoutcomes.Ifnothing elseanRCTwouldquantifythebenefit,ifthereisany,which couldbeusedtoinformthedebate,anddriverationalpolicies. Thesameisalsotrueofprotonbeaminlungcancerwhere theunpredictablebehaviorofprotonbeamacrossaircavities makestheultimateoutcomeuncertain.
Despite the media and internet hyperbole patients do appearwillingtoparticipateinsuchatrialforprostatecancer andseveralmajorUSprotoncentersledbytheMassachusetts GeneralHospitalandUniversityofPennsylvaniahaverecently launched aphaseIIIstudycomparingproton beamagainst IMRT for localized low and low-intermediate risk prostate cancer(http://clinicaltrials.gov/ct2/show/NCT01617161),with patient-reportedqualityoflifeoutcomes,aswellasother clin-ical,physical,biological,andeconomicend-points.Itishoped thattheresultsofthis trialwillcomebeforethe landscape ofprostatecancertreatmenthasbeenchangedinadramatic and,perhapsneedless,fashion.
Financial
disclosure
statement
Nonedeclared.Conflict
of
interest
statement
Nonedeclared.r
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