结直肠癌肝转移新辅助化疗的共识与争议课件

结直肠癌肝转移新辅助化疗的共识与争议第三军医大学西南医院肿瘤中心梁后杰结直肠癌肝转移新辅助化疗的共识与争议第三军医大学西南医院肿瘤Epidemiologyofcolorectalcancer(CRC)EpidemiologyofcolorectalcanResultsofHepaticResection

forMetastaticColorectalCancerResultsofHepaticResection

LivermetastasesofCRCLivermetastasesofCRCManagementofMCRC:

AnEvolvingTreatmentAlgorithmManagementofMCRC:

AnEvolvinNeoadj:whereisthemostcontroversyNeoadj:whereisthemostcontConceptofresectability手术的关注重点由“哪些可以切除”转变为“哪些可以保留”TimothyM.Pawlik2008Conceptofresectability手术的关注重只要能够完全切除，转移灶的个数与长期生存率无关Altendorf-HofmannA,ScheeleJ.Acriticalreviewofthemajorindicatorsofprognosisafterresectionofhepaticmetastasesfromcolorectalcarcinoma.SurgOncolClinNAm2003;12:165–192

No.ofmetandresectability只要能够完全切除，转移灶的个数与长期生存率无关No.ofm(A):不完全性切除患者的MST只有14月，而完全切除患者的MST为44月。Altendorf-HofmannA,etal.SurgOncolClinNAm2003;12:165–192.(B):只要能够完全切除，切除边界的宽度对生存时间无明显影响。PawlikTM,etal.Effectofsurgicalmarginstatusonsurvivalandsiteofrecurrenceafterhepaticresectionforcolorectalmetastases.AnnSurg2005;241:715–722;discussion722–724Marginandresectability(A):不完全性切除患者的MST只有14月，而完全切除

Neoadjuvantchemotherapy

forresectablelivermetastasesofCRCresectableNeoadjuvantchemotherapyPreoperativechemotherapy

whatarepossiblebenefits?TumorshrinkagemayfaciliteresectionwhithahopeforhighersurvivalratesTestchemoresponsivenessofmatastasesSelectcandidatesforresection-Excludetumorsprogressingwhileonchemotherapy-BemoreaggressiveonrespondingtumorsPreoperativechemotherapy

whatEORTC40983:

Peri-operativechemotherapyEORTC40983:

Peri-operativechSizeoflesionsafter

pre-opchemotherapySizeoflesionsafter

pre-opPhase3TrialofPerioperativeFOLFOX4

andSurgeryforResectableCRCLiver

Metastases(EORTC40983):PFSPhase3TrialofPerioperativeRationaleAGAINSTneoadjuvantCTRiskthatmetastasesbecomeunresectableiftheyprogressduringchemotherapyUncertaintyabouthowtodealwith“completeresponse”tochemotherapyLiverdamageinducedbychemotherapyRationaleAGAINSTneoadjuvantPreoperativechemotherapy:

potentialproblems

Lostwindowofopportunity

TumorgrowthinacriticalareamayrendermetastasesunresectableChemotherapy–inducedportalveinthrombosis

1.DonadonM,etal.WJGastroenteral12:6556,2006Preoperativechemotherapy:

potSurvivalaccordingtoresponsetoneoadjuvantchemotherapySurvivalaccordingtoresponse结直肠癌肝转移新辅助化疗的共识与争议课件

ATE：cerebralinfact,myocardialinfarction,TIA,anginaRiskfactorsfordevelopingATE–Age≥65y(P=0.01)–PriorhistoryofATE(P<0.01)Hurwizetal,NEnglJMed350:2335,2004Giantonioetal.ASCO,2005Cassidyetal,ESMO,2006Sandleretal,NEnglJMed355:2542,2006Milleretal,SABCS,2005Bevacizumab:ArterialThromboembolicEventscomplicatesubsequentliverresectionATE：cerebralinfact,myocardPreoperativechemotherapy:

potentialproblems

Hinderdetectionofknownmetastases

Radiographiccompleteresponse1–Frequency:6.5%–Rareifinitialtumor>4.5cm–Residualtumoridentified:83%ChemotherapyreducessensitivityofPETdetectionofmatastases2,3BenoistS,etal,JClinOncol24:3939,2006AkhurstT,etal,JClinOncol23:8713,2005Tan,MCBetal,JGastrointestSurg11:1112,2007Preoperativechemotherapy:

pot“Completeresponse”:doesitcure?“Completeresponse”:doesitcuCompleteresponseCompleteresponsePreoperativechemotherapy:

potentialproblemsRadiographicCR≠PathologocCR

RadiographicCR≠PathologocCR1Resectionstrategymustremovetheselesions“Blind”removalsoundseasyinconcept…BenoistS,etal,JCO24:3939,2006Preoperativechemotherapy:

pot结直肠癌肝转移新辅助化疗的共识与争议课件Chemotherapyinducesliverdamage

The“blue”liverChemotherapyinducesliverdamThetypeofliverinjurydependsondrugadministered

Vascularlesions:Oxaliplatin

(Rubbia-Brandtetal,2004)

Steatosis:5FU,Irinotecan?

(Parikhetal,2003)

Steatohepatitis:Irinotecan

(Vautheyetal,2006)LiverdamageinducedbychemotherapyThetypeofliverinjurydepenSinusoidallesionsSinusoidallesionsSteatohepatitisSteatohepatitisASCOAMERICANSOCIETYOFCLINICALONCOLOGYASCOAMERICANSOCIETYOFCLINIVascularChangeinLiverPostSystemicChemotherapyVascularChangeinLiverPostClinicalsignificance:impactonsurgeryClinicalsignificance:impactoClinicaloutcomerelatedtoliverdamageSteatosisassociatedwithhigherinfectionrate(Koobyetal,2003)Steatohepatitisassociatedwithhighermortalityrateduetoliverfailureaftersurgery(Vautheyetal.2006)Vascularinjuryassociatedwithhigherrateofoperativebleedingandtransfusionrequirement

(Vautheyetal.2006.Aloiaetal.2006)Clinicaloutcomerelatedtoli结直肠癌肝转移新辅助化疗的共识与争议课件结直肠癌肝转移新辅助化疗的共识与争议课件Peroperativechemotherapy:

potentialproblemsPeroperativechemotherapy:

potEORTC40983:impactofpre-operativechemotherapyonsurgeryEORTC40983:impactofpre-oper结直肠癌肝转移新辅助化疗的共识与争议课件BOS(Biologics,Oxaliplatin,Surgery)

EORTC40051BOS(Biologics,Oxaliplatin,SResectableCRClivermetastases:UnansweredQuestionsIsperi-operativechemotherapysuperiortopost-operativechemotherapy?Howmuchpreoperativechemotherapy?Howdoyouassessnatureandextentofchemotherapy-inducedliverinjury?Dotargetedagentsmodulatechemotherapy-inducedliverinjury?ResectableCRClivermetastaseNeoadjforunresectablelivermetastasesofCRCNeoadjforunresectableliverChemotherapyforunresectableIsthereabenefittoaddsurgerytochemotherapy?Towhichpatients?Withwhatregimens?Afterhowmuchdurationoftreatment?Take-homemessageChemotherapyforunresectaChemotherapyforunresectableIsthereabenefittoaddsurgerytochemotherapy?Towhichpatients?Withwhatregimens?Afterhowmuchdurationoftreatment?Take-homemessageChemotherapyforunresectabl结直肠癌肝转移新辅助化疗的共识与争议课件DownstagingUnresectable

ColorectalMetastasesDownstagingUnresectable

ColorResponsetoneoadjuvantchemothrapyResponsetoneoadjuvantchemotSurvivalafterliverResectionofNonResectable

ColorectalMatastasesafterSystemicChemotherapy

SurvivalafterliverResectionSurvivalafterliverResectionofColorectalMatastases

SurvivalafterliverResectionSurvivalAfter

ChemotherapyForCRLMSurvivalAfter

ChemotherapyFEffectivePreoperativeTherapy+HepaticResection:

Long-termResultsin“unresectable”PatientsEffectivePreoperativeTherapy结直肠癌肝转移新辅助化疗的共识与争议课件ChemotherapyforunresectableIsthereabenefittoaddsurgerytochemotherapy?Towhichpatients?Withwhatregimens?Afterhowmuchdurationoftreatment?Take-homemessageChemotherapyforunresectaAModeltopredictSurvivalafterLiverresection

ofNonResectableColorectalMetastasesAModeltopredictSurvivalComparisonofpatientcharacteristicsbetweencuredandnon-curedpatientsAdamR,ASCO2008abstr4023ComparisonofpatientcharacteClinicalriskscoringsystem

(Fongetal)disease-freeinterval<12monthsnumberofmetastases>1pre-operativeCEAlevel>200IUperml,sizeoflargesttumor>5cmlymphnodepositiveprimarytumor.05ysurvival60%≥35ysurvival＜20%ClinicalriskscoringASCO2008abstr4076

SurvivalafterresectionoflivermetastasesfromcolorectalcancerwithpoorclinicalriskfactorsusingadjuvantsystemicplushepaticarterialtherapyASCO2008abstr4076SurvivalChemotherapyforunresectableIsthereabenefittoaddsurgerytochemotherapy?Towhichpatients?Withwhatregimens?Afterhowmuchdurationoftreatment?Take-homemessageChemotherapyforunresectaResectabilitycorrelateswithrsponseResectabilitycorrelateswithOverallsurvivalcurves(Kaplan-Meier)ofpatientswith

andwithoutcompletepathologicresponse(CPR)

完全缓解患者术后10年生存率约68％，而部分缓解者约29％RenéAdam,DennisA，etal.J.Clin.Oncol.,2008,26(10):1635-1641Overallsurvivalcurves(KaplaLiverResectionafterchemotherapy

ininitiallyunresectablepatientsLiverResectionafterchemotheFOLFOXIRIEGFRantibodies–Crystal:FOLFIRI+/-Cetuximab–OPUS:FOLFOX+/-CetuximabVEGFinhibition–SafetyofbevicizumabIsthereabettertreatmentthanFOLFOXFOLFOXIRIIsthereabettertreLong-termOutcomeofUnresectableMetastaticColorectal

Cancer(MCRC)Patients(Pts)TreatedWithFirst-line

FOLFOXIRIFollowedbyR0SurgicalResectionofMetastasesLong-termOutcomeofUnresectaResectionaftercombinaton

ofcytotoxicsandtargetedagentsResectionaftercombinaton

ofOPUStrial:

responseratesbysubgroupOPUStrial:

responseratesbyOPUStiral:secondaryendpointsOPUStiral:secondaryendpointCRYSTALtrial:

SurgerywithcurativeintentCRYSTALtrial:

SurgerywithcCetuximabStudiesinNon-ResectableLiverMetastases(non-selectedpatients)RosenbergAH,etal.ProcASCO2002;20(AbstractNo.536);

PeetersM,etal.EurJCancerSuppl2005;3:188(AbstractNo.664);

FolprechtG,etal.AnnOncol(2005);CervantesA,etal.EurJCancerSuppl2005;3:181(AbstractNo.642)

爱必妥+FOLFIRI爱必妥+AIO/伊立替康Erbitux+FOLFOX-4患者数422142有效率（％）6267（10％CR)72（10％CR)疾病稳定（％）212917疾病控制率839595肝转移切除率(％)

242423CetuximabStudiesinNon-ReResponserateandresectability有效率和切除率(%)有效率切除率ERBITUX

FOLFOX41ERBITUX

AIOIRI2ERBITUX+

FOLFIRI3FOLFIRI4AIO+IRI5FOLFOX41CervantesA,etal.ECCO(2005);2FolprechtG,etal.AnnOncol(2005);3RougierP,etal.ECCO(2005);

4Tournigand,etal.JClinOncol(2004);5KöhneC-H,etal.EORTC-Study40986(2005)ResponserateandresectabilitEMR604-CELIM研究:

肝转移灶不可切除的mCRC患者治疗8个周期(~4个月)不可切除可切除4继续治疗4个周期可切除切除继续治疗6个周期(~3个月)主要终点:有效率54例患者/组随机FOLFOX+ERBITUXFOLFIRI+ERBITUXEGFR阳性/未检测手术无法切除/≥5个肝转移灶

无肝外转移EMR604-CELIM研究:

肝转移灶不可切除的mCRBevacizumabinunresectable

livermetastasesofCRCASCO2008Abr4022Surgerywithcurativeintentinpatientstreatedwithfirst-linechemotherapyplusbevacizumabformetastaticcolorectalcancer:FIRSTBEATandNO16966Bevacizumabinunresec结直肠癌肝转移新辅助化疗的共识与争议课件ChemotherapyforunresectableIsthereabenefittoaddsurgerytochemotherapy?Towhichpatients?WithwhatregimensAfterhowmuchdurationoftreatment?Take-homemessageChemotherapyforunresectabRisksofProlongedChemotherapyInpotentialcandidatesforSurgery

ComleteClinicalResponse:aparadoxProgressionafterinitialresponseHepatotoxiceffectRisksofProlongedChemotherapCCR:Toachieveortoavoid?

Acompleteradiologicalreaponsedosenotmeancurein83%ofthelesions(1)and94%ofthepatients(2)Althoughrareandconceptuallyvalorizing,thissituationshouldbeavoidedandresectionperformedassoonasresectabilityisobtainedWhatisadreamformedicaloncologistscouldbeanightmareforsurgeons…CCR:Toachieveortoavoid?

PreoperationChmotherapy–1990’s→SteatosisElias,JACS1995;BehmsJGIS1998Withintrarterialchmotherapy–2000’s→VascularlesiorsRubbia-Brandt,Annoncol2004CentrolobularnecrosisAdam,AnnSurg2004Regenerativenobularhyperplasia

–Steatohepatitis(Irinotecan)Vauthey,JCO2006Impactonpostop.Complications

-Nortality:NoexceptsteatohepatitisVauthey,JCO2006-Norbidity:YesNordlinger,ASCO2005-Relationshipdurationofchemo:YesKarroui,BJS2006