大肠癌肝转移综合治疗进展教学课件

LiverMetastasesofColorectalCancer:

Wherearewestandingincurrentpractice?大肠癌肝转移综合治疗进展郝纯毅季加孚北京肿瘤医院外科LiverMetastasesofColorectal1我的老婆和丈母娘我的老婆和丈母娘2BreastcancerWithpositiveAxillarylymphnodesColorectalcancerWithLivermetastasesDifferent?Similar!BreastcancerColorectalcancer315~25％patientswithprimaryCRCpresentwithsynchronouslivermetastasesAnadditional20%willdevelopmetachronoushepaticsecondaries20%arecandidatesforcurativeresectionoflivermetastasesU.S.150000newcases20000~30000China500000newcases70000~100000EPIDEMIOLOGY15~25％patientswithprimaryC4author yearpatients opmortality5yearsuvival#(%)(%)Adson1984 1412.8 23Hugues1986 859 5 33Nordlinger1987 80525Nordlinger1996 1568 2.3 26Fong199910012.837Yamamoto199996━51Minagawa*2000 235 038Scheele2001 5165.838OverallResultsofHepaticResectionforCRCMetastasesauthor yearpatients opmor5Longtermresults(Frenchstudy,n=1985)

5yearsurvivalOverall 26% Confinedtoliver 28%Withextrahepaticextension 15%Positivenodes 12%Palliativeresections 0%Longtermresults(Frenchstu6OverallSurvivalafterResection(FrenchStudy)LiveronlyOverallSurvivalafterResecti7OverallSurvival-DiseaseFreeSurvival(Frenchstudy)OverallSurvival-DiseaseFree8PrognosticFactorsafterR0-resection(Ｉ)Demographicfeatures:gender,agePrimarytumor:LNinvolvement,size,differentiation,stagingandlocation(espinsychronousmetastases)Metastases:multiplicityoflesionsandtheintrahepatictumordistribution?SatellitemetastasesSizeoftumorHistopatholigicalfeaturesSynchronousandmetachronousmetastasesPrognosticFactorsafterR0-re9PrognosticFactorsafterR0-resection(Ⅱ)TherapeuticapproachOthers:PS,weightloss,serumalbumin,preoperativeCEA,tumorploidy,oncogen/oncosupressorgeneexpression,etc.SurgeonperformingtheoperationPrognosticFactorsafterR0-re10PrognosticFactorsInfluencingSurvivalandRecurrences(FrenchStudy) RiskFactors RelativeRiskPrimarytumor:serosa+ 1.4Primarytumor:N+ 1.5Delay(primarytometastase)<2years 1.4Numberofmetastases>3 1.6Resectionclearance<1cm 1.4Sizeofmetastases>5cm 1.3Age>60yrs 1.2PlasmaCEA>30ng/ml 2.2PrognosticFactorsInfluencing11SurvivalAccordingtoNumberofRiskFactorsNordlingerB.Cancer1996;77:1254-620-276%01008060402052103years43-459%5-744%SurvivalAccordingtoNumbero12*FongY.AnnSurg1999;230:309-321SurvivalAccordingtotheNumberofMetastases010080604020602412036Months48ONE

42%TWOtoTHREE30%MOREthanFOUR

23%*FongY.AnnSurg1999;230:30913ProbabilityofsuvivalyearsfromR0resection1098765432101.9.8.7.6.5.4.3.2.10≥4metastases(n=48)1~3metastases(n=425)Scheeleetal,1999SurvivalAccordingtotheNumberofMetastasesP=0.99Probabilityofsuvivalyearsfr14*JaeckD.AnnSurgOncol2002;9:430-8

SurvivalAfterResection━NodesinLiverPedicle010080604020301260182436N-N+proximalN+distal*JaeckD.AnnSurgOncol2002;151.8.6.4.201086420Multiplebilateral(n=79)Multipleunilateral(n=121)Solitary(n=273)102129462687P=0.25yearsProbabilityofsurvivalInfluenceofNumberandDistributionofCRCMetastasesScheeleetal,1999OperativemortalityexcludedR0resection1.8.6.4.201086420Multiplebila161.8.6.4.208642010yearsProbabilityofsurvivalR0resection(n=490)Disease-freesurvivalR1/2resection(n=114)SurvivalafterLiverResectionforCRCLiverMetastasesP=4.9*10-34vs29.5%(60)28.3%(57)41.3%(159)35.4%(137)1.8.6.4.208642010yearsProbabil17ContraindicationstoCRCLiverMetastasesRadical(R0)resectionnotpossiblebut:occasionallyjustifiedforsymptomaticpalliation(RARE！)Lymphnodesmetastasesattheliverhilumbut:anecdotalsuccessreportedbyNakamura,1992Extrahepatictumorexceptfordirectinvasionofadjacentstructures,localrecurrence,andasolitary(1~3?〕lungmetastases

━━━Asforanysurgicalproceduretherearepatients,andsituations,inwhichtheriskoftheprocedureistoohighinrelationtothepotentialbenefits.ContraindicationstoCRCLiver18FactorsContributingtotheImproved

ResultsofLiverMetastasesofCRC肝脏外科技术的提高一些新的辅助/姑息治疗手段的出现术前影像诊断技术的改进多中心、大规模临床总结的发表(回忆性、多中心/非前瞻性随机对照研究〕FactorsContributingtotheIm19PreoperativeInvestigationTheprimarytumorsiteTheextentofliverinvolvementThepresenceofextrahepaticdiseaseMarkerstoprovideabaselineforfollow-upPreoperativediagnosticstudiesmustbesupplementedbythoroughintraoperativeassessmentPreoperativeInvestigationThe20TimingOfLiverResectiona“testoftime〞rangingfromseveralweeksto6monthsThereexistscontroversy,andnoconclusivedataareavailabletosupporteitheroftheassertions,whichallowsstatementofpersonalposition.Metastasisexceeded4cmindiameter━━resectatfindingthetumorhasalreadypassedthe“testoftime〞Verysmalllesions━━waitforaperiodwithin3monthsrecheckthelesionsbyultrasoundat4-weekintervalsTimingOfLiverResectiona“t21TechnicalAspectsofLiverResection(Ｉ)

━━TheprimegoaliscompletetumorremovalwithclearmarginsandwithminimaloperativeriskSelectionoftheprocedure:anatomicalandnon-anatomicalproceduresParenchymaltransectionFingerfracture,ultrasonic/waterjetdissectorsInflowocclusionTechnicalAspectsofLiverRes22TechnicalAspectsofLiverResection(Ⅱ)

━━TheprimegoaliscompletetumorremovalwithclearmarginsandwithminimaloperativeriskManagementoftherawsurfaceRisksofresectionMortality:0~5%,morbidity:10~15%QualityoflifeTechnicalAspectsofLiverRe23TherapeuticOptionsinCaseof

TumorRecurrenceUsuallyoccurswithinthe1sttwoyears20%ispossibleforthe2ndR0resection,andthe5-yearsurvivaliscomparabletothe1stR0resectionSimilarresultsobtainedaftersubsequentresectionoflungmetastasesThesedatawarrantaclosefollow-uppolicyafterthe1stR0resection!TherapeuticOptionsinCaseof24 number mortalitymorbidity5yearsurvivalTutle(1997) 23 0 22% 32%Adam(1997) 64 0 ━ 26%Yamamoto(1999) 90 0 ━ 31%Imamura(2000) 20 0 18% 22%Nordlinger(1996)143 1 25% 16%

SurvivalAfterRe-resectioninRecurrentPatients number mortalitymorbidity25AdvancesofintheTreatmentofColorectalCancer1980198519901995200020055-FUIrinotecanCapecitabineOxaliplatinCetuximabBevacizumabTherapeuticconceptspalliativeCtxadjuvantCtxneo-adjuvantCtxAdvancesofintheTreatmento26Docombinationtherapiesofferadvantageover5FUalone?Oxaliplatinbasedregimens: MOSAIC&N9741 NSABPCO-7Irinotecanbasedregimens: CALGB PETACCDocombinationtherapiesoffer27MOSAICLVOxaliR*BaxterLV5infusorsLV5FU2FOLFOX4:LV5FU2+oxaliplatin85mg/m²Every2weeks,12cyclesoftreatmentLVLV5-FUinfusion*5-FUinfusion*LVLV5-FUinfusion*5-FUinfusion*D1D1D2D25-FUbolus5-FUbolus5-FUbolus5-FUbolusMOSAICLVOxaliR*BaxterLV5infu28IROX CPT-11: 200mg/m2d1q3wks Oxaliplatin: 85mg/m2d1q3wks IFL CPT-11: 125mg/m2/wkx4wks,q6wks 5FU: 500mg/m2/wkx4wks,q6wks LV: 20mg/m2/wkx4wks,q6wks

FOLFOX4 Oxaliplatin: 85mg/m2d1q2wks 5-FU: 400b/600CImg/m2d1,2q2wks LV: 200mg/m2d1,2q2wks

N9741RIROX IFL FOLFOX4 N9741R29NSABPC-07CompletedphaseIIItrial158NSABPinstitutionsRFLOX(Eloxatin®+LV+5-FUi.v.)BolusFL(LV+5-FUi.v.)StageII~IIIRoswellParkregimen(5-FUperweekx6,2weeksrest,threecycles;24weekstotal)RoswellParkregimen(5-FUperweekx6,

2weeksrest,threecycles;24weekstotal)+Eloxatin®85mg/m2/2hrsi.v.SmithR,etal.ProcAmSocClinOncol2003;22(abst1181)NSABPC-07CompletedphaseIII30XELOXinCRCOralCapecitabine

1,000mg/m2,BidRepeatatday22Díaz-RubioEetal.AnnOncol2002;13:558–65Day1(pm)15(am)Eloxatin130mg/m2(2-hourinfusion)1815RESTDayXELOXinCRCOralCapecitabine

31MetastasesfromColorectalCancerbeforeFOLFOXafterFOLFOX〔12cycles)rightlobectomy+cryo.onleftlobeMetastasesfromColorectalCan32Infusional5-FU/LVBackbones600600400400LV5FU2q2wks2400400sLV5FU2q2wks2400vsLV5FU2q2wks2600AIOweeklyxxxxOxaliplatinIrinotecanFOLFOX4

85(mg/m2)FOLFOX6100(mg/m2)FOLFOX7130(mg/m2)FUFOX50(mg/m2)“Douillard〞180(mg/m2)FOLFIRI180(mg/m2)FUFIRI80(mg/m2)2000D1D2Infusional5-FU/LVBackbones6033ResectionratesafterFOLFOXininitially

un-operablepatientsStudy GiacchettiGiacchettiAdamAlbertsTournigandResected

51%32%13.6%35.7%21.0%R0resection38%21%13.6%28.5%12.6%5-yrsurvival50%–35%

––ResectionratesafterFOLFOXi3454%ProportionSurvivingSurvivalTime(years)29%34%50%34%19%27%1098765432101.9.8.7.6.5.4.3.2.10Resectable

(n=425)Initiallynon－resectable

(n=95)Bismuthetal,1996SurvivalafterPrimaryorSecondaryResectionofLiverMetastases54%ProportionSurvivingSurviva35Oxaliplatincombinationsasfirst-linetherapyinadvancedCRC22.350.70.00011653<0.000114.716.2n.s.6.29.0<0.0001FU/LVinf.FOLFOX4p-valueDeGramont,JCO8/2000#42019.919.4n.s.6.18.70.048FU/LVinf.FOLFOXp-valueGiacchetti,JCO1/2000#20022.649.1<0.000116.119.7n.s.5.37.80.0001FU/LVBolus(Mayo)FUFOXp-valueGrothey,ASCO2002#252RR(%)OS(mos)PFS(mos)ProtocolAuthorOxaliplatincombinationsasfi36Irinotecancombinationsasfirst-linetherapyinadvancedCRC3149<0.0012139<0.00114.117.40.0314.46.7<0.001FU/LVinf.“Douillard〞p-valueDouillard,Lancet3/2000#33812.614.80.044.37.00.004FU/LVbolus(Mayo)IFLp-valueSaltz,NEJM9/2000#45731.554.2<0.000116.920.1n.s.6.48.50.0001FU/LVinf.FUFIRIp-valueKoehne,ASCO2003#430RR(%)OS(mos)PFS(mos)ProtocolAuthorIrinotecancombinationsasfir37Capecitabine/Oxaliplatin1VanCutsemEetal.ASCO2003(Abst1023)2GrotheyAetal.ECCO2003(Abst295)3GoldbergRetal.ASCO2003(Abst1009)

4deGramontAetal.JClinOncol2000;18:2938–47Capecitabine/Oxaliplatin1Van38Capecitabine/Irinotecan1PattYZetal.ASCO2003(Abst1130)2GrotheyAetal.ASCO2003(Abst295)

3GoldbergRetal.ASCO2003(Abst1009)

4DouillardJYetal.Lancet2000;355:1041–7Capecitabine/Irinotecan1Patt395-FU/LV+OxaliplatinasNeo-adjuvantTreatmentinMetastaticCRCGiacchettietal.,AnnOncol1999151patientswithinitiallyunresectablelivermetastasesPrimaryCtxwithOxaliplatin+5FU/LV51%ofpatientsunderwentsecondaryliverresection74non-operablepts58pts:macroscopically

completeresection50%77operatedpts30%0123456789020406080100yearsOverallsurvival(%)5-FU/LV+OxaliplatinasNeo-40SecondarySurgery:FROMCARETOCURE

NewGoalsintheTreatmentofAdvancedCRC020406080100Overallsurvival(%ofpts)TimeCtx=ProlongationCtx+Surgery=Cure?SecondarySurgery:FROMCARET41Dose-to-Grade3NeurotoxN9741010203040506070809010005001000150020002500CumulativeOxaliplatinDose(mg/m2)%NeurotoxFreeDose-to-Grade3NeurotoxN974142MurineAb“momab〞ChimericMouse-HumanAb“ximab〞HumanizedAb“zumab〞FcFabHumanAbMonoclonalAntibodiesinOncology17-1ACetuximabBevacizumab(Trastuzumab)EMD-72000ABX-EGFMurineAbChimericHumanizedAbF43Canwefurtherimproveresultswithbiologicals?Anti-EGFR:Cetuximab(C-225)Anti-VEGF:BevacizumabCanwefurtherimproveresults44大肠癌肝转移综合治疗进展教学课件45TheAngiogenicSwitch1-2mmAngiogenicSwitchSmalltumorNonvascular“Dormant〞LargertumorVascularMetastaticpotentialTheAngiogenicSwitch1-2mmAng46...................................................................................................................................................MaturationfactorspresentNormalandTumorVasculatureNormalBloodVesselsTumorBloodVesselsReducedintegrinexpressionLessdependentoncellsurvivalfactors.........LesspermeableLeakyPreferentialexpressionofv3v5&51integrinsFewerpericytesGrowthandsurvivalfactors(eg,VEGF)present.........Supportingpericytespresent..............................47FutureofAdjuvantTherapyinCRCIntegrationofnewtherapeuticsOxaliplatinandIrinotecanCapecitabineassubstitutefor5-FU/LV?BevacizumabandCetuximabIndividualizationoftherapyPrognosticfactorsPredictiveparametersPharmacogenomics!?FutureofAdjuvantTherapyin48PrognosticFactorsDendriticcell

countsAlleles:

CCND1870ABRCA1LOHMutations:p53K-rasMad2Invasion:

DepthLymphaticVenousPerineuralSerosalDifferentiationNo.ofnodespositiveDNAploidyCEASurgicalskillMSI/MSSLOH18qSocioeconomic

statusNo.ofnodes

examinedPerforationOcclusionPrognosticFactorsDendriticce49AchievementsandGoalsinCRCBSC1980s5-FU/LV1990s5-FU/LV/Irino20005-FU/LV/Oxali2000FOLFOX/FOLFIRIFUFOX200206121824(mos)medianOS"all3drugs"

+molecularTx?AchievementsandGoalsinCRCB50Whatisthefutureadjuvanttherapyincoloncancer?PresentPatientsABAllpatientsreceive

standardtherapyAClinicaltrialsSurvivalbenefitinAFuturePatientsPrognostic/

predictivefactors

PharmacogenomicsABCDIndividualized

adjuvant

therapyWhatisthefutureadj