Aggarwal, A; Hughes, S (2016) Palliative radiotherapy: Evolving role
and policy challenges. Journal of Cancer Policy, 10. pp. 21-29. ISSN
2213-5383 DOI: https://doi.org/10.1016/j.jcpo.2016.05.003
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Journal
of
Cancer
Policy
j o ur na l ho me p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j c p o
Palliative
radiotherapy:
Evolving
role
and
policy
challenges
Ajay
Aggarwal
a,b,∗,
Simon
Hughes
aaGuy’s&StThomas’NHSTrust,London,UK bLondonSchoolofHygieneandTropicalMedicine,UK
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received16November2015 Accepted30May2016 Availableonline31May2016
Keywords:
Palliativeradiotherapy Cancer
Dosefractionation Reimbursementpolicy Clinicaltrialendpoints Inequity
Access
Evidencebasedguidelines
a
b
s
t
r
a
c
t
Radiotherapyremainsakeymodalityinthepalliationofadvancedmalignancymanagingbothlocal primarytumoureffectssuchaspainandbleedingaswellasthesequelaeofmetastaticdisease.Itsrole continuestoevolveinlinewithadvancesinradiationtechnology,whichhavefacilitateddoseescalation andreducedtoxicity.Injudicioususeofsuchadvancementshasthepotentialtomagnifythecostof deliveringpalliativeradiotherapywithoutachievingsignificantgainsintermsofoutcomes,andtherefore well-designedtrialstoassesstheclinicalefficacyareessential.Fromapolicyperspectiveakeyconcern remainstheheterogeneityindosefractionationschedulescurrentlyutilisedinternationallywhichlack astrongevidencebaseandmaybeinfluencedbyreimbursementpolicythatincentiviseslonger,more complexandlesscost-effectiveschedules.
Internationalconsensusisrequiredonstudyend-pointsinpalliativeradiotherapyresearchtoenable comparisonbetweencaseseriesandfacilitaterandomisedcontrolledtrialdesign.Patientreported out-comemeasuresshouldbedevelopedthatcapturethevalueofradiationtreatmentfordifferentindications bothinachievingsymptomcontrolbutalsoimprovingqualityoflife.Thetimingandappropriateuseof radiationtherapyaregenerallyguidedbytheclinicalassessmentoftheradiationoncologist,oncea refer-ralhasbeenmade.Ananalysisofoutcomesfromnational-levelepidemiologicalstudieshasthepotential toguideappropriateutilisationandidentifythosepatientsmostlikelytoderivebenefitfrom radiother-apyindifferenttumourtypes.Lastlyeducationandtrainingremainattheheartofreducinginequalities inaccesstoradiotherapyforpatientswhowouldbenefit.Thisincludesbothradiationoncologistsfor whommanytrainingschemesdonotprioritisepalliativecareandthewidermultidisciplinaryteamwho areinvolvedinthemanagementofcancerpatientsatallstages.
©2016ElsevierLtd.Allrightsreserved.
Contents
1. Introduction...22
2. Whatguidesthedeliveryofpalliativeradiotherapy?...22
2.1. Locallyadvanceddisease...22
2.2. Oligometastaticdisease...22
2.3. Symptomcontrol...23
3. Policyissuesinpalliativeradiationoncology...23
3.1. Variationinaccesstopalliativeradiotherapy...23
3.2. Reimbursementpolicyanduseofpalliativeradiotherapy...24
3.3. Reimbursementpolicyintheeraoftechnologicalevolution...24
3.4. Educationandmultidisciplinarymanagementinpalliativeoncology...25
3.5. Trialendpointsforpalliativeradiotherapy...25
3.6. Evidenceframeworktoguideutilisationofappropriatepalliativemodality...26
3.7. Thevalueofauditindefiningpracticeofcare...26
∗Correspondingauthorat:LondonSchoolofHygieneandTropicalMedicine,DepartmentofHealthServicesResearchandPolicy,London,WC1H9SH,UK.
E-mailaddress:[email protected](A.Aggarwal).
http://dx.doi.org/10.1016/j.jcpo.2016.05.003
22 A.Aggarwal,S.Hughes/JournalofCancerPolicy10(2016)21–29
4. Conclusions...26 References...27
1. Introduction
Approximately50% of patientsreceivingradiotherapy do so withpalliativeintent[1–3],managingbothlocalprimarytumour effectsaswellasthesequelaeofmetastaticdisease.Increasingly, palliativeregimensarealsodesignedtoachievelong term con-trolandimprovesurvival,inapopulationcohortinwhichdisease stage,comorbidities,performancestatusandpatientchoicemay precluderadicaltherapy.Thishasbeenfacilitatedbythe introduc-tionofradiationtechniquessuchashighdoseratebrachytherapy (insertionofradioactivesourcesdirectlyintothetumour)in addi-tiontonewmethodsofdeliveringexternalbeamradiotherapysuch asintensitymodulatedradiotherapy(IMRT)andstereotacticbody radiotherapy(SBRT).
Thisreviewwillexploretheevolutionofpalliativeradiotherapy
inthemanagementofcancer,includingthedevelopmentofnew
radiotherapydoseschedulesaimedatimprovinglongtermcontrol andsurvival,andtheintegrationofnewradiationtechnologies.We willalsohighlightpolicyimplicationsofthevariationinpatterns ofpalliativeradiotherapydeliveryandthefactorsthatinfluence this:practitionerautonomy,radiotherapy access,thepaucity of
evidencebasedmanagementguidelines,andthereimbursement
policyofdifferenthealthsystems.
2. Whatguidesthedeliveryofpalliativeradiotherapy?
Thecornerstoneofpalliativeradiotherapyistoachieve
symp-tomcontrolfromtheeffectsofthecancer.Symptomsamenable
totreatmentinclude:pain,bleeding,neurologicaldysfunctionand luminalobstruction.Patientsmayreceivepalliativeradiotherapyat diagnosis,relapseoratseveralpointsduringtheirdiseasecourse. Palliativeradiotherapycontinuestoevolveanditisimportantto definewherethepatientliesontheirdiseasepathway:patients withnewlydiagnosedlocallyadvancedoroligometastaticcancer mayhavedifferentprioritiesandclinicalaimstothosenearingthe endoflife.
2.1. Locallyadvanceddisease
Inpatientswithsymptomaticlocallyadvancedcancer,not treat-ableradically,theaimsaretoimprovequalityoflife,delaylocal progression and possibly improve overall survival. Little work existslookingatoptimumradiotherapyschedulesandasaresult thosewiththebestperformancestatusandlongestlife-expectancy tendtobeofferedlongerschedulesofradiotherapybasedon indi-vidualclinician experience.In contrast,lowerdoseregimens of shorterdurationaredeliveredtothosewithapoorperformance statuswiththeaimofrapidameliorationofsymptoms.
Theuseofcomplextechniquesandtheactualdosedelivered willalsobeinfluencedbythesiteandvolumeofdisease(e.g. prox-imitytosensitivestructuressuchasthespinalcord,opticchiasm andsmallbowel).Forinstancethespinalcordhasadosethreshold abovewhichtheriskofsubsequentmyelopathyincreases signifi-cantly[4].Assuchhighdosepalliativetherapymayinvolvegreater utilisationofmorecomplexplanningtechniquessuchasIMRT(a techniquethatallowsthehighdoseregiontobetightlyconformed totheshapeofthetarget,minimisingdamagetoadjacentnormal tissue)[5].
Someevidence based schedules do exist to guide palliative radiotherapydeliveryforlocallyadvanceddiseasewithgood
per-formance status. In non-small cell lung cancer a meta-analysis revealednosignificantdifferenceinsymptomcontrolforpatients withdifferentradiotherapyschedulesrangingfromasingle
frac-tion to 6 weeks of treatment.However there may be a small
survival benefit for good performance status patients receiving higherdoses/longercoursesofradiotherapy(atleast35Gyin10 fractionsover2weeks),butattheexpenseofslightlyincreased toxicity[6].
Glioblastomas of the central nervous system are incurable
tumours. However, for good performance status patients a
60Gyfractionated scheduleis recommended withconcomitant
chemotherapytoimprovesurvival[7].However,forlessfitpatients either30Gyin6fractionsover2weeks,orbestsupportivecare alonearethetreatmentsofchoice[8].
Patientswithlocallyadvancedormetastaticcancersofthehead andneckarealsogivenhigh-dosepalliativeschedules,oftenover 20fractions,forlocalcontrolgivenpotentialissuesfrom uncon-trolledprimarydiseasesuchaspain,bleeding,neuralcompression, dysphagia,andairwaycompression[9].
2.2. Oligometastaticdisease
Theconceptofthe“OligometastaticState”(OS)wasfirst out-linedin1995[10].Itwasproposedthatsometumoursprogress fromalocalisedtoawidelydisseminatedstate,viaastageof lim-itedmetastaticdisease.TheOScanalsobe“induced”withsystemic therapy(i.e.lowvolumeresidualmacroscopicdisease),orariseat relapse.Palliativesystemictherapyhastraditionallybeenthe treat-mentofchoiceforallmetastaticsolidtumours,althoughevidence hasbeenaccumulatingfortheuseoffocaltherapytotargetmore limiteddisease.Theuseoffocalradiotherapyhasfollowedonfrom promisingresultsfromsurgicalmetastasectomyforlungandliver metastases[11,12].
Comparedtosurgery,radiotherapyhastheadvantageofbeing aminimallyinvasiveout-patienttechnique,requiringno
anaes-thetic, and which can target multiple lesions simultaneously,
encompassingadjacentsubclinicaldisease.Thishasthepotential tochangethenaturalhistoryofthedisease,achievingimproved localcontrol,delayedcancerprogression,andevencureinselected cases.Howeverwhilstrandomisedtrialevidenceisawaited,there remainslimitedclinicalevidencetoguidepatientselection,as evi-dencedbysignificantoff-labeluseintheUnitedStates(Institute ofMedicine2016).Thoselikelytoderivebenefitincludepatients withlowvolumemetastaticdisease(1–3metastases,small vol-ume),alongdiseasefreeintervalfromtreatmentoftheprimary (>6months),andfavourablehistology(e.g.breastcancer)[13].
StereotacticRadiotherapy(SBRT)israpidlybecomingthe tech-nologyofchoicefortreatingoligometastaticdisease.Stereotactic describesthepreciseirradiationofanimage-definedlesionusing a highradiationdosedelivered ina small numberof fractions. WhenappliedoutsidethebrainitisreferredtoasSABR (Stereo-tacticAblativeBodyRadiotherapy)[14].Thistechniquerequires complexmethodsofpatientimmobilisation,targetlocalisationand treatmentplanning.Itisthereforemoreresourceintensivethan conventional2Doreven3Dconformalradiotherapy[15,16]. Spe-cialisedsystemsdoexistfordeliveringstereotacticradiotherapy (e.g.Cyberknife®,andGammaknife®)howeveritisalsopossible todeliversuchtreatmentsonamodernlinearaccelerator[17].
For brain metastases a number of treatment options exist
tar-getedagents,bestsupportivecareandcombinations.Apatientwith afavourableprognosis,goodperformancestatus,andalesionless than4cmindiametermaybeofferedsurgicalresectionor stereo-tacticradiotherapy,withorwithoutwholebrainradiotherapy[18]. RTOG9508demonstratedthattheadditionofastereotactic radio-therapyboosttoconventionalwholebrainradiotherapyimproves both overallsurvival and performance status at6 months[19]. Howeverfornon-stereotactic“wholebrain”radiotherapy,no dif-ferencehasbeendemonstratedbetween5fractionand20fraction regimensinterms ofoverallsurvival orlocalcontrol[20],with aroundtwothirdsofpatientsderivingsomeneurologicalbenefit.
SABRforlungmetastaseshasreported2-yearlocalcontrolrates rangingfrom70to90%,withonlyminortoxicity(<5%grade3 tox-icity,upto10%pneumonitis)[21–25].Forlivermetastases,SABR datarevealsgoodlocalcontrolratesintheregionof80%at2-years, althoughthemajorityofpatientsfailsystemically[26].
Thekeytomovingforwardistoparticipateinrandomised con-trolledstudiestodeterminethebenefitandcosteffectivenessof
SABR.TheSABR-COMETstudyis anexample,lookingatoverall
survivalandqualityoflifeinpatientswith1–5metastaticlesions
randomisedtostandardofcaretreatmentwithorwithoutSABR
[27].
2.3. Symptomcontrol
Palliativeradiotherapy is frequently usedfor symptom con-trol,ofteninpatientsapproachingtheendoflife.Inthissituation itisimportanttoconsiderthedelayinefficacywhendelivering
radiotherapy,and thepossibleshort-termflarein symptomsin
thecontext of thepatient’s anticipated life expectancy.Factors
that suggesta lack of benefit fromradiotherapy include
immi-nentdeath,multipleprogressivesymptoms,anticipatedsideeffects beinggreaterthanthesymptombeingpalliated,andpoortolerance oftherequiredjourneysfortreatment.Cliniciansmayalsoadvise againstre-treatmentbasedonexceedingthesafenormal tissue toleranceconstraints.Depending onthehealthcaremodelbeing considered,cost,availabilityandcommunicationbetweenthe
pal-liativecareteamand theradiotherapy teammayalsoinfluence
referralpatterns[28].
Hypofractionatedregimens, deliveringa low total dose[29], aretypicallychosenwiththeaimofachievingrapidamelioration ofsymptoms atprimaryormetastatic sites[9,30–32].Theyare generallywelltolerated,eveninpatientswithpoorperformance status,and areconvenientandcost effective.However,there is markedvariationintheiruseinternationally[33].IntheUKthe RoyalCollege of Radiologists haspublishedguidelines on
opti-maldosefractionation schedulesaccordingtotumourtype and
treatmentintent[9].Howevertheserecommendationsarelargely basedonsinglecentreretrospectivecaseseriesgiventhepaucity ofrandomisedcontroltrialsevidence[34].However,somenotable exceptionsexist.
For lung cancer short course regimens (17Gy in 2#) have
demonstratedequivalentefficacy(symptomcontrolandsurvival) tolongerregimensinpatientswithpoorperformancestatus[35].In oesophagealcancerdosefractionationregimesconsideredinclude 30Gyin10dailyfractions,27Gyin6fractions(treatingthreetimes aweek)and20Gyin5dailyfractions[36,37].TheadditionofHigh
Dose Rate brachytherapyhasbeenfound toimprove symptom
resolutionandpotentiallyprolongsurvivalbyachievingdose esca-lation[37].Inbladdercancer,afractionationscheduleof21Gyin 3fractionsdeliveredonalternateweekdaysoveroneweekis cur-rentlyadvocatedbasedonaMRCtrial,whichfoundnodifferences inoutcomeswhencomparedwith35Gyin10fractions[38].
In cervical cancerone study demonstrated theeffectiveness (symptomcontrol)ofdelivering“quadshots”whichinvolve treat-ingthepatienttwiceadayfortwodaystoatotaldoseof14–16Gy
[39,40].Asimilarstrategyhasbeenadvocatedforheadandneck cancerbasedontheresultsofaphaseIIstudy[41].
Currentinternationalevidencesuggeststhatpalliative radio-therapymaybebeingdeliveredinappropriately.AnumberofUS studieshaveshownthatupto50%ofpatientsdiebefore comple-tionoftheprescribedradiotherapyschedule[42–44].Furthermore asignificantproportionofpatientsreceivingradiotherapywithin thelast30daysoflifehadmulti-fractiontreatment.Suchpractice inthelastweeksoflifemaydelaypalliativecareinput,endoflife planningandappropriatesymptomaticmanagement[28].
Ithasbeensuggestedthatprognosticmodelscouldguideboth
doctors and patients when making decisions about
radiother-apy near end-of-life. Doctors tend to be over-optimistic when
predictingthelife expectancyof patientsreferred forpalliative radiotherapy [45–47]andpatientswhoare overlyoptimisticin their understanding of theircancer are likely to receive more aggressivetreatment[48].Giventhatasignificantproportionofthe totalcostofcancertreatmentisaccruedinthelast30daysoflife withlittleifanyimpactonoutcome[49],itisclearthat evidence-basedguidelinesareessentialforoptimumpatientmanagement. Modelshavebeenproposed,butareyettobeadoptedinto rou-tinepracticeduetolackofphysicianengagementanddeficitsin training.Itcouldbearguedthatthemodelsaretoosimplisticand thatmoreprofoundchangescouldbeachievedbyculturalchanges inhowpalliativecareisapproached,andchangingfinancial incen-tivestoencourageappropriatepracticesofcare,aswillbediscussed
[50].
Whilstevidencebasedguidelineshavefocussedondoseand fractionation,theactualdecisiontoreferforradiotherapyor initi-atetreatmentisatthediscretionoftheindividualpractitioner.Itis thereforebasedlargelyontheirownpersonalexperienceand inter-pretationofthelikelybenefitandappropriatenessoftreatment.
3. Policyissuesinpalliativeradiationoncology
3.1. Variationinaccesstopalliativeradiotherapy
Evidencefromepidemiologicalstudieshasdemonstratedthat notallpatientswhomaybenefitfrompalliativeradiotherapyare receivingit.Ananalysisofthenationalradiotherapydatasetfor
Englandbetween2009and2011demonstrated atrendtowards
less useof bothradicalandpalliative radiotherapyinthemore socioeconomicallydeprivedgroups[1].
IntheUSastudyusingdatafromtheSEERdatabase (Surveil-lance,Epidemiology,and EndResults-Medicarelinkeddatabase) identified51,610patientswithstageIVlung,prostate,breastor colorectalcancerbetween2000and2007[51].Theresults demon-stratedthatblackmenwithprostatecancerandlungcancerwere 20%and28%lesslikelyrespectivelytoreceivepalliative
radiother-apycomparedtowhitemen.
AnotherSEERstudyanalysingratesofpalliativeradiotherapy usein63,221patientsdemonstratedonmultivariateanalysisthat comparedtopatientsaged66–69,thoseaged70–74,75–79,80–84, andover85hada7%,15%,25%,and44%decreasedrateofreceiving palliativeradiation,respectively(allp<0.0001)[52].Otherfactors associatedwithlowerpalliativeradiotherapyincludedincreased traveltimetoaradiotherapycentre,diagnosisatanon-specialist cancercentreandnursinghomeresidence[2,53].
Althoughepidemiologicalstudieshavebeenvaluablein elicit-ingthefactorsassociatedwithdifferentialutilisationinpalliative radiotherapythisdataislimitedasitcannotaccountfordifferences indiseasebiology,patientpresentation,physicianpracticeand pat-terns ofprogression,which mayallexplain apatient’s decision toforgoradiotherapy.Possiblereasonsmaythereforebegleaned froman analysisofthewider literature.For instance weknow
24 A.Aggarwal,S.Hughes/JournalofCancerPolicy10(2016)21–29
thattherelative survival of elderlypatientswithcanceris
sig-nificantlyworsecompared toyoungerpersons.Thereasonsare
multifactorialand include, advanced stageat diagnosis, comor-bidities,andbarrierstoaccessingcancerservices[54–56].There isstrongevidencethatelderlycancerpatientsaremorelikelytobe under-treated(evenafteradjustmentforperformancestatusand othercase mixcriteria)withmanynotconsideredfortherapies suchaschemotherapyorsurgery[57,58].Trainingand appropri-ateutilisationofgeriatricscreeningtoolsmayimproveaccessof elderlypatientstopalliativeradiotherapy[59].
Aswellasforpalliativeradiotherapy,ethnicdifferenceshave beennotedinutilisationofadvancedradiationtechnologiesand systemictherapies[60,61].Potentialfactorsinclude communica-tion difficulties(language/cultural), and differences in inherent tumourbiology[51,62].Raceaswithagemayalsoactasaproxy forsocioeconomicstatus,whichaffecttheabilitytoaccessandpay forcare[63].
Geographical location is also an important factor with sev-eralstudiesdemonstratingacorrelationbetweentraveltimeand
uptake of cancer treatment(surgery, radiotherapy,
chemother-apy)inboth theradicaland palliativesetting[64,65].Thisis in partattributabletotheincreasingcentralisationofcancerservices, howeverthishashadtheresultanteffectofincreasingtraveltimes forpatientsandmayinfactexacerbateinequitiesinaccessand survivaloutcomes[66–68].
Differentialaccesstopalliativeradiotherapymayonlybe over-comethrougheducationofpractitionersbothinthehospitaland communitysetting.Thereisevidencedemonstratingthepositive effect of primary care physicianeducation onreferral patterns forpalliativeradiotherapy[69].Patientsalsoneedtobeeducated specificallyaboutthepossiblesequelaeofmetastaticdiseaseand indicationsforself-referraltoaspecialist
Alackofradiationoncologyengagementwithpalliativecare practicehasbeenidentifiedinaUSstudy.Reasonsincludedlimited
financialreimbursement, emotional burden of care,insufficient
trainingandknowledgeandthereluctancetoprovidesharedcare
[70].Theonusisontheprofessionalbodiestoinitiateachangein culturetoaddresstheseattitudes.
3.2. Reimbursementpolicyanduseofpalliativeradiotherapy
Goalsofpalliativeradiationtherapyshouldbethatthe treat-mentiseffective(palliatingsymptomsandimprovingqualityof life),overalltreatmenttimeshouldbeshort,convenienceforthe
patientmaximisedandcostsminimised[71].Howevera review
offractionationschedulesinternationallyfor avarietyof pallia-tiveindicationssuggeststhatwearenotadheringtothesecore principles.Aprescientexampleisthecaseofuncomplicatedbone metastases.
Trial data has confirmed the equivalence of single fraction andmultiplefractionsofradiotherapy inpalliatingpain related
to uncomplicated bone metastases [72,73]. Furthermore single
fractiontherapyhasbeenshowntobemorecosteffectiveeven whenaccountingforthehigherratesofre-irradiationcompared tomulti-fractiontreatment[74].Thispromptedthedevelopment ofconsensusguidelinesfromtheAmericanSocietyforRadiation
Oncology(ASTRO) recommendingsinglefractiontherapyasthe
preferredtreatmentforuncomplicatedbonemetastasesandthat nomorethan10fractionsshouldbedelivered[30].Despitethis, multi-fractiontreatmentremainsthemostpopularschedule inter-nationally[33,75,76].
OnestudyintheUSlookingatfractionationschedulesformen withprostatecancertreatedforbonemetastasesfoundthat3.3% onlyreceivedsinglefractiontreatment,with50%receivinggreater than10fractions[77].Keydifferenceswerenotedbetween aca-demicandbothprivateandcommunityfacilitieswithradiation
oncologistsworkingatthelattersignificantlymorelikelytodeliver multi-fractiontreatment[76].
Further analysis demonstrates clear regional differences
betweenpracticesofcareintheUScomparedtoEurope,Canadaand Australia[75].IntheFairchildstudyrespondentstrainedinpartsof CanadaorEuropeweremorethantwiceaslikelytousesingle frac-tionregimens,whereasrespondentstrainedintheUSAwereupto 80%lesslikelytouseasinglefraction[33,78].Unfortunatelysuch variationshaveadirectimpactonthepatientintermsofqualityof lifeandconvenienceoftreatment.Equallyfromahealthpolicy per-spectiveinefficientpracticesofcarearestillcontinuingwhichaffect
boththeworkloadfacedbyradiotherapydepartmentsand
con-tributetoescalatingcostsoftreatmentforthehealthcaresystem
[79].
Oneofthekeyfactorsunderpinningthisvariationisthemodelof reimbursementwithinindividualcountries.Lievenshaspreviously
[80]reviewedtheimpactofreimbursementmodelsacrossWestern Europeonfractionationschedulesutilisedforpalliative radiother-apy.Acleardifferentialwasseenbetweencountriesemployinga feeforservicemodelwhereeachcomponentofradiationtherapy deliveryisreimbursed(simulation,planning,treatmentdelivery) e.g.GermanyandSwitzerland,andthoseemployingaglobal
bud-getorcasebasedsystemofreimbursementwherebydepartments
arereimbursedperpatientorafulltreatmentcoursee.g.Spainand TheNetherlands.
Afeeforservicemodelwasassociatedwithanincreased like-lihood of using multi-fractionschedules for palliation. Thereis thereforeadisincentiveforemployingefficientpracticesofcare. Ofnote,thegreateruseofsinglefractionschedulesinUSacademic institutionsmayrelatetothefactthatmanyphysiciansaresalaried intheseinstitutionsandgainnofinancialbenefitfromdelivering morefractions.Moreclearlyneedstobedoneespeciallygiventhat upto60%ofvariationincostsofradiotherapyintheUSrelateto geography,practicetypeandindividualradiationtherapyprovider
[81].
Afurtherconcernistheinterfacebetweenhospicecareand radi-ationoncology.AsurveyfromtheUSintheearly2000’sfoundthat lessthan1%ofhospicepatientsarereferredforradiotherapy[82]. Reasonsinclude,theinconvenienceofrepeatedjourneys, educa-tiondeficiencies,life-expectancyandmostimportantlyexpense. Thishasbeenexacerbatedbythepredominantutilisationof
multi-fractionschedules which cancost upward of $5000 US dollars
todeliver,and candissuadereferralduetotheirinconvenience
[33,77].Furthermorethesecostsare chargeddirect tothe
hos-picewhichhasanaveragedailyreimbursementrateof$150US
dollars.Astudyevaluatingtheimpactofarapidaccess radiother-apyclinicofferingaffordableradiotherapyandminimisingwaiting timesanddurationoftreatmentdemonstratedincreasedreferral activityfromhospices[83].
In reality country-specificreimbursement modelscannot be
whollycategorisedandusuallyemploymorethanonemodel.For
instanceintheUK,there hasbeena movetoareimbursement
perattendanceorproceduremodelwherebytreatmentsdelivered arereimbursedaccordingtoafixedtariffbasedonreferencecosts thataredefinednationally[84].Whilstthismaystimulateuseof longerfractionationschedules,adriverforcontinuedefficiencyis theneedtomaintaincapacityandreducewaitinglists[85,86]to ensurepalliativepatientsaretreatedwithin14days.Inaddition patientsrequiringthetreatmentoftwositesonthesamedayare stillreimbursedasasingleattendance.
3.3. Reimbursementpolicyintheeraoftechnologicalevolution
Thecostsofdeliveringradiationtherapyinboththeradicaland palliativesettingcontinuetoincrease[87].Whilstpalliative treat-mentcanbedeliveredquickly,cost-effectivelyandwithlowratesof
toxicityusingconventional2Dradiotherapy(utilisingx-ray local-isationandsimplebeamarrangements),culturallywearemoving touseofhighdosepalliationwithmoreadvancedtechnology.
Thishassignificantfinancialimplications.SBRTforbone metas-tasescostsuptotentimesmorepertreatment[88]whencompared withsinglefractiontherapydeliveredconventionallyand isnot cost-effective. Howeverthere is an increasing argumentto use thismodalitywhenlifeexpectancyisestimatedtobebeyond12 months,forre-treatmentwherefieldsarelikelytooverlap sensi-tivestructuresorindifficulttotreatareassuchaspelvicrecurrence andpara-aorticdisease[89–91].Likewiseforthemanagementof brainmetastases,hippocampalsparingwholebrainradiotherapy usingIMRTmayreducethelatesequelaeoftreatment,inparticular neurocognitivedecline[92].Howeverinmostinstancesthe dosi-metricadvantagesofnewertechnologiesarenotapplicableinthe palliativecaresetting.
Carefulpatientselectionisimperativeandweneedtoavoida cultureofmerelyusingnewtechnologybasedontheirintuitive
benefitsintheabsenceofobjectivedatafromrandomised
con-troltrials.Equallyreimbursementpoliciesshouldberealignedto dis-incentiviseutilisationofnon-evidencebasedmodalitiesordose fractionationregimes(e.g.throughtheintroductionofvaluebased usercharges[16]).
The provision of evidence based guidelines, use of health
technologyassessmentforevaluatingnewhighcostradiation tech-niques,andstrongreimbursementpolicyisthereforeessentialto encouragerationalutilisationof newtechnologiesand promote efficientpracticesofcare[93].“Coveragewithevidence develop-ment”hasbeenconsideredtobeonemechanismofensuringaccess
tonewtechnologieswhich havecapacity toimproveoutcomes
whilstcollectingdatatoinformtheevidencebaseaboutitsutility inarealworldpopulation[94].Thisisthepremiseforthecurrent assessmentofSABRintheNHS[95].
3.4. Educationandmultidisciplinarymanagementinpalliative oncology
Appropriatetrainingandeducationisalsoakeyaspectof ensur-ingimplementationofevidencebasedguidelines.Arecentsurvey ofRadiationOncologyresidentsacrosstheUSnotedkey deficien-ciesinpalliativecarecompetencies(e.g.symptommanagement, carecoordination)andmostviewedpalliativeradiationoncology trainingasinadequateandwishedforgreatertrainingintheseareas
[96].
Integrating palliative care into radiation oncology has been attemptedthroughthecreationofrapidaccesspalliative radio-therapyclinics(RapidresponseRadiotherapyprogram)whichwere firstdevelopedinCanada[97].Theclinicshavereducedwaiting timesforradiotherapyandensuredmultidisciplinaryassessment andmanagementofcomplexpatients,focussingonqualityoflife
andsymptomcontrol.Thismodelcontinuestoevolveandmany
examplesexistacrossNorthAmerica[98].
In theUS, althoughsporadic in theirimplementation, these
integrated palliative care modelshave helped to improve both
radiotherapyaccessandtheproportionofpatientstreated with singlefractionradiotherapyaccordingtoevidencebased guide-lines[99].Theyhavealsoreducedthedifferentialpracticepatterns
betweenacademiccentresandcommunitycentres.Suchmodels
provideaforumforknowledgetransferandtrainingofthewider multidisciplinaryteamaswellashelpingtosupportpatientsand theirfamilies.
3.5. Trialendpointsforpalliativeradiotherapy
Trialswithinpalliativeradiationoncologyhavefocussedonthe useofdifferingdosefractionationschedules,combinedmodality
therapies(e.g.chemoradiation),newradiationdeliverytechniques
and defining newindications for treatment(e.g. asymptomatic
oligometastases).Thelistofpotentialconfoundingfactorsisvast
given the heterogeneity of disease. From the patient
perspec-tive,differencesintheextentoffunctionalimpairment,impacton qualityoflife,burdenofmetastaticdisease,performancestatus, associatedcomorbiditiesandextentofprevioustherapymake eval-uationoftheefficacyofnewradiotherapytechniquesandregimes challenging.
Asaresulttheevidencebasehaslargelyemanatedfrom sin-glecentreretrospectivecaseserieswhicharelimitedduetopoor accountingforcasemixvariables(age,comorbidity,performance status)andfrequentlyappeartohave betteroutcomesthanthe
benchmarkfindingsfromstudiesinbroaderunselected,
popula-tions. It is thereforeimperative that selection biasis overcome byundertakingrandomisedtrialsorwell-constructedprospective studiesthatensureadequatecollectionofcasemixvariablesand whichusevalidatedend points[100].Whilstthereareinherent challengesindesigningradiotherapytrialsgiventherapidsoftware andhardwaredevelopmentsandthevariationinpracticesofcare betweencentres[101],manyoftheseissuesdonotapplyinthe palliativesetting.
Anareaofcontentionishow besttodefineappropriatetrial end-pointsinpalliativeradiationoncology.Aswithsystemic ther-apies,thegoalpostsareincreasinglymoving,withend-pointssuch asoverallsurvival(OS)andprogressionfreesurvival(PFS) increas-inglybeingutilised[102].Thisdespitenumerousqualitativestudies involvingpatientswithadvancedmalignancydemonstratingthat improvedqualityoflifeismostimportantgoaloftherapy[103,104]. Partoftheissueisthatthetermpalliativefromaradiation oncol-ogyresearchperspectivehasbecomeverybroadandessentially encompassespatientswithlifeexpectanciesintheregionofweeks tothosewhomaysurviveinexcessof5years.Thisconfusionis makingtheselectionofendpointsfortrialsmuchharderandthe
undertakingof systematicreviewsmore methodologically
chal-lenging.Ananalysisoftrialscomparingsinglefractionandmultiple fractiontreatmentsforbonemetastases[105]foundthatamajor reasonforthedifferentconclusionsconcerningtheeffectiveness ofalternativefractionationscheduleswasduetothevariabilityin endpointsusedinthestudies.Asaresultconsensusguidelines wereproducedinordertoformulatea frameworkforpalliative radiotherapytrialsinpatientswithbonemetastases[106]. Simi-larguidelinesforalternativediseasesitesareimperativetoenable
meaningfulcomparisonbetweentrialsandhelpdefinenew
stan-dardsofcare.
Progresshasbeenmadeinthedevelopmentofqualityoflife assessmenttoolsthatarenotonlycancerspecificbutaredirected toindividualswithadvanceddiseasesuchastheEORTCQLQ-C30, theQLQ-C15-PALscales[107].Abonemetastasisspecificqualityof lifetoolhasalsobeendeveloped−EORTCQLQ-BM22[108]. How-everdespitethisprogress,frequentcriticismsofpatientreported outcomesmeasures(PROMS)includeboththeirlackofspecificity forradiotherapyrelatedtreatmenteffectsandtheir inadaptabil-itywhenaccountingforrapidchangesintechnology,thusmaking comparisondifficultwithhistoricalstudies[109].Somestudiesuse anumberofdifferentquestionnairestogetthebalancebetween specificityandgeneralisability[110]howeveranumberof ques-tionsmayoverlapresultingindifferencesinPROMSresultsfrom thesamestudy[111].
MichaelPorterhaswritteneloquentlyabouttheneedforvalue basedend-pointswhichgobeyondtraditionalmethodsof assess-ment includingOS, PFS and quality of life[112]. Consideration shouldthereforebegiventoassessingalternativeoutcomes fol-lowingpalliativeradiotherapysuchas(1)frequencyandduration ofinpatientadmission;(2)frequencyofout-of-hourspalliativecare andGPconsultations;(3)returntowork;(4)durationoffunctional
26 A.Aggarwal,S.Hughes/JournalofCancerPolicy10(2016)21–29
independence.Theseend-pointsmayhelptobetterevaluatethe utilityofpalliativeradiotherapy.
3.6. Evidenceframeworktoguideutilisationofappropriate palliativemodality
Itisimportantthatevidencebasedguidelinesenableclinicians toselecttheappropriatepalliativestrategy(e.g.,systemic treat-ment,radiotherapy,bestsupportivecare)formanagingadvanced disease.For example a recent meta-analysis reviewed all trials comparingtheuseofEGFRtyrosinekinaseinhibitorswithcranial irradiationinpatientswithbrainmetastasessecondary toEGFR mutantnon-smallcelllungcancer[113].Asdiscussedthisis chal-lengingespeciallyintermsofdefiningappropriatetrialend-points andselectingpatientcohortsforcomparison.Howeversuch com-parisons arenecessary given thepotential role of radiotherapy inmanagingpatientswitholigometastaseswhopreviouslywould havebeenreferredforsystemictherapy.Iffoundtobeofsimilar efficacy,radiotherapymaybeconsideredtobeadvantageousgiven thatapartfromfatigue,itssystemiceffectsareminimalandthat treatmentdurationismuchshorter[29].Similarcomparisonsneed tobeperformedinotherindicationssuchaspalliationof dyspha-giafromadvancedoesophagealcancer,whichmaybeamenableto treatmentwithexternalbeamradiotherapy,chemotherapy, endo-scopicproceduresandHDRBrachytherapy.
3.7. Thevalueofauditindefiningpracticeofcare
IntheUK,currentlyalldeathswithin30daysof chemother-apyandsurgeryareauditedandsubjecttoretrospectivecasenote review[114].Asimilarsystemhasnotasyetbeenemployedfor radiotherapybuthasbeenrecommendedasaclinicalindicatorof avoidanceofharminradiotherapy.Therearecaveatsinusingsuch indicators.Forinstanceitmaybeimpracticalgiventhedifficulty inassessinglifeexpectancy.Furthermoretheburdenoftreatment withasinglefractionofradiotherapygiventhepotential pallia-tivebenefitsisminimal.Howeverauditing30-daymortalitydoes provideinsightsintopatternsofcarewhichcanguideappropriate utilisationofpalliativeradiotherapy.
AlargesinglecentrestudyintheUKreviewed 30-day mor-talityratesfollowingpalliativeradiotherapyfor14,972palliative episodes,betweenJan2004andApril2011andfound30-day mor-tality rates of approximately 12.3% [115]. Mortality rates were lowerinthosereceivingmulti-fractiontreatmentssuggestingthat caseselectionwaslargelyappropriate.Anotherinteresting find-ingwasthehigherratesof30-daymortalityforspecifictumour typesinpatientsreceivingradiotherapyforbrainmetastases(e.g.,
melanomaandcarcinomaofunknownprimary).Furtherstudies
arethereforeessentialtoguideappropriatepatientselectionfor palliativeradiotherapyandoptimiseendoflifecare.Itwillalsohelp tosupportthedevelopmentoftrialsrandomisingpatientsbetween bestsupportivecareandradiotherapy.
Itisalsoimperativethattumourspecificregistriesandnational auditsofprocessesandoutcomesofcancercare[116]aresetupin ordertocollectpopulationbaseddatawhichcanbebenchmarked againstbestpracticetoensurethatinequitiesinaccessand varia-tionsinpracticearehighlightedandsubsequentlyaddressed[117]. Theyalsohelptodefinenewstandardsofcare,especiallywhere limitedrandomisedtrialevidenceexiststosupporttheuseofone technologyoveranother.
4. Conclusions
Radiotherapyisanestablishedandeffectivetreatment modal-ityinthepalliationofsymptomsassociatedwithadvancedcancer.
Box1Keyrecommendationstoaddresscurrentpolicy issuesinpalliativeradiotherapy
•Professionalbodiestocontinuetodefinestandardsofcarein palliativeradiotherapy,specificallydosefractionation sched-ules.
•Encouragegreateruseofhealthtechnologyassessment pro-cessesfortheevaluationofnewradiationtechniquesinthe palliativesetting.
•Reconfigure reimbursement policy to incentivise cost-effectivepalliativeradiotherapypractices.
•Useofepidemiologicaldatatoenhanceourunderstanding oftheoutcomesofpatientstreatedwithpalliativeintentto ensurebetterselectionofpatientstoavoidmortalityduring treatment.
•Validateandintegrateprognosticmodelsintoclinical prac-ticetoguideutilisationofradiotherapytowardstheendof life.
•Consensusguidelines tobedeveloped ontrialend-points indifferenttumourtypestofacilitatecomparisonbetween outcomesfrompalliativeradiotherapytrials.
•Development of specialist palliative caremultidisciplinary teamstoensurethatsuitablepatientsgetrapidaccessto all appropriate treatment modalities, encourage evidence basedpracticesofcare,andimprovetrainingandeducation ofallteammembersincludingjuniorstaff.
Howeveritsrolecontinuestoevolveinlinewithadvancesin radia-tiontechnology.Theevidencebaseremainsinitsinfancyandmuch moreneedstobedonetodefinestandardsofcareinbothhighand lowdosepalliation.Thelattercontinuestobethemainindication ofradiotherapyinadvanceddisease.
Althoughclinicalacumenisavaluableresource,itsindividuality hasthepotentialtoresultininequalitiesincare.Multidisciplinary
teamworking,anddiscussionofpatientmanagementincomplex
caseshasthepotentialtominimisevariationsindecisionmaking withrespecttotheutilisationofradiotherapy.Inaddition,guidance isalsorequiredforthewidermultidisciplinaryteamregardingthe utilityofradiotherapyandbenefitsofatimelyreferral.
Giventheheterogeneityofinternationalpractice, reimburse-mentpolicyneedstoalignwiththeneedsofthepatientasmany ofthecurrentfractionationschedulesusedforroutineindications arebothinefficientandaredeliveredatgreaterinconvenienceto thepatient.Likewisegiventhecomplexityofmanagingadvanced disease,trainingandeducationofallmembersofboththeoncology andpalliativecareteamarenecessaryinordertoensure radiother-apyisinstitutedwithintheappropriatetimeframeand delivers outcomesinkeeping withpatient’swishes.Thecreationof spe-cialistpalliativeradiotherapymultidisciplinaryteamswillfacilitate thisandimproveaccesstoradiotherapyservices.
Greaterresearchprioritisationneedstobeaffordedto devel-opinghigh-valuefractionationschedulesforthemanagementof advanceddiseasethatareabletopalliatesymptomsrapidly, min-imisingtoxicity andmaximisingconveniencetothepatients. In thefuturethismaybeachievedthroughmulti-modalitytherapyor useofnewradiationtechniquesbuttrialevidenceideallyneeds toinform this. Currently much of theevidence baseis derived fromsinglecentreretrospectivecaseserieswherecomparisonis oftennotpossibleduetotheuseofnon-standardisedendpoints. Giventheinherentchallengesofdesigningrandomisedcontrol tri-alsinthiscohort,coveragewithevidencedevelopment,ifcorrectly implementedusingstandardisedend-pointsandrigorous collec-tionofcase-mixvariables,offersapotentialalternative.
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