Role of modern radiation therapy in early stage Hodgkin's lymphoma: A young radiation oncologists’ perspective

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j ourna l h o me p a g e :h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / r p o r

Review

Role

of

modern

radiation

therapy

in

early

stage

Hodgkin’s

lymphoma:

A

young

radiation

oncologists’

perspective

Andrea

Riccardo

Filippi

a,∗

,

Pierfrancesco

Franco

b

,

Patrizia

Ciammella

c

aRadiationOncology,DepartmentofOncology,UniversityofTorino,Torino,Italy

bRadiationOncologyDepartment,TomotherapyUnit,OspedaleRegionale‘U.Parini’,AUSLValled’Aosta,Aosta,Italy cRadiotherapyUnit,AdvancedTechnologiesDepartment,ArcispedaleS.MariaNuovaHospital,IRCCS,ReggioEmilia,Italy

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Articlehistory:

Received22December2011 Receivedinrevisedform 27March2012

Accepted27May2012

Keywords:

Hodgkin’slymphoma Radiotherapy

Combinedmodalitytherapy

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Theroleofradiotherapyiswellestablishedincombinedmodalityprogramsforearlystage Hodgkin’slymphoma,butstilldebatedwithregardstolatetoxicityissues.Modern radio-therapyprescribingattitudesincludelower dosesand smallerfields,together withthe implementationofsophisticatedanddedicateddeliverytechniques.Aimofthisreviewis tobrieflydiscussthecurrentroleofradiotherapyinthisfieldandthepotentialfuture devel-opments.MajortrialsconductedinrecentyearsinearlystageHodgkin’slymphomaare criticallyreviewedanddiscussedwithafocusonradiotherapy-relatedissuesandwithan attentiontocurrenttreatmentoptionsbya“young”radiationoncologists’perspective.

©2012GreaterPolandCancerCentre.PublishedbyElsevierUrban&PartnerSp.zo.o.All rightsreserved.

1.

Background

ForpatientswithHodgkin’slymphoma(HL)inanystage,the primarygoaloftherapyiscure.Inrecentstudies,thesurvival rateinearlystageshasconsistentlybeen90% orhigher.In studieswithlong-termfollow-up,treatment-related compli-cationdeathsexceedthenumber ofcancer-relateddeaths. The frequency of late complications is dependent on the treatmentused.Radiation-relatedcardiacdisease (coronary arterydisease,myocardialinjury,valvulardisease,pericardial fibrosis) and second malignancies (breastand lung cancer) may occur many years after thoracic irradiation and are dependentonradiationdosesandvolumes.Theriskoflate complications afterchemotherapy (cardiac toxicity, second malignacies)appearstobedependentonthetypeofdrugs

Correspondingauthorat:RadiationOncology,DepartmentofOncology,UniversityofTorino,ViaGenova3,10126Torino,Italy.

Tel.:+390116705352.

E-mailaddress:andreariccardo.filippi@unito.it(A.R.Filippi).

prescribed(alkylatingagents,anthracycline,bleomycin)and onthecumulativedose.TreatmentstrategiesinHLchanged thereforedramaticallyduringrecentyears,withcurrent clin-ical protocols focusing, especially on early stage HL, on minimizingtheintensityoftreatmenttoavoidlatepotentially fataltoxiceffects,withouttheriskofloweringoverallsurvival rates.

1.1. RadiotherapyinthecureofHodgkin’slymphoma

For many decades, the optimal and standard treatment forearly stageHLwas extendedfield radiotherapy (EF-RT), totally replaced right now with a combination of short-termchemotherapywithinvolvedfieldradiotherapy(IF-RT). The evolution ofeffective treatments forearly stage HLis best exemplifiedbythesuccessiverandomizedtrialsofthe

1507-1367/$–seefrontmatter©2012GreaterPolandCancerCentre.PublishedbyElsevierUrban&PartnerSp.zo.o.Allrightsreserved.

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German Hodgkin’s Study Group (GHSG), as discussed in a paperbyHansTheodorEichandRolf-PeterMüllerin2007.1 Thefirst protocol dealing witha radiotherapy-related end-point was the HD4 trial, designed in the early eighties (1988–1994).ThemajoraimofHD4wastoshowwhetherthe radiationdosetothenon-involvedlymphaticregionscouldbe reducedwhilemaintainingeffectivetumourcontrol.Thistrial wasconceivedasanefforttowardsafurtherimprovementof resultsobtainedin1962–1984bytheStanfordgroupinearly stageswithradiotherapy,showingcompleteremissionratesof 100%andrecurrencefreesurvivalof80%instagesIA,IIAand IIBwithoutlargemediastinaltumour(excellentresults uncon-firmedbyothergroups).InHD4,patientsinstageIorIIwithout risk factors (largemediastinal mass, extranodal extension, massivespleeninvolvement,>3lymphnodeareas,highESR) wererandomizedbetweenstandardtreatmentconsistingof 40GyEF-radiotherapy(armA)and30GyEF-radiotherapyplus additional10Gy to the IF(armB).Staginglaparotomy was obligatoryin this protocol.The resultsshowed no statisti-callysignificantdifferencesinrecurrentfreesurvival(RFS)and overallsurvival(OS)betweenthetwotreatmentarms,butthe overallrecurrence rateapproached20%,asreportedbythe Stanfordstudies.Duetoaneffectivesalvage therapy (poly-chemotherapy),RFSaftersevenyearswentupto80%andthe overallsurvivalwas93%.2Thepatternofrelapseinthisstudy showedinterestingresults,withthemajorityofrecurrences documentedoutsidehighdoseradiationfields,probablydue toerrorsininitialstagingorinradiotherapyprescription.Due tothecrucialimportanceofgoodqualityradiotherapyinsuch studies,GermanHodgkinStudyGrouppromotedthecreation ofataskforceforradiotherapyqualityassurance,andforall patientsenrolledinthestudyatreatmentplanwasgivenby theradiotherapyreferencecentrebasedonthe documenta-tionofthediseaseextensiononcasereportforms(CRF),and aftercompletionoftheEFradiotherapy,simulationand veri-ficationfilmsofeveryindividualpatientaswellastreatment dataanalysisbyanexpertpanel.Thisretrospectivequality controlstudyshowedthatdeviationsofradiationtreatment portalsandradiationdosesfromprospectivetreatment pre-scriptionswere unfavourableprognosticfactorsforpatients withearly-stageHL.3NextresearchstepofGHSGwasatrial designedtokeeptheapproachoflow-doseEFofHD4while try-ingtoeradicatemicroscopicdiseasewithchemotherapyand improvingRelapse-FreeSurvival.InHD7(1994–1998),patients wererandomizedbetweenradiotherapyalone(30GyEF+10Gy IF)(armA)orupfront2cyclesABVDfollowedbyradiotherapy (30GyEF+10GyIF)(armB)forearlystagesPSIA,IIA,IIB with-outriskfactors.Staginglaparotomywasnotobligatoryand thespleenwasirradiatedwith36Gyinbothtreatmentarms. At7years,therewasnodifferencebetweentreatmentarmsin termsofcompleteresponserate(armA:95%,armB:94%)or OS(armA:92%,armB:94%;P=0.43).However,freedomfrom treatmentfailure(FFTF)wassignificantlydifferentwith67% inarmAand88%inarmB(P≤0.0001).Thiswasmainlydue tosignificantlymorerelapsesafterEF-radiotherapyonly(arm A:22%;armB:3%).4

HD10trial(1998–2002)wasdesignedtoeliminatethe EF approach, including IF only and with the primary aim of reducing acute and long term toxicitieswhilemaintaining optimaltumourcontrol.Thistrialalsoincorporatedresultsof

majorstudiespublishedintheninetiesbyNorth-American, European/French and Italian Groups, focusing on the role of chemotherapy and including the “involved fields” con-cept. All these studies showed a complete equivalence for thebriefchemotherapy+IFvs.EFaloneorchemotherapy+EF approach. As well pointed out by HT Eich and RP Muller, theHD10trialrepresentsaverydecisivestep,since irradia-tionwasperformedasIFradiotherapyinalltreatmentarms. TheHD10isthe firsttrialdesignedtoinvestigate the opti-malintensityofchemotherapyandradiotherapy.Thewhole treatmentstrategyisbaseduponaselectionofpatientswith favourable prognostic factors,in whom reduced treatment intensityshouldofferverygood resultsintermsofdisease controlwhilereducingtoxicity.Therefore,patientsinstagesI orIIwithoutriskfactors(nobulkydisease,lessthan4involved sites,lowESRvalues)wererandomizedinafour-armstudy betweenanIF-radiotherapydoseof30Gyversus20Gyand2 versus4cyclesofABVD.TomakesurethatIF-radiotherapy was performedexactlyaccordingtotheRT-prescriptionsof the protocol, an extensive quality assurance program was performed. Results of HD10 were published in 20105: the 2 chemotherapy regimens did not differ significantly with respecttofreedom fromtreatmentfailure(P=0.39)or over-all survival(P=0.61).At5years,the ratesoffreedomfrom treatment failure were 93.0% (95% confidence interval [CI], 90.5–94.8)withthefour-cycleABVDregimenand91.1%(95% CI,88.3–93.2)withthetwo-cycleregimen.Whentheeffectsof 20-Gyand30-Gydosesofradiationtherapywerecompared, there were alsono significant differencesin freedomfrom treatmentfailureoroverallsurvival(P=0.61).HD10 demon-stratedthattreatmentwithtwocyclesofABVDfollowedby 20Gy of involvedfield radiation therapy is as effective as, andlesstoxic(acutetoxicity)than,fourcyclesofABVD fol-lowedby30Gyofinvolved-fieldradiationtherapy.Aparallel but differentstudy isongoinginearlystagefavourable and unfavourablepatients,designedbyEORTC/GELA/IIL,theH10 trial,comparingatreatmentstrategybasedoninterim(after 2 ABVD cycles) 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)and ontheintroduction ofan inno-vative radiotherapy concept, the so-called“Involved Nodes RadiationTherapy”(INRT).Thistrialisnowclosedandfinal resultswillbeavailableinnextyears.Twomajortrials investi-gatingtheroleofchemotherapyalone(ABVD)werepublished someyearsago,showingthatCTaloneisafeasibleoptionfor patientswithnon-bulkyearly-stageHodgkin’slymphoma.6,7 Anincreasedfreedomfrom progressionwas shownforthe combined-modalityarmswhen comparedwith chemother-apyalone (86%vs.81% and93%vs. 87%,respectively), and sincecurrentrecommendedapproachestowardsrelapseafter primarytherapyincludeautologousstemcelltransplant,the current dilemma facing clinicians is whether all patients shouldbeirradiatedtopreventprogressionin5–6%ofcases or whether it is justified to withhold radiation, knowing thatpatientswithprogressionwillbereferredtohigh-dose chemotherapy.

Forpatientswithunfavourableearlystagedisease presen-tation(bulkydisease,multipleinvolvedsites,highESRvalues), the treatment approachwas similar but results should be evaluated separately;all major trialsinvestigateda combi-nation ofatleast 4chemotherapycycles (however 6cycles

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Table1–TemporalevolutionofradiationtherapyforHodgkin’slymphoma.

RTapproach Years Dose Technique Tools Facilities

EFRT 1960–1990 40–44Gy 2DRT 2Dplanning CobaltUnits;firstLINACs

IFRT 1995topresent 30–36Gy 3DCRT Forwardplanning LINACswithcerrobendblocks Static-IMRT Inverseplanning LINACswithMLC

IFRT-INRT 2008topresent 20–30Gy

3DCRT Forwardplanning LINACswithMLC Static-IMRT Inverseplanning

Arc-therapy Biologicoptimization

Tomotherapy Multimodalityimaging IGRT/dynamicIMRTdedicatedLINACs Dosepainting

IGRT in the majority of treatment arms)+EF or IF radiotherapy

(EORTCH7U,EORTC/GELAH8U,EORTC/GELAH9U),showing thatthe IFapproachissafeand equivalenttoEFand that, globally,theresultsofcombinedmodality therapyare infe-riortothoseinfavourablestages,withFFTFratesintherange of84–94%.Inthissetting,areductionintreatmentintensity didnotdemonstrateanyequivalenceintermsofdisease con-trol.TherecentlypublishedGHSGHD11trial8wasdesignedto specificallyinvestigatethisissue.Withatotalof1395patients included,BEACOPPwasmoreeffectivethanABVDwhen fol-lowedby20GyofIFRT(5-yearFFTFdifference,5.7%;95%CI, 0.1–11.3%),however, therewasno differencebetween BEA-COPPandABVDwhenfollowedby30GyofIFRT(5-yearFFTF difference,1.6%;95%CI,−3.6%to6.9%).Similarresultswere observedfortheradiotherapyquestion:after4cyclesof BEA-COPP,20Gywasnotinferiorto30Gy(5-yearFFTFdifference, −0.8%;95% CI,−5.8%to4.2%),whereas inferiority of20Gy cannotbeexcludedafterfourcyclesofABVD(5-yearFFTF dif-ference,−4.7%;95%CI,−10.3%to0.8%).Atthemoment,in unfavourableearlystageHL,4ABVDfollowedby30GyIF-RT continuestorepresentastandardclinicalapproach(waiting forthe finalresultsofHD17 on2ABVD+2 BEACOPP+IFRT 30Gy).

Table 1 summarizes the time-trend in radiotherapy

changesinHodgkin’slymphomainrecentyears.

1.2. Openissuesandfuturedevelopments

Asbrieflydiscussed,currentlyradiotherapyinearlyfavourable andunfavourablepresentationsisanessentialcomponentof thestandardtreatment,asconfirmedbyarecentstudybythe CochraneCollaborationGroupontheoutcomeofcombined modalitytherapyvs.chemotherapyalone(primaryendpoint overallsurvival).9Thisimportantmessageisincorporatedin therapeuticindicationswithininternationalguidelines(such the ones from NCCN or ESMO) where combined modality treatmentstillrepresentsamainstayoptionasHLtherapeutic strategy.10,11Globallyandindependentlyfromthetreatment approach,the issue oflatetoxicitystill remainscrucial.In almost all trials with long-term follow-up, the number of patientswhodiefromother causesexceedsthenumberof patients dying from lymphoma. Second malignancies and fatalcardiaceventsarethemaincausesofdeathinacohort ofpatientswhopresentlyshowarelapse-freesurvival prob-abilityofapproximately90%.Duetotheestablishedtoxicity ofextendedfieldradiotherapy,especiallyinpatients receiv-ingmediastinalirradiation,severalstudiesweredesignedin

recentyearsinordertodecreasetoxicityeitherbyreducing or avoiding radiotherapy, trying toshow a superior overall survivalrateinchemotherapyonlyarmssecondarytoa reduc-tionofRT-relateddeaths.Anexampleofthisresearchstrategy isthe already citedNCICHD6 trial,designed withtheaim of comparing chemotherapy only(4–6 ABVD cycles) to RT onlyorwith2ABVDcycles (accordingtoriskgroups),with subtotalnodalirradiationof35Gy.ANewEnglandJournalof Medicinespecialissuededicatedtohaematology-related stud-ieswaseditedinDecember2011concurrentlywiththe2011 ASHAnnualMeeting,andthemainpaperofthisissueisthe final reportofthisstudy.12 Resultswere verydisappointing fortheradiotherapyarm.Themedianlengthoffollow-upwas 11.3years.At12years,overallsurvivalratewas94%among those receivingABVD alone,ascomparedwith87%among thosereceivingsubtotalnodalradiationtherapy.Theratesof freedomfromdiseaseprogressionwere87%and92%inthe twogroups,respectively,andtheratesofevent-freesurvival were85%and80%,respectively.Amongthepatientsrandomly assignedtoABVDalone,6diedfromHodgkin’slymphomaor anearlytreatmentcomplicationand6diedfromothercauses; amongthosereceivingradiationtherapy,4deathswererelated toHodgkin’slymphomaorearlytoxiceffectsfromthe treat-mentand20wererelatedtoothercauses.Anobviouscritical point inthistrial isthatthe subtotalnodal radiation ther-apyisnolongeremployedandradiationinducedtoxicityis expectedtobelessrelevantinthefuturewithmodern radio-therapystrategiesand techniques(IF-RT,IN-RT,IMRT,IGRT, CT-PET-driven contouring) employedin recentyears. Com-ments inthe Editorial by DavidJ. Straus13 are focused on thefinaldemonstrationthatABVDonlyisprobablyabetter approach, taking into account that efficient salvage thera-piescancompensatethehigherrelapserateofchemotherapy only.Inthiscomplexscenario,asbrieflyshown,manyother groupstesteddifferentstrategies,basedontoxicityreduction bymeansofradicalmodificationofradiotherapydosesand volumes.Theseapproachesarebasedontheassumptionthat latetoxicitydataonradiationtherapyfrom historicaltrials cannotbefullytranslatedtocurrentprotocols,andprobably itisunrealisticthateverykindofradiationtherapystrategyis harmfulatthesamelevel.Anewradiationoncologyquestion, suchasthepossibilityofafurtherreductionofradiationfields comparedtotheclassicalinvolvedfieldconcept,limiting irra-diationonlytothesinglenodalstationinvolvedbythedisease atdiagnosis(IN-RT)ratherthanthewholeanatomicalregion, is underinvestigation bythealready citedEORTC-GELA-IIL H10trialandbytheongoingGHSGHD17trial,quiterecently

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openedtoaccrual.BelowtheINRTconcept,thetechnological break-troughsinradiationoncologyledtotheemploymentof newtreatmenttechniquessuchasIntensityModulated Radio-therapy(IMRT) alsoin the field ofhemato-oncology.14 The extendedfieldsofthepastlimitedtheradiationtechniqueto simpleparallel-opposedanterior-posteriorfields,butreduced andbetterdefinedradiationvolumesallowfortheutilization ofmore conformal radiation therapy, based on more con-sistentimagingandadvancedradiationdeliverytechniques. Theserecentlyintroducedradiotherapyplanningand deliv-erytechniqueshavealreadydemonstratedbettersparingof theheart,coronaryarteries,lungandbreast.Theachievable dosereductioncanbeprotectivefornormaltissuesforwell knowndose-relatedradiotherapylateeffectssuchasradiation pneumonitis/fibrosisorcoronaryarterydisease,withanopen issueregardingtheimpactonsecondarymalignancyrisk.15,16 AspointedoutbyPaumieret al.in2011,the optimal com-binedmodalityapproachinearlystageHLshouldencompass minimalchemotherapyand subsequentminimal radiother-apywithsimultaneouseffort todecreaselate complication ratewithout jeopardizing clinical outcome results.17 It has beendemonstratedthattheriskofradiation-inducedsecond malignancies(particularlybreastandlungcancer)islinearly dependent ondelivered dose and becomesofa detectable magnitudeat20–30Gy.18BothIMRTtechniqueandINRT con-ceptareabletoreducethevolumeofnormaltissuereceiving highdosesandconsequentlymightreducetheriskofsecond malignanciesdueto‘highdoses’and‘extendedfields’. Histor-ically,theshrinkageofradiationfieldsfromEF-RTtoIF-RThas beenshowntodecreasetheriskofsecondcancers,asreported byDeBruinetal.19Hence,thiseffectmightbepostulatedalso whenevershiftingfromIF-RTtoIN-RTisperformed.However, asamatteroffact,IMRT techniquesincreaselow-radiation dosebathtonormaltissues.Theclinicalimplicationsofthis issueintermsofcarcinogeneticriskaredifficulttoassess,as isthemagnitudeofthiseffect.Somewell-known determinis-ticdose-relatedeffectsofradiotherapy,suchasheartdiseases (mainlycoronaryarteriesdisease,butalsomyocardic dam-ageleadingtolateheartfailure)orhypothyroidism,should bedrasticallyreducedwithlow-dose INRT(eventuallywith IMRTplanningandfurtherreductioninnormaltissues expo-sure);regardingthisissue,apartfromsomeveryinteresting dosimetricstudies,20,21wecurrentlydonothaveenoughdata toclearly demonstrate a clinical benefit.Joachim Yahalom underlinedinhisrecentpaperthatalthoughitwilltakemore yearsofcarefulfollow-upofpatientsinrandomizedstudiesto displaythefullmagnitudeofrisktaperingbycurrent reduc-tionofradiationfieldsanddoses,recentdatasuggestthatthis islikelytobethecase.22

AsyoungRadiationOncologistsinvolvedinthe multidis-ciplinaryLymphomaTeam,weassumethatthesedifferent approachestotheissueoflatetoxicity(noRTatall, modi-fiedlow-toxicityRT)arenotnecessarilymutuallyexclusive. AconsistenteffortintryingtounderstandifnewRT modal-itiesare able to reducethe negativeimpact on survivalof secondmalignanciesand cardiaceventsshouldbedoneby monitoringlatetoxicityinclinical practiceand notonlyin clinicaltrials,and aneffort inoptimizingradiationtherapy planningand deliverywiththeprimaryendpoint of reduc-ingtoxicityshouldbeimplemented.Inaparallelview,new

combinedmodality protocolssuchas,forexample,ABVDx 2cycles+IFRT-INRT20Gyinfavourablepresentations,should beprospectivelytestedagainstchemotherapyonly,with over-allsurvivalasprimaryendpoint.Currently,itisverydifficult to assess whether a low-dose, small-volume RT+2 cycles ofchemotherapycombinationismoretoxicthan4–6ABVD cycles(intheCanadiantrial10outof196patientsinthe CT-onlyarmdevelopeda secondmalignancyand 16 acardiac event,with6/12 nonHodgkin’s relateddeaths),evenif the twooptionsarelikelytobesimilarintermsofdisease con-trol (comparingglobalresultsofGHSGHD10studyand the chemotherapyonlyarmofNCICHD6trial,withOSratesof respectively95%an94%andFFSratesofrespectively87.1% and87%at8years).Therateofsecondmalignanciesinthe HD10studywasglobally4.6%,withoutsignificantdifferences betweentreatmentarms,butthefollow-uptimeisprobably tooshorttobeconclusive,aswearenotcertainthatthe low-doseapproachwillbelesscarcinogenetic.Wealsodonotknow aboutlong-termresultsofINRT.Toconclude,inouropinion themajorityofpatientsshouldbepossiblyincludedin clin-icaltrials;outsidethesestudies,combinedmodalityshould remainastandardtherapeuticapproach,asspecifiedin sev-eralInternationalGuidelines,withathoughtfulattentionon lateeffectsandonthepossibilitiesofloweringcardiactoxicity andprobablesecondmalignancyriskwithlow-doseprograms forfavourablepatientsand/orwiththeemploymentofnewRT techniquesincriticalpresentations.

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