系统性大肠癌治疗PPT课件.ppt

系系统统性大性大肠肠癌治癌治疗疗AdenomatoCarcinomaPathwayAdenomaNormalCancerNormalepitheliumDysplasticACFEarlyadenomaLateadenomaCarcinomaMetastaticcarcinoma5qLOH*(APC/-catenin)?K-ras?K-ras18qLOHDCC/SMAD4/SMAD217qLOHMMRactivationACF=aberrantcryptfoci;MMR=mismatchrepair.Stage Systems:Terminology vs.Contents(概念与内涵);Populations vs.Individuals(群体与个体)Stage IStage IIStage IIIStage IVDisease developmentStagingT1,N0,M0T2,N0,M0A:T3,N0,M0B:T4a,N0,M0C:T4b,N0,M0A:T1-2,N1a-c;T1,N2a;B:T3-4a,N2a,T2-3,N2a;T1-2,N2bC:T4a,N2a;T3-4a,N2b;T4b,N1-2M1:Distal MetastasisM1a:One organ site(liver,lung,ovary,nonregional node)M1b:one organ/site or PeritoneumDefinitionInvades submucosa(T1)/muscular propria(T2)T3:Invades through muscularis propria into pericolorectal tissuesT4a:penetrates to the surface of the visceral peritoneumT4b:invades or is adherent to other organs or structuresN1:metastasis in 1-3LNN1a:1 LN,N1b:2-3LN N1c:deposits in the subserosa,mesentery,oro nonperitonealized pericolic tissue w/o LNN2:4LNN2a:4-6 LN,N2b:7 LNInvolves distant metastasesUsual treatmentSurgerySurgery chemotherapySurgery+chemotherapyChemotherapy surgerySEERColonCancer1973-2005(USA)N=28,49101 yr.2 yr3 yr4 yr5 yrI91.487.082.678.274.0IIA89.983.477.872.068.5IIB85.477.869.162.958.6IIC66.052.545.341.537.3IIIA98.388.083.679.173.1IIIB83.470.859.351.746.3IIIC71.950.339.032.928.0IV39.919.711.37.65.7HistoryofTherapeuticRegimensfortheTreatmentofMCRC*Both first-and second-line exposure to therapy.Van Cutsem and Verslype.ASCO Educ Book.2002.MedianOS*(mo)061218244-6mo12-14mo15-20mo15-17mo11-12mo1980s2000s1990s1960s5-Fluorouracil(5-FU)5-FUbiomodulationIrinotecanOxaliplatin5-Fluorouracil(5-FU)AdvancesintheTreatmentofColorectalCancer198019851990199520002005TherapeuticconceptsPalliative CTAdjuvant CTPre-operativeCTCapecitabineOxaliplatinCetuximabBevacizumabIrinotecan5-FUPanitumumabTargetedtherapiesKRas WT/MTBraf2008ManagementofMCRC:AnEvolvingTreatmentAlgorithmDiagnosisofMCRCResectableUnresectableAdjuvanttherapySurgeryNeoadjuvant/preoperativetherapyFirst-lineSecond-lineThird-lineBorderline/potentiallyresectableFourth-lineTreatmentcontinuumChemotherapyFluorouracil:5-FU,Xeloda,(S-1):efficacy,dose,vs.toxicityEnzymes vs.food.FOLFOX/XELOX vs.FOLFIRI(XELIRI):1st line vs.2nd lineRegimens FOLFOX(4,6,7),XELOX,Neurological Toxicity:Dose modification vs.Maintenance FOLFIRI:Irintotecan-UGT1A1:*28-6/6,6/7,7/7Avastin:When,how?Cetuximab in WT patients0.00.10.20.30.40.50.60.70.80.91.006121824303642MonthsIrinotecan/5-FU/LV(N=231)5-FU/LV(N=226)IFLP=0.042*Probability*log-ranktestlog-ranktest14.814.8momo12.612.6momoFOLFIRI*MediansMediansLog-ranktestLog-ranktestp0.032p0.032 CPT-11/5-FU/LV(N=198)CPT-11/5-FU/LV(N=198)5-5-FU/LV(N=187)FU/LV(N=187)17.417.4mo*mo*14.114.1mo*mo*MonthsMonthsProbabilityProbability0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.00 06 61212181824243030600600DouillardDouillardB400FOLFIRIFOLFIRIRegimens200B4001802004001802400-3000B400OverallSurvivalIFLFOLFOXPvalueIROXRR31%45%0.00234%TTP6.9m8.7m0.00146.5mOS14.8m19.5m0.000117.4m600600FOLFOX4B400mFOLFOX62400FOLFOX7FOLFOXRegimens200B40085200400852400-3000400130B400mFOLFOX74001003000FOLFOX64001002400-3000B400CPT-11180mg/mCPT-11180mg/m2 2+simplifiedLV5FU+simplifiedLV5FURandomized,multicentric,open-label,prospective,phaseIIItrialFOLFIRIFOLFIRIFOLFOX6FOLFOX6L-OHP100mg/m2IV+simplifiedLV5FURFOLFOX6FOLFOX6FOLFIRIFOLFIRIuntil progressionuntil progressionuntil progressionuntil progressionArmAArmBFOLFIRIvs.FOLFOXProbability0.00.20.40.60.81.006121824303642MonthsLogrank p=0.9 FOLFIRI/FOLFOXFOLFIRI/FOLFOXFOLFOX/FOLFIRIFOLFOX/FOLFIRIOverallSurvivalFOLFIRI/FOLFOXFOLFOX/FOLFIRIMedian(months)20.416.7-24.921.517.3-24.8Events/patients65/10967/111Medianfollow-up18.6monthsOPTIMOX-1Tournigandetal,JCO20066xFOLFOX7-12xsLV5FU2-6xFOLFOX7FOLFOX4620ptsRCum.Oxali7801560(%)FOLFOX4FOLFOX7RR58.558.3PFS9.08.7DDC9.010.6OS19.321.2G3/4NTox17.913.3PrimaryendpointOPTIMOX StudiesOPTIMOX-1FOLFOX4untilTFFOLFOX7FOLFOX7sLV5FU2OPTIMOX-2mFOLFOX7mFOLFOX7sLV5FU2mFOLFOX7mFOLFOX7CFICFI:ChemotherapyFreeIntervalPhase II OPTIMOX2 Trial:Study DesignOPTIMOX1:maintenance therapy mFOLFOX7 x 6 cyclessLV5FU2 until baseline progressionFOLFOX7 reintroductionOPTIMOX2:chemotherapy-free intervalmFOLFOX7 x 6 cycles No maintenance until progressionFOLFOX7 reintroductionRANDOMIZATIONmFOLFOX7LV 4005-FU 3000Oxali 100H0 H2 H24 H48sLV5FU2LV 4005-FU 3000H0 H2 H24 H485FUb 4001 cycle=14 daysDose=mg/m2PhaseIIITrialBevacizumabinFirst-LineMCRC(AVF2107g)*PatientsreceivingAvastincouldcontinuetherapypastdiseaseprogressionincombinationwithsecond-linetherapy.Previously untreated MCRC(n=923)IFL+placebo(n=411)5-FU/LV+bevacizumab(5 mg/kg,q2w)(n=110)IFL+Bevacizumab(5 mg/kg,q2w)(n=402)Primary endpoint:SurvivalPhaseIIITrialofBevacizumabinFirst-LineMCRC:EfficacyIFL+Placebo(n=411)IFL+Avastin(5mg/kg,q2w)(n=402)PValueHazardRatioMedian OS(mo)15.620.30.001*0.66PFS(mo)6.210.60.001*0.54ORR(%)35450.01Duration of response(mo)7.110.4PhaseIIITrialofBevacizumabinFirst-LineMCRC:SurvivalError bars represent 95%confidence intervals.PercentsurvivingMonths2001218300801004060TreatmentGroupIFL+placebo(n=411)IFL+Avastin(n=402)246Mediansurvival:15.6vs20.3moP0.001E3200:High-doseBEV+FOLFOX4:StudyDesignRANDOMIZE FOLFOX4+Bevacizumab(BEV 10 mg/kg q2 wk)(n=289)N=822Previously treated mCRCFOLFOX4(n=290)Bevacizumab(10 mg/kg q2 wk)(n=243)E3200(FOLFOX+Bevacizumab):Overall SurvivalP r o b a b i l i t y0.00.10.20.30.40.50.60.70.80.91.0OS(months)0369121518212427303336ALIVEALIVEDEADDEADMEDIANMEDIANTOTALTOTALA:FOLFOX4+bevacizumabA:FOLFOX4+bevacizumab289289246246434312.912.9B:FOLFOX4B:FOLFOX4290290257257333310.810.8C:bevacizumabC:bevacizumab243243216216272710.210.2HR=0.76AvsB:p=0.0018BvsC:p=0.95Bevacizumab with 5-FU/LV:PFSHazardratio=0.50MedianPFS:5.5vs9.2(P=0.0002)200630080100406024MonthsPercentprogression-free18125-FU/LV+Avastin(n=104)5-FU/LV+placebo(n=105)Bevacizumab with 5-FU/LV:OverallSurvivalHazardratio=0.79Mediansurvival:12.9vs16.6mo(P=0.16)200630080100406024MonthsPercentsurviving5-FU/LV+Avastin(n=104)5-FU/LV+placebo(n=105)1812XELOX+placebon=350FOLFOX-4+placebon=351XELOX+bevacizumabn=350FOLFOX-4+bevacizumabn=349XELOXn=317FOLFOX-4n=317Initial 2-arm open-label study(n=634)Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III data became available(n=1400)RecruitmentJune 2003 May 2004RecruitmentFeb 2004 Feb 2005XELOX-1/NO16966 Trial:Study Design EffectofBevacizumabonPFSHR=0.8397.5%CI0.720.95p=0.0023XELOX+placebo(X+P)FOLFOX-4+placebo(F+P)XELOX+bevacizumab(X+A)FOLFOX-4+bevacizumab(F+A)VS036912151821monthsPFSestimate9.4m8.0m1.00.80.60.40.20CRYSTAL:studydesignPrimary endpoint:PFSSecondary endpoints:OS,ORR,safetyFOLFIRIFOLFIRI+cetuximabRFirst-linemCRC,unresectable(n=1198)VanCutsem,etal.NEJM2009CRYSTAL:K-rasWTefficacyupdateCRYSTAL updateCetuximab plus FOLFIRI vs FOLFIRI(n=666)OS,months23.5 vs 20.0(HR=0.796;p=0.0094)PFS,months9.9 vs 8.4(HR=0.696;p=0.0012)ORR,%57.3 vs 39.7(OR=2.0693;p0.0001)VanCutsem,et.ECCO-ESMO2009(abstractNo.6077)Lang,etal.ECCO-ESMO2009(abstractNo.6078)CRYSTALK-rasWTefficacyupdate:significantlylongerOSinthecetuximab+FOLFIRIgroupVanCutsem,etal.ECCO-ESMO2009(abstractno.6077)Probabilityofoverallsurvival1.00.90.80.70.60.50.40.30.20.1006121824303642485460Time(months)350316311281246237179198132144921086482486518212400Numberofpatients:FOLFIRICetuximab+FOLFIRICetuximab+FOLFIRIFOLFIRINo.ofeventsMedianOS95%CIHR(95%):p-value:FOLFIRI(n=350)28820.017.421.70.7960.6700.9460.0094(log-rank)Cetuximab+FOLFIRI(n=316)24223.521.226.3OPUS:studydesignPhase IIPrimary endpoint:ORRSecondary endpoints:rate of curative metastatic surgery,duration of response,disease control rate,PFS,OS,safetyFOLFOX4FOLFOX4+cetuximabRFirst-linemCRCunresectable(n=337)Bokemeyer,etal.JCO2009OPUS:K-rasWTefficacyupdateOPUS updateCetuximab plus FOLFOX4 vs FOLFOX4(n=179)OS,months22.8 vs 18.5(HR=0.855;p=0.3854)PFS,months8.3 vs 7.2(HR=0.567;p=0.0064)ORR,%57.3 vs 34.0(OR=2.5512;p=0.0027)Bokemeyeretal.ECCO-ESMO2009(abstractNo.6079)PRIME:studydesignPrimary endpoint:PFS by K-ras statusSecondary endpoints:OS,ORR,duration of response,time to response,safety Study populationOriginally designed to study the overall populationdesign amended to analyse outcomes with respect to the presence or absence of K-ras mutationstumour K-ras status not ascertained in all patients(3 metastases(P5 cm(P=0.03)Preoperative CT improved survival only in patients with 5 metastasesAdam et al.ASCO,2006.Abstract 3521.66 patients Liver only mets with CR on CT scanafter ChemotherapySurgeryMacroscopic cancer:20No lesion:4615 site resected31 sites left in placeViable tumor cells:12In situ recurrence:2355/66(83%)of Metastases were not curedNordlinger JCO2008TreatmentOptions&HowLongCyclesFOLFOXCRFOLFOX+BevCRpOverallRRp18 cycles38/81(43%)44/76(58%)0.0001757%0.738912/40(30%)15/22(68%)0.001155%MaruDMetal.ASCOGI2009,abs:295CyclesSinusoidalInjuryLiverInsufficiency18 cycles26%4%942%11%p0.0170.035Adjuvant5-FU(Capecitabine)vs.FOLFOX(XELOX)Avastin?Cetuximab in WT patients?Goal of Adjuvant ChemotherapyTo eradicate micrometastases,thereforeTo increase cure/survival rate after curative surgical resectionFive-year DFS(%)Five-year OS(%)5-FU/LEV,12months56635-FU/LV(HD),6monthsRoswellPark59655-FU/LV(LD),6monthsMayo60665-FU/LV/LEV,7months6067Numberofpatients=3759Standard Adjuvant therapy(1998-2004)(Based on INT 0089)Haller,D.G.etal.JClinOncol;23:8671-86782005X-ACTtrialinadjuvanttreatmentofDukesCcoloncancer1endpoint:disease-freesurvival(DFS)2 endpointsrelapse-free survival(RFS)overall survivaltolerability(NCIC CTC)pharmacoeconomicsQoL Chemo-naveDukesC,resection 8weeksCapecitabine:1250mg/m2twicedaily,d114,q21dn=1004Bolus5-FU/LV:5-FU425mg/m2plusLV20mg/m2,d15,q28dn=983Recruitment1998200124weeksConfirmed by per protocol analysis,HR 0.89(95%CI 0.76-1.04)PrimaryendpointmetandtrendtosuperiorDFS(ITT)1.00.80.60.40123456YearsEstimatedprobabilityHR=0.87(95%CI:0.751.00)p=0.05283-yearCapecitabine(n=1004)64.2%5-FU/LV(n=983)60.6%Phase III MOSAIC RFOLFOX4LV5FU2(de Gramont)6months(12Cycles)Aim:25%decrease in recurrent risk at 3 years(Expect 3-year DFS:79%vs.73%)2,236 pts148 Centers20 CountriesMOSAIC 4-yr DFS:ASCO 20051.00.90.80.70.60.50.30.40.20.10.0 0FOLFOX4LV5FU2HR 95%CI:0.75 0.62 0.89(0.76 0.62-0.92)DFSprobability666121824303642485460Data cut-off:January 16,20058.6%(6.9%)Disease-freeSurvivalinStageIIIPatients:N1&N2DeGramont,A,etalProc.ASCOGIJan.2005661.00.90.80.70.60.50.30.40.20.10.0 0FOLFOX4 N1LV5FU2 N1FOLFOX4 N2 LV5FU2 N2MonthsDFS61218243036424854607.2%11.5%HR:0.76HR:0.72NSABPC-07FU500+LV500weeklyx6every8weeksx3+Oxaliplatin85weeks1,3&5ofeach8weekcycleN=2492Primary endpoint:3-year DFSp0.004HR:0.790.670.9321%RiskReductionNSABP C-07 Trial(FLOX vs.FU/LV)3-year Disease-free Survival0.50.60.70.80.9101234NSABPC-07:toxicityandmortality1.0%4.7%1.1%8.0%1.2%2.8%0246810Gr3NCI-sanofineurotoxicityDiarrhea/dehydration*DeathsPercentageofpatientsFU/LVFLOX*Diarrhearequiringhospitalizationanddehydrationduetobowelthickening0.5%at12monthsWolmark et al.ASCO 2005;Abstract LBA35003-yrDFSHRC-0776.5%4.9%0.79MOSAIC77.9%5.1%0.77C-07andMOSAIC3-yrDFS:StageIIandIIIChemo/radiotherapy-naivestageIIIcolon8weekssinceresectionN=1886Primaryendpoint:superiorityofDFSSecondaryendpoints:RFS,OS,tolerabilityn=944n=942RANDOMISATIONAdjuvantXELOXvs5-FU/LV:NO16968(XELOXA)PhaseIIItrialBolus5-FU/LV(6months)MayoClinicn=664orRoswellParkn=278XELOX(6months)capecitabine1000mg/m2bidd114oxaliplatin130mg/m2d1q3w8cyclesBaselinetumourcharacteristicsXELOXn=9445-FU/LVMayon=6645-FU/LVRoswelln=278Primarytumour(%)T1326T2878T3747376T415189Regionallymphnodes(%)N1656467N2353633Numberoflymphnodesexamined12515055Schmolletal.JCO2007DiarrhoeaNeutropenia/granulocytopeniaHFS(grade3)Neurosensorytoxicity*Similarratesofgrade3/4AEs(5%)inallarms*NotreportedSafetypopulationNauseavomiting0102030Patients(%)40XELOX(n=938)5-FU/LVMayo(n=657)5-FU/LVRoswell(n=269)Stomatitis*Schmolletal.JCO2007Doseintensity/treatmentmodifications*Ratiodosereceivedvsplanned5-FU/LV(n=926)Mayo(n=657)RP(n=269)XELOX(n=938)Median dose intensity*85%87%84%Cape 84%Oxal 87%Reductions47%49%44%Cape 30%Oxal 35%Interruptions15%8%32%Cape 14%Oxal 0%Delays37%42%26%Cape 56%Oxal 54%5-yearDFS:benefitwithXELOXmaintainedandincreasedovertimeXELOX5-FU/LV1.00.00.20.40.60.80123456YearsITTpopulationat4years:6.1%at5years:6.3%at3years:4.5%70.9%68.4%3-yearDFS66.5%62.3%4-yearDFS5-yearDFS59.8%66.1%Years2460.40.60.81.000.40.60.81.0Years824608Cross-trialcomparisonofMOSAICandXELOXA:OSinstageIIIdiseaseXELOX5-FU/LVFOLFOX4LV5FU2XELOXA(57mo)MOSAIC1(81.9mo)ITTpopulation1.00.60.81.Andretal.JCO200912345678Cross-trialcomparisonofMOSAICandXELOXA:OSinstageIIIdiseaseYearsXELOX(n=944)FOLFOX4(n=672)5-yrOS6-yrOS72.9%77.6%NO16968(XELOXA)*MOSAIC1*Medianobservationtime:57.0months*Medianfollow-up:81.9monthsITTpopulation0.40NO16968subgroupanalysisofDFSbyage3-year DFSHazard ratio(95%CI)XELOX5-FU/LV65 vs.65 years 65 years,n=114272%69%0.80(0.65,0.98)65 years,n=74468%62%0.81(0.64,1.03)70 vs.70 years 70 years,n=147772%69%0.79(0.66,0.94)70 years,n=40966%60%0.87(0.63,1.18)ITTpopulationNO16968subgroupanalysisofOSbyageITTpopulation5-year OSHazard ratio(95%CI)XELOX5-FU/LV65 vs.65 years 65 years,n=114280%77%0.87(0.67,1.13)65 years,n=74473%70%0.90(0.68,1.19)70 vs.70 years 70 years,n=147780%76%0.86(0.69,1.08)70 years,n=40969%67%0.94(0.66,1.34)1.Saltzetal.JCO20072.VanCutsemetal.JCO2009;3.Ychouetal.AnnOncol2009NR=notreportedTrialDFSHRDFS (%)pCALGB 898031NRNR0.85PETACC-320.902.40.11ACCORD-230.893.10.44Irinotecancombinations:NOsurvivaladvantageinstageIIIOSHROS (%)pNRNR0.74NR2.30.091.0910.69IrinotecanasAdjuvantsetting:NoBenefit,moretoxicitiesnoRole24weeks24weeksNSABPC-08:BevacizumabasAdjuvantSettingPrimary endpoint:DFS at 3 yearsSecondary endpoints:survival and tolerabilityPatient recruitment completed 10/06mFOLFOX6alonemFOLFOX6+Bevacizumab5mg/kgevery2weeksStageIIIcoloncancer(n=2,710)Bevacizumab5mg/kgevery2weeksObservation Ev3yDFSmFF6+B29177.4mFF631275.5HR=0.89P=0.15NSABP-08:DFS%YrsRoleofBevacizumabinAdjuvantSetting:-Notshownyet-ShouldNOTbeusedasleastrightnow.BO17920(AVANT)PhaseIIITrialPrimary endpoint:DFS at 3 years for stage IIISecondary endpoints:OS and safetyAccrual completed Q2 2007SurgeryforhighriskstageII+stageIIIcoloncancer(n=3,450)FOLFOX4FOLFOX4+Avastin(5mg/kgevery2weeks)XELOX+Avastin(7.5mg/kgevery3weeks)Avastinalone(7.5mg/kgevery3weeks)Avastinalone(7.5mg/kgevery3weeks)ObservationDurationoftreatmentphases24weeks24weeksAVANT:patientrecruitmenttimelinelOpened:December2004lClosed:June2007lTotalaccrual:3451patientslAveragemonthlyaccrual:115patientsAccrualtemporarilyonholdduetoDSMBdecision:FebruaryMay2006Hoff,etal.ECCO-ESMO2009(abstractNo.6010)AVANT:patientdemographicsHoff,etal.ECCO-ESMO2009(abstractNo.6010)CharacteristicFOLFOX4(n=1151)FOLFOX4+Avastin(n=1155)XELOX+Avastin(n=1145)Disease stage,n(%)II(high risk)III N1 III N2192(17)585(51)370(32)194(17)590(51)370(32)187(16)572(50)380(33)Male,%57 5155Median age,years 5858 58ECOG PS,%01861486148614AllpatientsrandomisedAVANT:mortalityDeath ratea,N(%)FOLFOX4(n=1126)FOLFOX4+Bev(n=1145)XELOX+Bev(n=1135)60 day 2(0.18)4(0.35)5(0.44)6 month 9(0.80)5(0.44)11(0.97)18 mo