2009ASCO结肠癌进展课件

2009ASCO结肠癌进展2009ASCO结肠癌进展2009ASCO结肠癌进展分子指标预测Ⅱ期结肠癌高危复发大型研究结果Ceteximab疗效的预测结肠癌辅助化疗终点Oxaliplatin相关synchronousstageIVcolorectalcancer化疗策略和方案的调整其它2009ASCO结肠癌进展分子指标预测结肠癌高危复发及指导化疗Abr4000高通量Abr4001MSIAbr4002Abr401218qLOH2009ASCO结肠癌进展Background:NSABPC-01/C-02、CCF、C-04、C-0648genessignificantlyassociatedwithrecurrenceriskand66genespredictiveof5FU/LVbenefit.Multivariateanalysisyielded18genes(7prognosticgenes,6predictivegenes,5referencegenes)andseparateprognosticrecurrencescore(RS)andpredictivetreatmentscore(TS)algorithms.Methods:GeneexpressionwasquantitatedbyRT-PCR.Recurrence-freeinterval(RFI),disease-freesurvival(DFS),andoverallsurvival(OS)wereanalyzedusingCoxregressionResults:IntheQUASARvalidationstudytheRSpredictedrecurrencerisk(p=0.004).TheRSalsopredictedDFS(p=0.01)andOS(p=0.04).RecurrenceriskincreasedmonotonicallywithincreasingRS.Inmultivariateanalyses,RSretainedprognosticsignificance(p=0.008)independentofmismatchrepair(MMR),Tstage,nodesexamined,grade,andlymphovascularinvasion.MMRdeficiency(p<0.001)andT4stage(p=0.005).However,TSwasnotvalidatedasapredictorof5FU/LVbenefitConclusions:RSisavalidated,independentpredictorofindividualizedrecurrenceriskforstageIIcoloncancerKerretl.2009ASCOAbstractNo:4000

2009ASCO结肠癌进展ToinvestigatetheincidenceofMSI-HinstageII(n=395)andstageIII(n=859)COC,itsassociationwithhistopathologicalvariablesanditsprognosticandpredictiveimpact。Patients：PETACC3-EORTC40993-SAKK60/00trialResults：MSIHwaspresentin22%(85)ofStageIIand12%(103)ofStageIIIcoloncancer.MicrosatelliteinstabilityisastrongprognosticfactorforRFSandOSwhenconsideringStageIIandStageIIICOC.SubgroupanalysissuggestsastrongereffectinStageIIthaninStageIII.ThereisnoevidenceforaneffectoftheadditionofIRI.

Tejparetl.2009ASCOAbstractNo:40012009ASCO结肠癌进展Object:TocomparetheincidenceofmolecularmarkersinstageII(SII)andIII(SIII)coloncancerandtestedtheirprognosticvalueperstage1564Patients：PETACC3-EORTC40993-SAKK60/00trialP53,SMAD4,thymidylatesynthetase(TS)andhTERT,mutationsofKRASandBRAF,microsatelliteinstability(MSI)and18qLOHResultsConclusions:

Molecularmarkersincoloncancerhaveastagespecificprognosticvalue.Thepossibilitythatthestagesrepresentdifferentdiseases,ratherthansequentialstepsintheevolutionofasingledisease,needstobeconsidered.

Tejparetl.2009ASCOAbstractNo:40022009ASCO结肠癌进展Thisprospectivestudyinvestigatedtheroleof18qLOHamongpatientswithlow-riskstageIIcoloncancer.1738stageIIpatientsInCancerandLeukemiaGroupB(CALGB)protocol9581chemotherapy-naiveResults:

Asignificantlylowerproportionofpatientswith18qLOH-positivetumorshadproximaltumors(46.5%vs65.5%;p=0.02).SignificantlydecreasedDFSandOSwereobservedinpatientswith18qLOH-positivetumors.Five-yearDFSamongpatientswith18qLOH-positivetumorswas0.78vs0.93amongpatientswith18qLOH-negativetumors[HR0.39;95%CI(0.16,0.94);logrankp=0.03basedon33events].Five-yearOSamongpatientswith18qLOH-positivetumorswas0.85vs0.98amongpatientswith18qLOH-negativetumors[HR0.25;95%CI(0.07,0.83);logrankp=0.01].Conclusions:LOHat18qwasprognosticforDFSandOSamongpatientswithlowriskstageIIcoloncancer.Bertagnollietal.2009ASCOAbstractNo:40122009ASCO结肠癌进展大型研究结果ResultsofNSABPProtocolC-08Impactofolderageontheefficacyofneweradjuvanttherapies：FindingsfromtheACCENTDatabase.FinalresultsoftheAGITGMAXtrialAquality-of-life(QoL)analysisoftheCRYSTALtrial.InterimsafetyanalysisofDREAMstudy.2009ASCO结肠癌进展AphaseIIItrialcomparingmFOLFOX6tomFOLFOX6plusbevacizumabinstageIIorIIIcarcinomaofthecolon:ResultsofNSABPProtocolC-08.Results:Conclusions:TheadditionofbevacizumabtomFF6didnotresultinanoverallstatisticallysignificantprolongationinDFS.

Tejparetl.2009ASCOAbstractLBA42009ASCO结肠癌进展Impactofolderageontheefficacyofneweradjuvanttherapiesin>12,500patients(pts)withstageII/IIIcoloncancer:FindingsfromtheACCENTDatabase.Background:todeterminetheimpactofptsage<70v≥70yrsoncoloncancerrecurrenceandmortalityfromadjrxwiththeseneweroptionsResults:Conclusions:pts>70donotreceivethesamebenefitfromcombinationand/ororalFUasthose<70.Anybenefit,ifpresent,comparedtoIVFU/LVwouldnotbeclinicallymeaningful.Tejparetl.2009ASCOAbstractLBA42009ASCO结肠癌进展InternationalrandomizedphaseIIIstudyofcapecitabine(Cap),bevacizumab(Bev),andmitomycinC(MMC)infirst-linemetastaticcolorectalcancer(mCRC):FinalresultsoftheAGITGMAXtrial.patients:eitherunfitfororwhodonotrequireinitialoxaliplatin/irinotecan.Methods:armACap(Cap2000mg/m2/dor2500mg/m2d1-14q21d),armBCapBev(Bev7.5mg/kgq3w)armCCapBevMMC(MMC7mg/m2q6w).ResultsConclusions:TheadditionofBev±MMCtoCapsignificantlyimprovedPFSwithoutsignificantadditionaltoxicity.OSwassimilarforallarms.CapBev±MMCisanactive,lowtoxicityregimenthatmaybeconsideredasatreatmentoptionforptswithmCRC.

Tebbuttetl.2009ASCOAbstract40232009ASCO结肠癌进展InphaseIIICRYSTALtrial，QoLwasasecondaryendpointMethods:EORTCQLQ-C30(v3.0)questionnaireResults：InptswithmCRC,cetuximabplusFOLFIRIfirst-linesignificantlyprolongsPFScomparedwithFOLFIRIalonewhilepreservingQoL.ThePFSbenefitisevenmorepronouncedforptswithKRASwttumors.Folprechtetl.2009ASCOAbstract40762009ASCO结肠癌进展mFOLFOX-bevacizumaborXELOX-bevacizumabthenbevacizumab(B)aloneorwitherlotinib(E)infirst-linetreatmentofpatientswithmetastaticcolorectalcancer(mCRC):InterimsafetyanalysisofDREAMstudy.Results:inductionwithmFOLFOX-BorXELOX-BaswellasmaintenancewithBorB+Eappearstobewell-tolerated,withoutunexpectedsideeffectsTournigand

etl.2009ASCOAbstract40772009ASCO结肠癌进展Ceteximab疗效的预测

EGFRligand:amphiregulinepiregulininsulin-likegrowthfactor1(IGF-1)BRAF-1皮疹EGFRpolymorphisms2009ASCO结肠癌进展Background:GeneexpressionoftheEGFRligandepiregulin(EREG)mayfurtherpredictbenefitfromcetuximabMethods:CRCtumoursampleswereanalyzedfromaphaseIIIclinicaltrialofcetuximabplusBSCvsBSCalone(NEJM2007;357(20))Results:IntheK-rasWTsubset,OSwasbetterforcetuximabthanBSCamongpatientswithhighEREG(HR0.43;p<0.0001)butnotforlowEREGpatients(HR0.77,p=0.28).HighEREGANDK-rasWTstatus("Combimarker")waspresentin139(36%).WithintheCombimarkerpositivegroupthemedianPFSwas5.4vs1.9months(HR,0.31;p<0.0001),andmedianOS9.8vs5.1months(HR,0.43;p<0.001)inthecetuximabvsBSCarmsConclusions:patientswithbothhighEREGgeneexpressionandK-raswild-typestatusmaybenefitfromcetuximabtherapy.DeterminationofEREGgeneexpressionlevelsshouldbeprospectivelyevaluatedinpatientselectionforEGFRtargetedtherapy.Jonker

etal.2009ASCOAbstract40162009ASCO结肠癌进展Background:70%to40%ofpatientswithK-RASwildtypedoesnotseemtobenefitfromCetuximab.ColorectalcancercellswithIGF-1systemactivationmayescapeanti-EGFRmediatedcelldeathMethods:

IGF-1expressionandK-RASmutationalstatuswasassessedinadvancedcolorectalcancerpatientsreceivingirinotecan/cetuximabResults:IGF-1wasoverexpressedin41cases(66%).IGF-1negativeIGF-1positiveprogressivedisease6(29%)26(63%)MedianTTP7.7months2.3monthsAmongK-RASwildtypepatients,IGF-1negativeandpositivetumorsshowedapartialresponsetocetuximab-irinotecanin7(50%)and1(5%)casesrespectively(p=0.004).MedianTTPinIGF-1negativetumorswas11monthsand3.2monthsinIGF-1positivecolorectalcancers(p=0.03).

Conclusions:

IGF-1provedtobeareliablepredictivefactorforresistancetoanti-EGFRmonoclonalantibodiesinK-RASwildtypecolorectalcancerScartozzi

etal.2009ASCOAbstract40172009ASCO结肠癌进展Background:Tostudythepowerofepiregulin(EREG)andamphiregulin(AREG)expressioninprimarytumorstopredicttheoutcomeinpatientswithchemorefractorymetastaticcolorectalcancer(cmCRC)treatedwiththecombinationofcetuximabplusirinotecan.Methods:amphiregulinandepiregulinmRNAexpressionResults:InKRASwild-type(WT)patients,therewasasignificantassociationbetweenlog-transformedligandexpressionandresponseInaCox-regressionmodellog-transformedligandexpressionwassignificantlyassociatedtoprogression-freesurvival(PFS)andoverallsurvival(OS)TherewasnopredictivepowerofligandexpressioninKRASmutantpatients.Conclusions:

ExpressionofEGFRligandsinprimarytumorssignificantlypredictsfavorableoutcomeinKRASWTmCRCtreatedwithcetuximabandirinotecanPrenen

etal.2009ASCOAbstract40192009ASCO结肠癌进展Abstract4021retrospectivelyassessedKRASmutationalstatusandAmphiregulinexpressionbyimmunohistochemistry(IHC)in86irinotecan-refractoryEGFR-positivemCRCpatientstreatedwithcetuximabplusirinotecan,Results:AR-lowpatientsreportedasignificantlyworseRR(2/22,9%)comparedwithAR-high(10/27,37%)(p=0.024)andatrendtowardshorterPFS(3.5vs5.3months,HR0.88[95%CI:0.46-1.60],p=0.628)andOS(8.8vs15.1months,HR0.60[95%CI:0.30-1.10],p=0.106).Conclusions:AbsentorlowARexpressionatIHCmayberelatedtoresistancetocetuximabplusirinotecan.Loupakisetal.2009ASCOAbstract40212009ASCO结肠癌进展Background:re-assessingtheimpactofKRASstatusandotherpossiblepredictivefactorsforOSResults:

OSinptswithKRASwttumorswassignificantlyimprovedcomparedtoptswithKRASmttumors(median20.8vs15.9mo;hazardratio(HR)=1.62;p=0.0296).CoxproportionalhazardanalysisshowedthataswellasKRASwtstatus(vsKRASmt),anacne-likerashofgrade2/3(vsgrade0/1)inthefirst6weeksandnopriortreatment(vspriorneo-/adjuvanttreatment)werethestrongestindependentpredictorsforprolongedsurvival(eachp<0.005).Kozaetal.2009ASCOAbstract40552009ASCO结肠癌进展Abstract4058：InKRASwild-typepatients,BRAFmutationsareconfirmedtopredictresistancetocetuximabtreatmentAbstract4060：EGFRSNPisnotapredictivemarkerofefficacytoEGFR-inhibitors.OurstudysuggestthatptswithWTKRASand>1xULNlevelsofLDH,havemajorbenefittoanti-EGFRtherapyinsecond-thirdlinetherapy.Abstract4063：Co-expressionofpIGF-1RandMMP7isassociatedwithresistancetoanti-EGFRtherapyinWTRASpts.2009ASCO结肠癌进展结肠癌辅助化疗观测终点Abstract40112009ASCO结肠癌进展Object(1)2yrDFSpredicts5yrOS?(2)astrongerrelationshipbetweenDFSandOSinstageIIIpts?(3)6or7yrsarenecessarytodemonstrateDFSandOS?associationinfuturetrialsduetoextendedsurvivalfollowingrecurrence12,676patientsfromMOSAIC,X-ACT,PETACC-3,NSAPBC-06andC-07,andC89803Methods:

Concordancebetween2and3yrDFS,and5and6yrOSwasexaminedin6randomizedphaseIIItrialsfrom1997-2002.ResultsConclusions:

InrecenttrialsinstageIIIpts,DFSHRsbasedon2yrmedianf-uparehighlypredictiveof5and6yrOSHRs.InallptstheassociationbetweenDFSandOSHRsisstrongerfor6yrOS,but7yrfollow-upmayberequired.Thesedatasupport3yrDFSasaprimaryendpointformodernstageIIItrials,andindicatethat2yrDFSwouldalsobeanappropriateprimaryendpoint.

Sargentetal.2009ASCOAbstract40112009ASCO结肠癌进展Oxaliplatin相关TodefinethesensitivitytooxaliplatinreintroductionCaMgonchronicandacuteneurotoxicityassociatedwithoxaliplatinPicoplatin2009ASCO结肠癌进展Background:Todefinethesensitivitytooxaliplatinreintroductionbasedontheoxaliplatin-freeintervalPatients:StageIVptsenteredintheOPTIMOX1and2studiesResults:Conclusions:

AprolongedintervalbetweentwoFOLFOXtherapiesoraprolongedPFSatfirst-lineFOLFOXpredicttheefficacyofoxaliplatinreintroduction.deGramont

etal.2009ASCOAbstract40242009ASCO结肠癌进展Background:toinvestigatewhetherCaMgreducedacuteand/orchronic,cumulativesNT.Methods:104patientsFOLFOX+CaMgVSFOLFOX+placeboResults:acutesNT:nodifference(sensitivitytocold,swallowingofcoldliquids,throatdiscomfort)cumulativesNT:significantlyreducenumbnessinfingers(p=0.02),impairedabilitytobuttonshirts(p=0.05),tinglinginfingers(p=0.06),andmusclecrampsoverthecourseoftherapy(p=0.01).Grotheyetal.2009ASCOAbstract40252009ASCO结肠癌进展Background:Picoplatin(Pico)wasdesignedtoovercomeplatinumresistanceandhasthepotentialforimprovedsafetyTheincidenceofgrade(G)3-4neurotoxicitywithsingle-agentPicoacrossstudieswas<2%Methods:PicoQ4W(150mg/m2)withQ2WFUandLV(FOLPI)vs.modified(m)FOLFOX-6(FOLFOX)as1stlinetreatmentforpatients(pts)withadvancedCRCResults:Neurotoxicitywasobservedin65%ofptsonFOLFOX(10%G3/4)and28%ofptsonFOLPI(noG3/4).MostfrequentG3/4AEsonFOLPIwereneutropenia(60%),thrombocytopenia(40%)andanemia(14%).IntheFOLFOXarm,otherthanneuropathy,themostfrequentG3/4AEswereneutropenia(20%)andthrombocytopenia(12%).Diseasecontrol(CR+PR+SD)was76%forFOLPIand76%forFOLFOX.IntheFOLPIarmtherewere1CR(2%)and11PR(22%).IntheFOLFOXarmtherewerenoCRsand13PR(26%).Conclusions:FOLPIwithPicoQ4WshowscomparablediseasecontrolwithlessfrequentNeurotoxicity.Earhart

etal.2009ASCOAbstract40262009ASCO结肠癌进展synchronousstageIVcolorectalcancer是否需要切除原发灶？是否需要修改CRC分期标准？2009ASCO结肠癌进展Background:Intheabsenceofsymptoms(bleeding,perforation,obstruction)orresectablemetastaticdisease,primarytumorresectioninpatientswhopresentwithsynchronousmetastaticcolorectalcancer(CRC)isofuncertainbenefit.Methods：prospective233patientsinitialtreatment：oxaliplatin-oririnotecan-based,triple-drugchemotherapy(FOLFOX,IFL,orFOLFIRI)withorwithoutbevacizumab。

Results：

217(93%)neverrequiredsurgicalpalliationoftheirprimarytumor.16(7%)requiredemergentsurgeryforprimarytumorobstructionorperforation10(4%)requirednonoperativeintervention(stentorradiotherapy213(89%)neverrequiredanydirectsymptomaticmanagementfortheirintactprimary

Conclusions:MostpatientswithsynchronousstageIVCRCwhoreceiveup-frontmoderncombinationchemotherapyneverrequirepalliativesurgeryfortheirintactprimary.Thesedatasupporttheuseofchemotherapy,withoutroutineprophylacticresection

neitherobstructednorhemorrhaging

2009ASCO结肠癌进展Background:AJCCV.6(2002)placespatientswithinoperablehepaticMCRCcanbemadeoperablewithcurativeintentwithchemotherapyyetremaininginStage4.Results：1998-200168,307individuals5-yearsurvivalofpatientswhounderwentHPXwas41.6%betterthanthatforbothStage3(38.6%(95%CI37.9%-39.2%,P<0.01)and4(6.1%95%CI5.3-6.9%,P<0.01)overall.

Conclusions:5-yearsurvivalfollowingHPXforMCRCisbetterthanthatseenoverallforallStage3patie.OurdatasupportthehypothesisthatallMCRCthatispotentiallyresectablewithcurativeintentshouldbestratifiedwithinStage3,andStage4shouldonlycontainthoseMCRCpatientsforwhomsurgeryisnotanoption.Morrisetal.2009ASCOAbstract40992009ASCO结肠癌进展化疗方案和策略的调整AbstractNo4078：PhaseIIIstudyofstandardtriweeklyversusdose-densebiweeklycapecitabine(C)+oxaliplatin(O)+bevacizumab(B)asfirst-linetreatmentformetastaticcolorectalcancer(mCRC):XELOX-A-DVS(denseversusstandard):Interimanalysis.AbstractNo4125："Poker"scheduleofweeklyalternating5-fluorouracil,irinotecan,bevacizumab,andoxaliplatin(FIR-B/FOX)inadvancedcolorectalcancer:AphaseIIstudy.2009ASCO结肠癌进展Doses:Q3W:C850mg/m2BIDd1-14+O130mg/m2d1+B7.5mg/kgd1Q2W:C1500mg/m2BIDd1-7+O85mg/m2d1+B5mg/kgd1forupto72weeksResults：

Q3WQ2WpvaluePFS9.7m8.4m0.84mediantimetoDP10.8m9.4mORR29.4%21.7%grade3/4diarrhea24%29%hand-footsyndrome8%12%Conclusions:dose-denseQ2WCOBwasnotsuperiortostandardQ3WCOB.2009ASCO结肠癌进展Object：theadditionofBEVtothetripletcombinationCPT-11/OHP/5-fluorouracil(5-FU)asfirstlinechemotherapyinmetastaticcolorectalcarcinoma(MCC).Treatmentschedule:weekly5-FU12-htimed-flat-infusion(from10:00pmto10:00am)900mg/m2/d1-2,8-9,15-16and22-23;CPT-11160mg/m2plusBEV5mg/kgdays1and15;OHP80mg/m2days8and22,every4weeks.Results

：

efficiency：

Forty-eightptswereenrolled，ORwere84%(2completeand35partialresponses,4stablediseaseand5progression.）MedianTTPwas12monthsmedianOSwas25monthstoxicities

：CumulativeG3-4toxicitieswere:diarrhea27%,mucositis6%,hypertension2%,hypertransaminasemy2%,neutropenia10%Conclusions:"Poker"combinationwithFIR-B/FOXscheduleshowshigheractivitythantripletcombinations.ThusitmaybeconsideredasthemostactivefirstlinetreatmentofMCC.Santomaggioetal.2009ASCOAbstract41252009ASCO结肠癌进展其它年龄和合并症对mCRC患者治疗的影响延迟辅助化疗是否影响临床效果?年轻对结肠癌预后的影响Oralfluoropyrimidinesversus5-fluorouracil中性粒细胞减少预测FOLFOX疗效2009ASCO结肠癌进展Background:todeterminetheimpactofCCandage(<70and≥70yrs)onsurvivalandtoxicityinmCRCpts

Patients：fromCALGB80203Results：Conclusions:WhiletheearlyclosureofCALGB80203presentssamplesizelimitationsforsubsetanalyses,wedidnotobserveanimpactonPFSorOSbyageand/orCC.Olderptsdidexperiencemoretoxicityfromrx.Meyerhardt

etal.2009ASCOAbstract40382009ASCO结肠癌进展Object:Doesdelayofadjuvantchemotherapyaffecttheclinicaloutcomeinpatientswithcoloncancer?Methods

Group1:within60daysGroup2:after60days

Results:

groupIgroupIIpvalueFive-yearOS75.2%61.3%HR2.11,p=0.049Five-yearRFS65.7%59.0%HR:1.19,p=0.570Conclusions:DelayofACmorethan60daysaf