lancet直肠癌文献分享汇报.ppt

Organpreservationforrectalcancer(GRECCAR2):aprospective,randomised,open-label,multicentre,phase3trial,Lancet2017;390:46979PublishedOnlineJune7,2017/10.1016/S0140-6736(17)31056-5,EricRullier,PhilippeRouanet,Jean-JacquesTuech,AlainValverde,等,Summary,BackgroundOrganpreservationisaconceptproposedforpatientswithrectalcancerafteragoodclinicalresponsetoneoadjuvantchemotherapy,topotentiallyavoidmorbidityandside-effectsofrectalexcision.Theobjectiveofthisstudywastocomparelocalexcisionandtotalmesorectalexcisioninpatientswithagoodresponseafterchemoradiotherapyforlowerrectalcancer.MethodsWedidaprospective,randomised,open-label,multicentre,phase3trialat15tertiarycentresinFrancethatwereexpertsinthetreatmentofrectalcancer.Patientsaged18yearsandolderwithstageT2T3lowerrectalcarcinoma,ofmaximumsize4cm,whohadagoodclinicalresponsetoneoadjuvantchemoradiotherapy(residualtumour2cm)werecentrallyrandomlyassignedbythesurgeonbeforesurgerytoeitherlocalexcisionortotalmesorectalexcisionsurgery.Randomisation,whichwasdoneviatheinternet,wasnotstratifiedandusedpermutedblocksofsizeeight.Inthelocalexcisiongroup,acompletiontotalmesorectalexcisionwasrequirediftumourstagewasypT23.Theprimaryendpointwasacompositeoutcomeofdeath,recurrence,morbidity,andside-effectsat2yearsaftersurgery,toshowsuperiorityoflocalexcisionovertotalmesorectalexcisioninthemodifiedintention-to-treat(ITT)population(expectedproportionsofpatientshavingatleastoneeventwere25%vs60%forsuperiority).ThistrialwasregisteredwithClinicalT,numberNCT00427375.FindingsFromMarch1,2007,toSept24,2012,186patientsreceivedchemoradiotherapyandwereenrolledinthestudy.148goodclinicalresponderswererandomlyassignedtotreatment,threewereexcluded(becausetheyhadmetastaticdisease,tumour8cmfromanalverge,andwithdrewconsent),and145wereanalysed:74inthelocalexcisiongroupand71inthetotalmesorectalexcisiongroup.Inthelocalexcisiongroup,26patientshadacompletiontotalmesorectalexcision.At2yearsinthemodifiedITTpopulation,oneormoreeventsfromthecompositeprimaryoutcomeoccurredin41(56%)of73patientsinthelocalexcisiongroupand33(48%)of69inthetotalmesorectalexcisiongroup(oddsratio133,95%CI062286;p=043).InthemodifiedITTanalysis,therewasnodifferencebetweenthegroupsinallcomponentsofthecompositeoutcome,andsuperioritywasnotshownforlocalexcisionovertotalmesorectalexcision.InterpretationWefailedtoshowsuperiorityoflocalexcisionovertotalmesorectalexcision,becausemanypatientsinthelocalexcisiongroupreceivedacompletiontotalmesorectalexcisionthatprobablyincreasedmorbidityandside-effects,andcompromisedthepotentialadvantagesoflocalexcision.Betterpatientselectiontoavoidunnecessarycompletiontotalmesorectalexcisioncouldimprovethestrategy.,Background,Thestandardtreatmentforrectalcanceristotalmesorectalexcisionwithorwithoutneoadjuvantchemoradiotherapyaccordingtoinitialstagingdefinition.Organpreservationisanewconceptforpatientswithrectalcancertreatedbyneoadjuvanttherapy.Forpatientswithacompleteorsubcompleteclinicalresponse,thestrategiesofobservation(watch-and-wait)ortransanallocalexcisionareavailable.,Background,Single-institution,retrospective,andprospectivecohortstudieshavereportedfindingsfromuseoftheobservationstrategy(15%to30%oflocalrecurrenceusuallycontrolledbycurativeradicalsurgeryand58%to92%stoma-freewithsurvivalupto80%inmoststudiesat2or3yearsoffollow-up).Localexcisionhasbeenassessedinsingle-institutionandmulticentrestudies(butnotcomparativestudies),allofwhichincludedveryfewpatients.Onlyonephase2UStrialhasreportedtheexperienceoforganpreservationatanationallevel,includinglowrectalcanceratstageT2N0treatedbylocalexcisionafterchemoradiotherapy.Resultswerepromisingwithlessthan5%localrecurrenceand88%survivalat3years;however,thisstudycouldnotchangestandardpracticeoftotalmesorectalexcisionbecausetherewasnocomparativegroup.Moreover,onlypatientswithstageI(T2N0)tumourswereincluded.,Introduction,WethereforedidarandomisedclinicaltrialcomparinglocalexcisionwithtotalmesorectalexcisioninpatientswhoweregoodrespondersafterchemoradiotherapyforT2T3N0-1(stageIIII)lowerrectalcancer.Theprimaryobjectiveofthestudywastotesttheoverallsuperiorityoflocalexcisioncomparedwithtotalmesorectalexcisionwithregardstoacompositeendpointofefficacyandsafety(death,recurrence,majorsurgicalmorbidity,andsevereside-effectsat2yearsaftersurgery);secondaryobjectiveswereassessmentofthetumourresponseandwhetherthestrategywassafefromanoncologicalperspectiveupto3yearsaftersurgery.（Oncologicaloutcomesat3years(KaplanMeier)）,MethodsStudydesignandparticipants,Inclusioncriteriaaged18yearsorolderabletoreceiveradiochemotherapyandmajorsurgery,havinglowerrectalinfiltratingcarcinoma(8cmfromtheanalverge),greatestdiameter4cm,clinicallystagedT2orT3,andN0-1(nonetothreenodes8mminvolved).Exclusioncriteriametastaticdisease,analsphincterinvolvement,contraindicationforchemotherapy,previouspelvicradiotherapy,historyofothercancerandtumourspresentingwithmajoradenomacomponent.,Figure1:StudydesignT=tumourstage.N=nodalstage.p=pathologicalstage.,MethodsProcedures,Radiotherapyconsistedof3Dconformalpelvicradiotherapydelivering50Gywithhigh-energy(18MV)photonsinfractionsof2Gy,5daysaweekover5weeks.Capecitabine1600mg/m2perday,5daysperweek,andoxaliplatine50mg/m2perweek,wereadministeredduringradiotherapy.InJanuary,2009,oxaliplatinewasstoppedbecauseofresultsfromphase3trialsshowingincreasedtoxicitywithoutincreasedresponsewhenoxaliplatinewasaddedtoconventionalchemoradiotherapy.Restagingwasdone68weeksafterchemoradiotherapybypelvicMRI.Agoodclinicalresponsewasdefinedasaresidualtumourscarof2cmorless,withnovegetativecomponentandnosignificanthollowordeepinfiltrationintothemuscularlayer.Bothpatientswithcompleteandsubcompleteclinicalresponseswerethereforeadmitted.,MethodsProcedures,Surgerywasdone8weeksafterirradiation.Localexcisionwasafullthicknessexcisionoftherectalwall,withabowelmarginof1cm,performedconventionallyorwithtransanalendoscopicmicrosurgery.Identificationoftheresidualscarwasobtainedbyvisualisationofabnormalmucosal(whitecolourwithtelangiectasies),residualulcers,orsuperficialhollows.Inthetotalmesorectalexcisiongroup,sphincterpreservationwasanticipatedbecauseinclusioncriteriaweresmallrectaltumourswithoutanalsphincterinvolvementandexperiencedsurgeonstrainedintheintersphinctericresectiontechniquedidthesurgery.Acompletiontotalmesorectalexcisionwasrecommendedat14weeksafterlocalexcisionforpatientswithabadpathologicalresponseafterlocalexcision(ypT23orR1).,MethodsStatisticalanalysis,Wehypothesisedthattheincidenceofeacheventofthecompositeendpointafterlocalexcisionversustotalmesorectalexcisionfordownstagedrectalcancerwouldbethefollowing:operativedeath0versus2%,majormorbidity5%versus20%,severecomplications5%versus2550%,andweexpectedlocalrecurrence(5%)andmetastaticrecurrence(10%)tobesimilarinbothgroups,assumingthatlocalexcisionwouldbeassuccessfulastotalmesorectalexcisiononthoseoncologicalendpoints.26Theproportionofpatientshavingatleastoneeventwasthereforeexpectedtobe25%versus60%(forsuperiority);46patientspergroupwererequired(=005,power=90%,two-sided2test).Assuming10%ofpatientsinthelocalexcisiongroupwouldhaveapoorpathologicalresponseandrequireacompletiontotalmesorectalexcision,120patients(60ineachgroup)wererequired.Afterinclusionof60patients,theindependentdatamonitoringcommitteerecommendedtoincreaseinclusionsupto72pergroupduetoanestimateof20%ofpatientshavingapoorpathologicalresponseafterlocalexcision.,MethodsStatisticalanalysis,Comparisonsofsurvivalandcumulativeincidenceratesbetweengroupswereanalysedwithmodifiedintent-to-treatandper-protocol(patientsanalysedaccordingtothestrategytheyactuallyreceived)approaches.Proportionalhazardmodelswereused,adjustedoncentres,tumour,andnodalstages.Adjustmentonpathologicaltumourresponsewasalsoconsideredintheper-protocolanalysesbecauseofthepotentialimbalancebetweengroups.Modelsassumptionswerecheckedwithcumulativesumsofmartingale-basedresiduals.Thesafetyanalysiswaspresentedinthreegroups,accordingtothesurgery(localexcisionalone,totalmesorectalexcisionalone,andlocalexcisionandcompletiontotalmesorectalexcision),becauseapost-hocexploratoryanalysisthatwasmeanttoexplorehowthenewstrategymighthavebeenaffectedinpatientsreceivingcompletiontotalmesorectalexcisionandlocalexcisionalone.,Results,intent-to-treatanalysis(ITT分析的数据集一定是全分析集，是尽可能接近意向性处理原则的理想的受试者集，而不管他们是否依从计划的处理过程。).per-protocol(PP分析是对符合方案集做出的分析总结，符合方案集的受试者均按照方案完成了试验全过程，且没有违反入组标准。)74inthelocalexcisiongroupand71inthetotalmesorectalexcisiongroupinthemodifiedintent-to-treatanalyses(81and61patientsinbothgroupsreceivedlocalexcisionandtotalmesorectalexcision,respectively,andwereincludedintheper-protocolanalyses).,Results,Results,Themedianintervalbetweenchemoradiotherapyandsurgerywas60days(range34132;IQR5167).Inthelocalexcisiongrouponepatienthadtotalmesorectalexcisionbecauseoftechnicaldifficulties,totalmesorectalexcisiongroup11patientsdidnothavetotalmesorectalexcisionbecauseofpatientrefusal(n=6)orsurgeondiscretion(n=5).Themedianintervalbetweenlocalexcisionandcompletiontotalmesorectalexcisionwas28days.(range288;IQR1549),Results,Intheper-protocolpopulation,among81patientsintotaltreatedbylocalexcision,58hadaconventionaltransanallocalexcisionand23hadtransanalendoscopicmicrosurgery;monoblocexcisionwasdonein80patients(onehadmissingdata),andrectalclosurebysuturingwasdonein70patients.Among61patientsintotaltreatedbytotalmesorectalexcision,tenhadalowanteriorresection,22hadacoloanalanastomosis,and29hadaintersphinctericresection.In28patientsintheper-protocolpopulationwhohadacompletiontotalmesorectalexcision,onehadalowanteriorresection,15hadcoloanalanastomoses,sevenhadintersphinctericresections,andfivehadabdominoperinealresections.Nopatients(of61)hadanabdominoperinealresectionatinitialtotalmesorectalexcision,butfive(18%)of28hadoneforcompletiontotalmesorectalexcision.,Results,Inthemodifiedintention-to-treatanalysis74(100%)of74inthelocalexcisiongroupand67(94%)of71inthetotalmesorectalexcisiongrouphadanR0resection(p=0055).57(40%)patientshadtumoursdefinedasypT0,29(20%)asypT1,44(31%)asypT2,and12(9%)asypT3.86(61%)of142patientshadagoodpathologicalresponse(ypT0-1),whichwashigherinpatientswithcT2thancT3tumours:52(69%)versus34(51%;p=0026).From89totalmesorectalexcisionspecimensseven(8%)of89hadpositivelymphnodes.Thesewereidentifiedinnopatients(of30)withypT0tumoursandnoneof13withypT1,three(8%)of36withypT2,andfour(40%)oftenwithypT3.Pathologicalpositivelymphnodes(ypN1)werefoundinone(2%)of55patientswithcN0versussix(18%)of34withcN1rectaltumours(p=0007).28rectalspecimensaftercompletiontotalmesorectalexcisionhadasimilarnumberoflymphnodesretrievedto61specimensafteraprimarytotalmesorectalexcision:median12(range128;IQR816)versus10(126;IQR814;p=063).ResidualtumourswerefoundinthebowelwallofonepatientstagedypT2afterlocalexcisionandypT3afteracompletiontotalmesorectalexcision.AllpatientshadanR0resection.Two(7%)of28patientswhohadacompletiontotalmesorectalexcisionhadpositivelymphnodes.,Results,Oneormoreeventfromthecompositeoutcomeoccurredin74of145randomlyassignedpatientsat2yearsfollow-up.Inthemodifiedintention-to-treatanalysis,oneormoreeventsoccurredin41(56%)of73patientsinthelocalexcisiongroupand33(48%)of69patientsinthetotalmesorectalexcisiongroup(oddsratio133,95%CI062286;p=043).Therewasnooperativemortalityineithergroup.Themodifiedintention-to-treatanalysisdidnotshowsuperiorityoflocalexcisionovertotalmesorectalexcisioninallcomponentsofthecompositeoutcome(table2).,Results,Results,Allpatientshada3-yearfollow-up,exceptthosewhodied.Medianfollow-upwas36months(range1136;IQR3636).Inthemodifiedintention-to-treatanalysis,thedifferencebetweengroupsforoncologicaloutcomesat3yearswasnotsignificant(table3,figure3).Perprotocolanalysissupportedtheseresultswithnodifferencebetweengroupsforalloncologicalendpoints(table3).,Results,Results,Theexploratoryanalysisshowedvariabilityinmorbidityandseverityofcomplicationsaccordingtotypeofsurgery:themoreaggressivethesurgery,thehigherthecomplicationrates(table4).Theseverityofcomplicationswasalsoinfluencedbysurgery;patientswithlocalexcisionhadminorcomplicationsrequiringmedicalorendoscopictreatmentmainlyforrectalbleeding,whereaspatientswithtotalmesorectalexcisionorcompletiontotalmesorectalexcisionhadseverecomplicationsrequiringreoperationforpelvicabscess,peritonitis,smallbowelobstruction,orcolonicischaemia.,Discussion,theresultsofthestudyfailedtoshowsuperiorityoflocalexcisioncomparedwithtotalmesorectalexcision;thefindingssuggesttheoncologicalsafetyoflocalexcision,withnosignificantdifferenceoflocalrecurrenceanddisease-freesurvivalat3yearsbetweenthetwogroups.Theabsenceofsuperiorityoflocalexcisioninourtrialwasduetoahighnumberofcompletiontotalmesorectalexcisionsundertaken,whichsignificantlyincreasedthemorbidityandcomplicationsoftheprocedureandthereforecompromisedthepotentialadvantagesoflocalexcision.,Discussion,Pathologicaldatashowedalowrateofpositivelymphnodes,8%fortheoverallpopulation,suggestingthatcompletiontotalmesorectalexcisionwasoverusedinourstudy.Positivelymphnodesoccurredin0,0,8%,and40%ofpatientswithypT0,ypT1,ypT2,andypT3tumours,respectively,afterchemoradiotherapyforsmallT2T3rectalcancer.thelowernumberofpositivepathologicallymphnodesinpatientsclinicallystagedN0thaninthosestagedN1suggeststhatpatientswithypT2andcN0tumours,conventionallytreatedwithcompletiontotalmesorectalexcision,mightnotrequirecompletiontotalmesorectalexcisionsinthefuture.,Discussion,limitations.First,thesamplesizewassmall,Theanticipatednumberofpatientsrequiredtotestourhypothesiswasobtainedandwedonotthinkthatinclusionofmorepatientswouldhavechangedtheconclusions.Second,weusedanon-usualcompositeprimaryendpoint.However,webelievethatthecompositeoutcomewasrepresentativeofwhatisexpectedfromapatientwithrectalcancerandgoodclinicalresponse,becauseitincludedoncological,toxicity,andfunctionalissues.,Discussion,limitations.Third,wealsoexploredanddescribedmorbidityandoncologicaloutcomesinthelocalexcision,localexcisionpluscompletiontotalmesorectalexcision,andtotalmesorectalexcisiongroups;althoughthisanalysiswasexploratoryanddoesnotcorrespondtocomparablegroupsasperrandomisation,itmightimplicatesomeimportantfeaturesforthefutureofresearchonthisproceduresuchasaclosefollowuptoscreenforlocalrecurrencesinpatientsun