[临床医学]ASCO大肠癌辅助化疗进展2003年

大肠癌辅助化疗的新进展ASCO03辅助化疗在大肠癌治疗中的作用•1988:NSABPC-O1–BSCvsMOF(MeCCNU,Oncovin,5FU)–三年生存率改善•1988:Meta-analysisbyM.Buyse–17随机对照研究证实–5FU辅助化疗能改善1年生存率减少复发危险40%减少死亡危险33%5FUIV+LevamisoleP0.0001(controlversus5FU+Levamisole)P0.0007(controlversus5FU+Levamisole)5FU+levamisole(n=304)Levamisole(n=310)Follow-uponly(n=315)10090807060504030201000123456789YearsfromRegistration1MoertelCGetal.AnnInternMed.1995;122(5):321-326.Patientsfreefromrecurrence(%)Patientssurviving(%)Atrisk5FU+levamisole(n=304)Levamisole(n=310)Follow-uponly(n=315)10090807060504030201000123456789YearsfromRegistrationAtriskMainstepsinadjuvanttreatmentofcoloncancer—6months=12monthsSurgery5FUleucovorin5FUlevamisole199019965FUIV+CF减少死亡危险22%减少复发危险35%IMPACT分析三个针对B2和C期病人的随机对照研究5FU=370-400mg/m2D1toD5+FA200mg/m2D1toD5(每28天重复—6疗程)n=736对照组n=7571.00.80.60.40.200123StageBStageCTimefromrandomization(years)ProbabilityofsurvivalPatientsatriskControl,StageB423403327189Fluorouracil/folinicacidStageB418399328188Control,StageC334298225125Fluorouracil/folinicacidStageC318300231161Overallsurvival1.00.80.60.40.2001234StageBStageCTimefromrandomization(years)ProbabilityofsurvivalPatientsatriskControl,StageB42334725613956Fluorouracil/folinicacidStageB41835726214060Control,StageC3342231416928Fluorouracil/folinicacidStageC31825017911842Overallsurvival1IMPACTinvestigators.Lancet.1995;345:939-944.*LeucovorinASCO1996•比较不同方案的化疗疗效:–5FU+AF–5FU+Levamisole–5FU+AF+Levamisole•有三个大宗临床研究报道:–NSABPC-04(2151patients)–INT0089(3759patients)–NCCTG-NCIC(915patients)辅助化疗方案：-ASCO1996结论5FU+CF每月方案化疗6个月:-与5FU+Levamisole化疗1年相当-优于5FU+Levamisole化疗6个月-绝对5年生存率增加:12to26%-主要获益者为DuckC期的病人Mainstepsinadjuvanttreatmentofcoloncancer—6months=12monthsSurgery5FUleucovorin5FUlevamisole19901996大肠癌辅助化疗存在的问题•B2的病人是否需要治疗•5FUBolus或CIV•新药的地位Oxaliplatine,CPT-11口服氟脲嘧啶类：CAPECITABINE,UFT正在进行的临床研究:FUFOL±CPT11oroxaliplatin?研究分期治疗分组MOSAICB2/CLV5FU2±OXARPRB2/CLV5FU2±CPT11FFCDC(4)LV5FU2±CPT11NSABPC07B2/CFUFOL±OXAOXALIPLATIN/5-FU/LVINADJUVANTCOLONCANCER:RESULTSOFTHEINTERNATIONALRANDOMIZEDPhaseIII“MOSAIC”TRIALA.deGramont,M.Banzi,M.Navarro,J.Tabernero,T.Hickish,J.Bridgewater,F.Rivera,A.Figer,G.Fountzilas,T.AndréMOSAIC:TreatmentarmsRLV5FU2FOLFOX4:LV5FU2+Oxaliplatin85mg/m²Primary:–DiseaseFreeSurvival(DFS)Secondary:–Safety(includinglong-term)–OverallSurvival(OS)EndpointsdeGramontAetal.JClinOncol2000GoldbergRetal.ASCO2002,20035-FUinfusion5-FUinfusionD15FUbolusD2LVLV5FUbolusOXAFOLFOX4inmetastaticcoloncancerComparedtoLV5FU2:improvedefficacymanageabletoxicity:neutropenia,sensoryneuropathyComparedtoIFL:improvedefficacydecreasedtoxicityLVOXARMOSAIC:Treatmentarms*BaxterLV5infusorsLV5FU2FOLFOX4:LV5FU2+Oxaliplatin85mg/m²Every2weeks,6monthsoftreatment(12cycles)D15FUbolusD25FUbolusLVLV5-FUinfusion*5-FUinfusion*D15FUbolusD25FUbolusLVLV5-FUinfusion*5-FUinfusion*MOSAIC:MaininclusioncriteriaStageII(DukesB2:T3,T4,N0,M0)andStageIII(DukesC:anyT;N1,N2,M0)CompleteresectionoftheprimarytumorTreatmentwithin7weeksfollowingsurgeryNopriorchemo-,immuno-,orradiotherapyAge18–75yearsoldECOGPS2MOSAIC:StatisticalhypothesesStageII/IIIratio=40/60%2.5yearenrollmentExpected3-yearDFS:79%fortestarmand73%forcontrolarmor25%reductioninriskofrecurrenceN=2200forastatisticalpowerof90%(a=0.05)MOSAIC:RandomizationTreatmentassignmentwasstratifiedfor:CenterExtentofinvasionoftheprimarytumor(T2,T3,orT4)Numberoflymphnodesinvolved(N0,N1,N2)BowelobstructionortumorperforationMOSAIC:Follow-upandrecurrenceEvery6months:Clinicalexamination,imaging,CEADiagnosisofrecurrence:-imaging-cytologyorbiopsyanelevatedCEA,asasolitaryfinding,wasnotconsideredasacceptableevidenceofrecurrenceMOSAIC:Accrualcurve050010001500200025002246ptsMonths2246patients病例分布2246patients477patients364patients294patients249patients135patients133patients107patients103patients69patients58patients51patients37patients36patients27patients26patients22patients21patients17patients17patients3patientsItPLFSpGrHnNLSDAtILDkNoChSgCyAuUKBMOSAIC:PatientcharacteristicsFOLFOX4LV5FU2(n=1123)(n=1123)Medianage,years6160Male/Female%56/4452/48KPS80-100%86.287.6StageII/III%40/6040/60Bowelobstruction%1819Perforation%77MOSAIC:TreatmentadministrationFOLFOX4LV5FU2Patientsrandomized11231123Patientstreated11081111Totalno.ofcycles1182912506Mean10.711.312cycles74.7%86.5%MedianRelativeDoseIntensity%Oxaliplatin81NA5-FU8598Statusofthestudybytreatmentarm(ITTpopulation)FOLFOX4LV5FU2N11231123Medianfollow-up[range]37.2[26-53]37.1[26-53]Numberofevents(%)234(20.8)288(25.6)DFSbytreatmentarm(ITT)0,50,60,70,80,9101020304050DFS(months)ProbabilityHazardratio:0.77[0.65–0.92]p0.01FOLFOX4(n=1123)77.8%LV5FU2(n=1123)72.9%23%riskreductionintheFOLFOX4arm3-yearDisease-FreeSurvivalStageIIIpatients0,50,60,70,80,9101020304050ProbabilityDFS(months)24%riskreductionforstageIIIpatientsintheFOLFOX4armHazardratio:0.76[0.62-0.92]FOLFOX4(n=672)71.8%LV5FU2(n=675)65.5%3-yearDiseaseFreeSurvivalStageIIpatients0,50,60,70,80,9101020304050Hazardratio:0.82[0.57-1.17]ProbabilityDFS(months)18%riskreductionforstageIIpatientsintheFOLFOX4armFOLFOX4(n=451)86.6%LV5FU2(n=448)83.9%3-yearDFSan