潘宏銘浙江大學附屬邵逸夫醫(yī)院腫瘤內(nèi)科內(nèi)容序言可切除肝轉(zhuǎn)移灶的治療不可切除肝轉(zhuǎn)移灶的治療總結結腸癌肝轉(zhuǎn)移發(fā)生率肝臟是結腸癌轉(zhuǎn)移的主要器官。首診時約20-30%結腸癌患者發(fā)生僅有肝臟轉(zhuǎn)移復發(fā)時大約30-40%結腸癌患者發(fā)生僅有肝臟轉(zhuǎn)移結腸癌肝轉(zhuǎn)移的治療DEFINITIONS:ASCO2006LIVERTHINKTANKNeoadjuvantTherapy-Preoperative

systemictherapyforresectablehepaticmetastasesfollowedbypostresectiontherapy.AdjuvantTherapy-Systemic/regionaltherapyposthepaticresection.ConversionTherapy–Systemic/regionaltherapyutilizedforpatientswithunresectable

hepaticmetastasesinanattempttomakethemetastasesresectable.內(nèi)容序言可切除肝轉(zhuǎn)移灶的治療不可切除肝轉(zhuǎn)移灶的治療總結結直腸癌肝轉(zhuǎn)移的切除指征

切緣距離

Peri-operativeFOLFOX4chemotherapyandsurgeryforresectablelivermetastasesfromcolorectalcancer

FinalefficacyresultsoftheEORTCIntergroupphaseIIIstudy40983.

B.Nordlinger,H.Sorbye,B.Glimelius,G.J.Poston,P.M.Schlag,P.Rougier,W.O.

Bechstein,J.Primrose,E.T.Walpole,T.GruenbergerStatisticalanalysisL.ColletteFortheEORTCGIGroup,CRUK,ALMCAO,AGITGandFFCDTrialDesignandObjectivesRFOLFOX4x6cyclesSurgeryFOLFOX4x6cyclesSurgery

364patientsPotentiallyresectable(1-4)livermetastasesGoal:Improveprogression-freesurvival

todemonstratea40%increaseinmedianPFS(HR=0.71)with80%powerand2-sidedsignificancelevel5%Pre-OperativeAssessmentOutcomeinchemotherapyarmCR:3.3%PR:35.2%Stable:33.5%Progression7.7%Notevaluable:20.3%Progression-freesurvivalineligiblepatientsHR=0.77;CI:

0.60-1.00,p=0.041

PeriopCT28.1%36.2%+8.1%

At3years

(years)01234560102030405060708090100ONNumberofpatientsatrisk:1251718357372281151711157443215SurgeryonlyAdjuvantChemotherapy-CurrentandFutureStudies

C-09:MetastasectomyfollowedbywithOxaliplatinandCapecitabine+/-FUDRResectionoflivermetastases(1-6)Capecitabine+OxaliplatinCapecitabine+OxaliplatinalternatingwithHAIFUDRRandomizeOpen–PlannedAccrual400FOLFOX6modified+cetuximab6cyclesRANDOMIZATIONResectableLiverMetastasesfromColorectalCancernoextrahepaticdiseaseWHOPS0,1NopreviouschemoformetsFOLFOX6modified+cetuximab+bevacizumab6cycles(nobevacizumabincycle#6)FOLFOX6modified+cetuximab6cyclesFOLFOX6modified+cetuximab+bevacizumab6cyclesfollowupfollowupSURGERYSURGERYTrial40051(BOS)內(nèi)容序言可切除肝轉(zhuǎn)移灶的治療不可切除肝轉(zhuǎn)移灶的治療總結LIVERMETASTASESRESECTABLE20-25%NONRESECTABLE75-80%SURVIVALBENEFIT30-40%AT5YEARSRESECTABLE10-20%DownsizingsizelocationnumberOncoSurgicalstrategiesinlivermetastases

frompalliativetocurative…PalliativeCurativeSurvivalTimeHepaticArteryInfusion(HAI)

forUnresectableLiverMetastasesCALGB9481:HAIFUDRversusSystemic5FUandLeucovorinEligibilityLiver-only,unresectablemetastasesfromCRCNopriortherapyformetastaticCRCHAIFUDR0.18mg/kg+DEX25mgover14daysEvery28days(N=68)5-FU425mg/m2+LV20mg/m2Dailyx5every4weeks(N=67)RKemenyNEetal.JClinOncol24:1395-1403,2006CALGB9481:OverallSurvival

HAI

5FU/LVMedOS(months)24.4 20.0(p=0.034)THP(months) 9.8 7.3(p=0.034)TEP(months) 7.7 14.8(p=0.029)RR 47% 24%HAI5FU/LVCALGB9481:HepaticvsNonhepaticDiseaseProgressionKemenyetal.JClinOncol.2006;24:1395.HepaticNonhepaticHAISystemic,P=0.034YearsfromtrialentryProportionhepaticprogression–free012300.20.40.60.81.0012300.20.40.60.81.0HAISystemic,P=0.029Proportionnonhepaticprogression–freeYearsfromtrialentryHAIasNeoadjuvantTherapyforInitiallyUnresectableDiseasePotentialLimitationsInvasivePercutaneouslyplacedcathetershaveahighrateofcomplicationsSurgicalplacementmaydelaysystemictherapyLackoftreatmentforpotentialextrahepaticdiseaseLimitedstudiesRoleofNeoadjuvantSystemicChemotherapyforLiver-onlyMetastasesResectionofnon-resectablelivermetastasesaftersystemicchemotherapyPublishedseriesAuthorsLevi

FowlerBismuthGiachettiAdamWeinRivoireYear1992199219961999200120012002NoPts98-33038970153131TypeChemoFu-Fol-OxaliFu-FolFu-Fol-OxaliFu-Fol-Oxali*Fu-Fol-OxaliFu-FolFu-Fol-Oxali

NoResect18(19%)1153(16%)77(20%)95(14%)6(11%)57(43%)5-yrSurv--40%50%39%--Fu-Fol-Oxali:Chronomodulated*LiveronlymetastasesSurvivalafterLiverResectionofColorectalMetastasesPaulBrousseHospital-473patients(Apr.88-Jul.99)Years20406080100012345678910Survival(%)91%48%30%66%33%23%52%P=0.01AdamRetal.AnnSurg2004NoSurgeryResectable:335Initiallynonresectable:138Collaboration:Oncologists-Surgeons

ForNonResectableMetastases1-Currentchemotherapyallowsatleast20%ofpatientstoberescuedbyliversurgery2-Thesurvivalbenefitofthesepatientsissubstantial(30%and20%rateat5and10years)3-Resectability:anewendpointfortreatmentstrategyNeoadjuvantOxaliplatin

PaulBrousseHospitalStudyAdamR.etal.,Ann.Surg.Oncol.,2001;8:347-353Chemo:701(80%)14%9008007006005004003002001000Resection:266(31%)86%36%64%95171872patients1988-1996Initiallynon-resectableNon-resectableResectable14%of701CT-treatedpatientsachievedaresponsepermittingresection

171ChemotherapyRoleofNeoadjuvantTreatmentPatientstatusatameanfollow-upof4.2years56dead(59%)39alive(41%)95patients25alivediseasefree(26%)14alivewithdisease(15%)Survivalafterprimaryorsecondary

resectionoflivermetastasesC225+FOLFIRI用于mCRC一線治療

BestoverallresponseC225+FOLFIRI(high-dose)%(n=42)Partialresponse62Stabledisease21Diseasecontrol83中位療效持續(xù)時間(months)10轉(zhuǎn)移灶切除率24%(10例)中位生存期(months)23Peetersetal.EurJCancer2005;Supplement3:Abstract664PhaseIIITrialofFOLFOXIRIvsFOLFIRIasFirst-LineTherapyofAdvancedColorectalCancerG.O.N.O.StudyDesign-StratificationCenterPS0/1vs2Adj.CtxRFOLFIRICPT-11 180mg/m2d1LV 100mg/m2d1,25-FU 400mg/m2bolusd1,25-FU 600mg/m222hinfd1,2q2wksx12cyclesFOLFOXIRICPT-11 165mg/m2d1Oxali 85mg/m2d1LV 200mg/m2d15-FU3200mg/m248hinfd1q2wksx12cyclesFalconeetal.,ASCO﹟4026,JCO2007PhaseIIITrialofFOLFOXIRIvsFOLFIRIasFirst-LineTherapyofAdvancedCRCFOLFIRI

N=122FOLFOXIRI

N=122P-valueRR*(%)3460<0.0001CR+PR+SD*(%)6881R0resection

(%)(allpatients)6150.033R0resection(%)(liverlimited)12360.017PFS(mos)6.99.80.0006OS(mos)16.7?22.60.032*externallyreviewed:?67%2ndlineFOLFOXFalcone.,ASCO﹟4026,JCO2007*CMHtestn=599/groupn=599/groupn=134/n=122p=0.0034*oddsratio3.0[95%CI:1.4-6.5]FOLFIRIaloneERBITUX+FOLFIRINoresidualtumorinpatientswithlivermetastasesITTpopulationLiver-limiteddiseasepopulationVanCutsemetal,ASCO2007CRYSTALTrial:

SurgerywithCurativeIntentSpecificChemotherapyAssociatedHepaticToxicityIrinotecan–SteatohepatitisOxaliplatin–Sinusoidal/vascularinjury

Acute&chronicclinicalsequelaeBiologics-????

Bevacizumab–6to8wksbeforeresection

Liverregeneration&hemorrhageMorbidityisincreasedwithprolongedcourseofchemotherapy(Aloiaetal,JClinOncol,2006)LiverToxicityofNeoadjuvantTherapy%ofPatientsSinusoidalDilationSteatosis>30%SteatohepatitisYesNoP

*YesNoP

*YesNoP

*Nochemotherapy

1.9

98.1–

8.9

91.1–

4.4

95.6–5-FU/LV

0

100NS

16.6

83.4NS

4.8

95.2NS5-FU/LV+irinotecan

4.3

95.7NS

10.6

89.4NS

20.2

79.80.00015-FU/LV+oxaliplatin

18.9

81.10.00001

3.8

96.2NS

6.3

93.6NSOther

0

100NS

8.3

91.7NS

0

100NSPatientswithsteatohepatitishadanincreased90-daymortalitycomparedwithpatientswhodidnothavesteatohepatitis(P=0.001)*Comparisonofeachgroupvsnochemotherapy. Vautheyetal.JClinOncol.2006;24:2065.Vasodilation&CongestionPeliosis:HemorrhagicCentrilobularNecrosisNodularRegenerativeHyperplasia

VascularChangesinLiverPostSystemicChemotherapy

Aloiaetal,JClinOncol24:4983,2006Hepaticatrophy&sinusoidalcongestion▼▼CollaborationOncologists-SurgeonsforTimingofSurgeryafterChemotherapy…Assoonasthemetastasesbecomeresectable…

Nottomissthe?

good

?therapeutic

window:

Tumoralprogression:Surgery

even

potentially

curative,haspoor

results

Notto?

overtreat

?thepatient

Completeresponse:

amajorproblemforthesurgeonwith

howeveraminorityofpathology-proven

necrosis

Hepatotoxicity:aclinicalimpactrelatedtodurationStudiesincludingnonselectedpatientswithmCRC(solidline)(r=0.74;p<0.001) Studiesincluding

selectedpatients

(livermetastasesonly,noextrahepaticdisease)(r=0.96;p=0.002)PhaseIIIstudiesincludingnonselectedpatients

withmCRC(dashedline)(r=0.67;p=0.024)FolprechtG,etal.AnnOncol2005;16:1311–1319Responserate0.90.80.70.60.50.40.3Resectionrate0.60.50.40.30.20.10ImpactofIncreasingResponseRatesN014A:ResectionofUnresectable

CRCLimitedtotheLiverUsingFOLFOX6+Cetuximab

CR/P