如何将不可切除的结直肠癌肝转移灶转为可手术切除

潘宏铭浙江大学附属邵逸夫医院肿瘤内科内容序言可切除肝转移灶的治疗不可切除肝转移灶的治疗总结结肠癌肝转移发生率肝脏是结肠癌转移的主要器官。首诊时约20-30%结肠癌患者发生仅有肝脏转移复发时大约30-40%结肠癌患者发生仅有肝脏转移结肠癌肝转移的治疗DEFINITIONS:ASCO2006LIVERTHINKTANKNeoadjuvantTherapy-Preoperative

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

hepaticmetastasesinanattempttomakethemetastasesresectable.内容序言可切除肝转移灶的治疗不可切除肝转移灶的治疗总结结直肠癌肝转移的切除指征

切缘距离

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)内容序言可切除肝转移灶的治疗不可切除肝转移灶的治疗总结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一线治疗

BestoverallresponseC225+FOLFIRI(high-dose)%(n=42)Partialresponse62Stabledisease21Diseasecontrol83中位疗效持续时间(months)10转移灶切除率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