结肠癌进展课件

2009ASCO结肠癌进展 南昌大学第一附属医院肿瘤科黎军和 分子指标预测 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 分子指标预测结肠癌高危复发及指导化疗 Abr4000高通量Abr4001MSIAbr4002Abr401218qLOH 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 independentpredictorofindividualizedrecurrenceriskforstageIIcoloncancer Kerretl 2009ASCOAbstractNo 4000 ToinvestigatetheincidenceofMSI HinstageII n 395 andstageIII n 859 COC itsassociationwithhistopathologicalvariablesanditsprognosticandpredictiveimpact Patients PETACC3 EORTC40993 SAKK60 00trialResults MSIHwaspresentin22 85 ofStageIIand12 103 ofStageIIIcoloncancer MicrosatelliteinstabilityisastrongprognosticfactorforRFSandOSwhenconsideringStageIIandStageIIICOC SubgroupanalysissuggestsastrongereffectinStageIIthaninStageIII ThereisnoevidenceforaneffectoftheadditionofIRI Tejparetl 2009ASCOAbstractNo 4001 Object TocomparetheincidenceofmolecularmarkersinstageII SII andIII SIII coloncancerandtestedtheirprognosticvalueperstage1564Patients PETACC3 EORTC40993 SAKK60 00trialP53 SMAD4 thymidylatesynthetase TS andhTERT mutationsofKRASandBRAF microsatelliteinstability MSI and18qLOHResultsConclusions Molecularmarkersincoloncancerhaveastagespecificprognosticvalue Thepossibilitythatthestagesrepresentdifferentdiseases ratherthansequentialstepsintheevolutionofasingledisease needstobeconsidered Tejparetl 2009ASCOAbstractNo 4002 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 4012 大型研究结果 ResultsofNSABPProtocolC 08Impactofolderageontheefficacyofneweradjuvanttherapies FindingsfromtheACCENTDatabase FinalresultsoftheAGITGMAXtrialAquality of life QoL analysisoftheCRYSTALtrial InterimsafetyanalysisofDREAMstudy AphaseIIItrialcomparingmFOLFOX6tomFOLFOX6plusbevacizumabinstageIIorIIIcarcinomaofthecolon ResultsofNSABPProtocolC 08 Results Conclusions TheadditionofbevacizumabtomFF6didnotresultinanoverallstatisticallysignificantprolongationinDFS Tejparetl 2009ASCOAbstractLBA4 Impactofolderageontheefficacyofneweradjuvanttherapiesin 12 500patients pts withstageII IIIcoloncancer FindingsfromtheACCENTDatabase Background todeterminetheimpactofptsage70donotreceivethesamebenefitfromcombinationand ororalFUasthose 70 Anybenefit ifpresent comparedtoIVFU LVwouldnotbeclinicallymeaningful Tejparetl 2009ASCOAbstractLBA4 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 2009ASCOAbstract4023 InphaseIIICRYSTALtrial QoLwasasecondaryendpointMethods EORTCQLQ C30 v3 0 questionnaireResults InptswithmCRC cetuximabplusFOLFIRIfirst linesignificantlyprolongsPFScomparedwithFOLFIRIalonewhilepreservingQoL ThePFSbenefitisevenmorepronouncedforptswithKRASwttumors Folprechtetl 2009ASCOAbstract4076 mFOLFOX bevacizumaborXELOX bevacizumabthenbevacizumab B aloneorwitherlotinib E infirst linetreatmentofpatientswithmetastaticcolorectalcancer mCRC InterimsafetyanalysisofDREAMstudy Results inductionwithmFOLFOX BorXELOX BaswellasmaintenancewithBorB Eappearstobewell tolerated withoutunexpectedsideeffects Tournigandetl 2009ASCOAbstract4077 Ceteximab疗效的预测 EGFRligand amphiregulinepiregulininsulin likegrowthfactor1 IGF 1 BRAF 1皮疹EGFRpolymorphisms 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 Jonkeretal 2009ASCOAbstract4016 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 RASwildtypecolorectalcancer Scartozzietal 2009ASCOAbstract4017 Background Tostudythepowerofepiregulin EREG andamphiregulin AREG expressioninprimarytumorstopredicttheoutcomeinpatientswithchemorefractorymetastaticcolorectalcancer cmCRC treatedwiththecombinationofcetuximabplusirinotecan Methods amphiregulinandepiregulinmRNAexpressionResults InKRASwild type WT patients therewasasignificantassociationbetweenlog transformedligandexpressionandresponseInaCox regressionmodellog transformedligandexpressionwassignificantlyassociatedtoprogression freesurvival PFS andoverallsurvival OS TherewasnopredictivepowerofligandexpressioninKRASmutantpatients Conclusions ExpressionofEGFRligandsinprimarytumorssignificantlypredictsfavorableoutcomeinKRASWTmCRCtreatedwithcetuximabandirinotecan Prenenetal 2009ASCOAbstract4019 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 2009ASCOAbstract4021 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 2009ASCOAbstract4055 Abstract4058 InKRASwild typepatients BRAFmutationsareconfirmedtopredictresistancetocetuximabtreatmentAbstract4060 EGFRSNPisnotapredictivemarkerofefficacytoEGFR inhibitors OurstudysuggestthatptswithWTKRASand 1xULNlevelsofLDH havemajorbenefittoanti EGFRtherapyinsecond thirdlinetherapy Abstract4063 Co expressionofpIGF 1RandMMP7isassociatedwithresistancetoanti EGFRtherapyinWTRASpts 结肠癌辅助化疗观测终点Abstract4011 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 2009ASCOAbstract4011 Oxaliplatin相关 TodefinethesensitivitytooxaliplatinreintroductionCaMgonchronicandacuteneurotoxicityassociatedwithoxaliplatinPicoplatin Background Todefinethesensitivitytooxaliplatinreintroductionbasedontheoxaliplatin freeintervalPatients StageIVptsenteredintheOPTIMOX1and2studiesResults Conclusions AprolongedintervalbetweentwoFOLFOXtherapiesoraprolongedPFSatfirst lineFOLFOXpredicttheefficacyofoxaliplatinreintroduction deGramontetal 2009ASCOAbstract4024 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 2009ASCOAbstract4025 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 Earhartetal 2009ASCOAbstract4026 synchronousstageIVcolorectalcancer 是否需要切除原发灶 是否需要修改CRC分期标准 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 neverrequiredanydirectsymptomaticmanagementfortheirintactprimaryConclusions MostpatientswithsynchronousstageIVCRCwhoreceiveup frontmoderncombinationchemotherapyneverrequirepalliativesurgeryfortheirintactprimary Thesedatasupporttheuseofchemotherapy withoutroutineprophylacticresectionneitherobstructednorhemorrhaging 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 2009ASCOAbstract4099 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 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 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 2009ASCOAbstract4125 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 Background todeterminetheimpactofCCandage 70and 70yrs onsurvivalandtoxicityinmCRCptsPatients fromCALGB80203Results Conclusions WhiletheearlyclosureofCALGB80203presentssamplesizelimitationsforsubsetanalyses wedidnotobserveanimpactonPFSorOSbyageand orCC Olderptsdidexperiencemoretoxicityfromrx Meyerhardtetal 2009ASCOAbstract4038 Object Doesdelayofadjuvantchemotherapyaffecttheclinicaloutcomeinpatientswithcoloncancer MethodsGroup1 within60daysGroup2 after60daysResults groupIgroupIIpvalueFive yearOS75 2 61 3 HR2 11 p 0 049Five yearRFS65 7 59 0 HR 1 19 p 0 570Conclusions DelayofACmorethan60daysafterresectionisassoc