系统性大肠癌治疗课件

系统性大肠癌治疗AdenomatoCarcinomaPathwayAdenomaNormalCancerNormalepitheliumDysplasticACFEarlyadenomaLateadenomaCarcinomaMetastaticcarcinoma5qLOH*(APC/β-catenin)?K-ras?K-ras18qLOHDCC/SMAD4/SMAD217qLOHMMRactivationACF=aberrantcryptfoci;MMR=mismatchrepair.StageSystems:Terminologyvs.Contents(概念与内涵);Populationsvs.Individuals(群体与个体)StageIStageIIStageIIIStageIVDiseasedevelopmentStagingT1,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:DistalMetastasisM1a:Oneorgansite(liver,lung,ovary,nonregionalnode)M1b:≥oneorgan/siteorPeritoneumDefinitionInvadessubmucosa(T1)/muscularpropria(T2)T3:InvadesthroughmuscularispropriaintopericolorectaltissuesT4a:penetratestothesurfaceofthevisceralperitoneumT4b:invadesorisadherenttootherorgansorstructuresN1:metastasisin1-3LNN1a:1LN,N1b:2-3LNN1c:depositsinthesubserosa,mesentery,orononperitonealizedpericolictissuew/oLNN2:≥4LNN2a:4-6LN,N2b:≥7LNInvolvesdistantmetastasesUsualtreatmentSurgerySurgery±chemotherapySurgery+chemotherapyChemotherapy±surgerySEERColonCancer1973-2005(USA)

N=28,49101yr.2yr3yr4yr5yrI91.487.082.678.274.0IIA89.983.477.872.068.5IIB85.477.869.162.958.6IIC66.052.545.341.537.3IIIA98.388.083.679.173.1IIIB83.470.859.351.746.3IIIC71.950.339.032.928.0IV39.919.711.37.65.7HistoryofTherapeuticRegimensfortheTreatmentofMCRC*Bothfirst-andsecond-lineexposuretotherapy.VanCutsemandVerslype.ASCOEducBook.2002.MedianOS*(mo)06121824~4-6mo~12-14mo~15-20mo~15-17mo~11-12mo1980’s2000’s1990’s1960’s5-Fluorouracil(5-FU)

5-FUbiomodulationIrinotecanOxaliplatin5-Fluorouracil(5-FU)AdvancesintheTreatment

ofColorectalCancer198019851990199520002005TherapeuticconceptsPalliativeCTAdjuvantCTPre-operativeCTCapecitabineOxaliplatinCetuximabBevacizumabIrinotecan5-FUPanitumumabTargetedtherapies{KRasWT/MTBraf2008ManagementofMCRC:

AnEvolvingTreatmentAlgorithmDiagnosisofMCRCResectableUnresectableAdjuvanttherapySurgeryNeoadjuvant/preoperativetherapyFirst-lineSecond-lineThird-lineBorderline/potentiallyresectableFourth-lineTreatmentcontinuumChemotherapyFluorouracil:5-FU,Xeloda,(S-1):efficacy,dose,vs.toxicityEnzymesvs.food.FOLFOX/XELOXvs.FOLFIRI(XELIRI):1stlinevs.2ndlineRegimensFOLFOX(4,6,7…),XELOX,NeurologicalToxicity:Dosemodificationvs.MaintenanceFOLFIRI:Irintotecan--UGT1A1:*28--6/6,6/7,7/7Avastin:When,how?CetuximabinWTpatients0.00.10.20.30.40.50.60.70.80.91.006121824303642MonthsIrinotecan/5-FU/LV(N=231)5-FU/LV(N=226)IFL

P=0.042*Probability*log-ranktest14.8mo12.6moFOLFIRI*Medians

†Log-ranktestp<0.032†CPT-11/5-FU/LV(N=198)5-FU/LV(N=187)17.4mo*14.1mo*MonthsProbability0.00.10.20.30.40.50.60.70.80.91.00612182430600600DouillardB400FOLFIRIFOLFIRIRegimens

200B4001802004001802400-3000B400OverallSurvivalIFLFOLFOXPvalueIROXRR31%45%0.00234%TTP6.9m8.7m0.00146.5mOS14.8m19.5m0.000117.4m600600FOLFOX4B400mFOLFOX6

2400FOLFOX7FOLFOXRegimens

200B40085200400852400-3000400130B400mFOLFOX74001003000FOLFOX64001002400-3000B400CPT-11180mg/m2+simplifiedLV5FURandomized,multicentric,open-label,prospective,phaseIIItrialFOLFIRIFOLFOX6L-OHP100mg/m2IV+simplifiedLV5FU

RFOLFOX6FOLFIRIuntilprogressionuntilprogressionuntilprogressionuntilprogressionArmAArmBFOLFIRIvs.FOLFOXProbability0.00.20.40.60.81.006121824303642Months

Logrankp=0.9

FOLFIRI/FOLFOXFOLFOX/FOLFIRIOverallSurvivalFOLFIRI/FOLFOXFOLFOX/FOLFIRIMedian(months)20.4[16.7-24.9]21.5[17.3-24.8]Events/patients65/10967/111Medianfollow-up18.6monthsOPTIMOX-1Tournigandetal,JCO20066xFOLFOX7-12xsLV5FU2-6xFOLFOX7FOLFOX4620pts

RCum.Oxali7801560(%) FOLFOX4

FOLFOX7RR 58.5 58.3PFS 9.0 8.7DDC 9.0 10.6OS 19.3 21.2G3/4NTox 17.9 13.3Primary

endpointOPTIMOXStudiesOPTIMOX-1FOLFOX4untilTFFOLFOX7FOLFOX7sLV5FU2OPTIMOX-2mFOLFOX7mFOLFOX7sLV5FU2mFOLFOX7mFOLFOX7CFICFI:ChemotherapyFreeIntervalPhaseIIOPTIMOX2Trial:

StudyDesignOPTIMOX1:maintenancetherapy

mFOLFOX7x6cyclessLV5FU2untilbaselineprogressionFOLFOX7reintroductionOPTIMOX2:chemotherapy-freeintervalmFOLFOX7x6cyclesNomaintenanceuntilprogressionFOLFOX7reintroductionRANDOMIZATIONmFOLFOX7LV4005-FU3000Oxali100H0H2H24H48sLV5FU2LV4005-FU3000H0H2H24H485FUb4001cycle=14daysDose=mg/m2PhaseIIITrialBevacizumabinFirst-LineMCRC(AVF2107g)*PatientsreceivingAvastincouldcontinuetherapypastdiseaseprogressionincombinationwithsecond-linetherapy.†PreviouslyuntreatedMCRC(n=923)IFL+placebo(n=411)5-FU/LV+bevacizumab(5mg/kg,q2w)

(n=110)IFL+Bevacizumab(5mg/kg,q2w)

(n=402)Primaryendpoint:SurvivalPhaseIIITrialofBevacizumabinFirst-LineMCRC:Efficacy

IFL+Placebo(n=411)IFL+Avastin(5mg/kg,q2w)

(n=402)PValueHazardRatioMedianOS(mo)15.620.3<0.001*0.66PFS(mo)6.210.6<0.001*0.54ORR(%)3545<0.01†Durationofresponse(mo)7.110.4PhaseIIITrialofBevacizumabinFirst-LineMCRC:SurvivalErrorbarsrepresent95%confidenceintervals.PercentsurvivingMonths2001218300801004060TreatmentGroupIFL+placebo(n=411)IFL+Avastin(n=402)246Mediansurvival:15.6vs20.3moP<0.001E3200:High-dose

BEV+FOLFOX4:StudyDesignRANDOMIZE

FOLFOX4

+Bevacizumab

(BEV10mg/kgq2wk)(n=289)N=822PreviouslytreatedmCRCFOLFOX4(n=290)Bevacizumab

(10mg/kgq2wk)(n=243)E3200(FOLFOX+Bevacizumab):

OverallSurvivalProbability0.00.10.20.30.40.50.60.70.80.91.0OS(months)0369121518212427303336ALIVEDEADMEDIANTOTALA:FOLFOX4+bevacizumab2892464312.9B:FOLFOX42902573310.8C:bevacizumab2432162710.2HR=0.76AvsB:p=0.0018BvsC:p=0.95Bevacizumabwith5-FU/LV:PFSHazardratio=0.50MedianPFS:5.5vs9.2 (P=0.0002)200630080100406024MonthsPercentprogression-free18125-FU/LV+Avastin(n=104)5-FU/LV+placebo(n=105)Bevacizumabwith5-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+placebo

n=351XELOX+

bevacizumabn=350FOLFOX-4+

bevacizumabn=349XELOX

n=317FOLFOX-4n=317Initial2-arm

open-labelstudy(n=634)Protocolamendedto2x2placebo-controlleddesignafterbevacizumabphaseIIIdatabecameavailable(n=1400)Recruitment

June2003–May2004Recruitment

Feb2004–Feb2005XELOX-1/NO16966Trial:StudyDesignEffectofBevacizumabonPFSHR=0.83[97.5%CI0.72–0.95]p=0.0023XELOX+placebo

(X+P)FOLFOX-4+placebo

(F+P)XELOX+bevacizumab

(X+A)FOLFOX-4+bevacizumab

(F+A)VS

0 3 6 9 12 15 18 21monthsPFSestimate9.4m8.0m1.00.80.60.40.20CRYSTAL:studydesignPrimaryendpoint:PFSSecondaryendpoints:OS,ORR,safetyFOLFIRIFOLFIRI+cetuximabRFirst-linemCRC,

unresectable

(n=1198)VanCutsem,etal.NEJM2009CRYSTAL:K-rasWTefficacyupdateCRYSTALupdateCetuximabplusFOLFIRIvsFOLFIRI

(n=666)OS,months23.5vs20.0

(HR=0.796;p=0.0094)PFS,months

9.9vs8.4

(HR=0.696;p=0.0012)ORR,%57.3vs39.7

(OR=2.0693;p<0.0001)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.ofeventsMedianOS[95%CI]HR(95%):p-value:FOLFIRI(n=350)28820.0[17.4–21.7]0.796[0.670–0.946]0.0094(log-rank)Cetuximab+FOLFIRI(n=316)24223.5[21.2–26.3]OPUS:studydesignPhaseIIPrimaryendpoint:ORRSecondaryendpoints:rateofcurativemetastaticsurgery,durationofresponse,diseasecontrolrate,PFS,OS,safetyFOLFOX4FOLFOX4+

cetuximabRFirst-linemCRC

unresectable

(n=337)Bokemeyer,etal.JCO2009OPUS:K-rasWTefficacyupdateOPUSupdateCetuximabplusFOLFOX4vsFOLFOX4

(n=179)OS,months22.8vs18.5

(HR=0.855;p=0.3854)PFS,months

8.3vs7.2

(HR=0.567;p=0.0064)ORR,%57.3vs34.0

(OR=2.5512;p=0.0027)Bokemeyeretal.ECCO-ESMO2009(abstractNo.6079)PRIME:studydesignPrimaryendpoint:PFSbyK-rasstatusSecondaryendpoints:OS,ORR,durationofresponse,timetoresponse,safetyStudypopulationOriginallydesignedtostudytheoverallpopulationdesignamendedtoanalyseoutcomeswithrespecttothepresenceorabsenceofK-rasmutationstumourK-rasstatusnotascertainedinallpatients(<10%)FOLFOX

q2weeklyFOLFOX

+panitumumab

q2weeklyRFirst-linemCRC(n=1183)Douillard,etal.ECCO/ESMO2009(abstractNo.10LBA)PRIME(first-lineFOLFOX±panitumumab):K-rasWTPFS01234567891011121314151617181920212223Time(months)325331313321294296284281254242243231204185187172156127145113111829465734157363929panitumumabFOLFOXNo.atriskFOLFOX+1009080706050403020100PFS(%)Events,

n(%)Median(95%CI)

monthsPanitumumab+FOLFOX199(61)9.6(9.2–11.1)FOLFOX215(65)8.0(7.5–9.3) HR=0.80(95%CI:0.66–0.97)

p=0.0228222216141210104212010100Douillard,etal.ECCO/ESMO2009(abstractNo.10LBA)PRIME(first-lineFOLFOX±panitumumab):K-rasWTOS(interimanalysis)1009080706050403020100Proportionalive(%)0Events,

n(%)Median(95%CI)

monthsPanitumumab+FOLFOX106(33)NE(20.3–NE)FOLFOX124(37)18.8(17.2–NE)HR=0.83(95%CI:0.64–1.08)

p=0.16123456789101112131415161718192021222324252632133132132531532031331131030129728928828127827226626524824322621920319318717716515214112511911010287887065524737292414159945121000Time(months)Douillard,etal.ECCO/ESMO2009(abstractNo.10LBA)panitumumabFOLFOXNo.atriskFOLFOX+PRIME(first-lineFOLFOX±panitumumab):responseratesPanitumumab+FOLFOX

(n=317)FOLFOX

(n=323)ORR(%)(95%CI)*55

(50–61)48

(42–53)CR00.3PR5547SD3036PD711*p=0.068(descriptive)Douillard,etal.ECCO/ESMO2009(abstractNo.10LBA)LivermetastaticdiseaseLiverresectionissues:ResectabilityTiming;treatmentselection…Chemo:FOLFOXvs.FOLIRIvs.FOLFOXIRI(FOLIRIOX)bevacizumab:EGFRinhibitor(K-ras,B-raf),PIK3,andmore….DefiningTherapeuticSettingsNeoadjuvanttherapyResectablehepaticmetastasesPreoperativesystemictherapyfollowedbypostresectiontherapyAdjuvanttherapyResectablehepaticmetastasesPostresectionsystemic/regionaltherapyConversiontherapyUnresectablehepaticmetastasesSystemic/regionaltherapyinanattempttomakethemetastasesresectableLiverMetastasesinCRCSurvivaldirectlyrelatedtolivermetastasesresectability5-yOS=40%-58%followingsuccessfulresectionAshighas71.5%followingsolitaryresectionRedefiningresectabilityBeforeRequiredlimitednumberofmetastases(3to4)NowNumberofmetastasesarelativedecisionfactorAnticipatednegativesurgicalmargins≥30%livermassAssociatedwithanear-zerooperativemortalityrateandlong-termsurvival

OS=overallsurvival.1.Vautheyetal.SeminOncol.2005;32:S118.

2.Aloiaetal.ArchSurg.2006;141:460.

3.Zorzietal.BrJSurg.2007;94:274.

4.Vautheyetal.AnnSurg.2004;239:722.LiverMetSurveyRegistry:PrognosticImportanceofIntrahepaticTumorBurdenInternational,Internet-basedregistry2122patientsNotarandomized,controlledclinicaltrialMedian,5-y,and10-yOSwere46months,42%,and26%,respectivelyIndependentpoorprognosticfactors>3metastases(P<0.0001)Bilateralmetastases(P=0.0002)Largestmetastasis>5cm(P=0.03)PreoperativeCTimprovedsurvivalonlyinpatientswith>5metastasesAdametal.ASCO,2006.Abstract3521.66patientsLiveronlymetswithCRonCTscanafterChemotherapySurgeryMacroscopiccancer:20‘Nolesion’:4615siteresected31sitesleftinplaceViabletumorcells:12Insiturecurrence:2355/66(83%)ofMetastaseswerenot‘cured’NordlingerJCO2008TreatmentOptions&HowLongCyclesFOLFOXCRFOLFOX+BevCRpOverallRRp1~8cycles38/81(43%)44/76(58%)0.0001757%0.738≥912/40(30%)15/22(68%)0.001155%MaruDMetal.ASCOGI2009,abs:295CyclesSinusoidalInjuryLiverInsufficiency1~8cycles26%4%≥942%11%p0.0170.035Adjuvant5-FU(Capecitabine)vs.FOLFOX(XELOX)Avastin?CetuximabinWTpatients?GoalofAdjuvantChemotherapyToeradicatemicrometastases,thereforeToincreasecure/survivalrateaftercurativesurgicalresection

Five-yearDFS(%)Five-yearOS(%)5-FU/LEV,12months56635-FU/LV(HD),6monthsRoswellPark59655-FU/LV(LD),6monthsMayo60665-FU/LV/LEV,7months6067

Numberofpatients=3759StandardAdjuvanttherapy(1998-2004)(BasedonINT0089)Haller,D.G.etal.JClinOncol;23:8671-86782005X-ACTtrialinadjuvanttreatmentofDukes’Ccoloncancer1°endpoint:disease-freesurvival(DFS)2°endpointsrelapse-freesurvival(RFS)overallsurvivaltolerability(NCICCTC)pharmacoeconomicsQoL

Chemo-naïveDukes’C,resection£8weeks

Capecitabine:1250mg/m2twicedaily,

d1–14,q21dn=1

004Bolus5-FU/LV:5-FU425mg/m2plus

LV20mg/m2,d1–5,q28dn=983Recruitment1998–200124weeksConfirmedbyperprotocolanalysis,HR0.89(95%CI0.76-1.04)Primaryendpointmet

andtrendtosuperiorDFS(ITT)1.00.80.60.40 1 2 3 4 5 6YearsEstimatedprobabilityHR=0.87(95%CI:0.75–1.00)

p=0.0528 3-yearCapecitabine(n=1

004) 64.2%5-FU/LV(n=983) 60.6%PhaseIIIMOSAICRFOLFOX4LV5FU2(deGramont)6months(12Cycles)Aim:25%decreaseinrecurrentriskat3years(Expect3-yearDFS:79%vs.73%)2,236pts148Centers20CountriesMOSAIC4-yrDFS:ASCO20051.00.90.80.70.60.50.30.40.20.10.00FOLFOX4LV5FU2HR[95%CI]:0.75[0.62

–

0.89](0.76[0.62-0.92])DFSprobability666121824303642485460Datacut-off:January16,20058.6%(6.9%)Disease-freeSurvivalinStageIIIPatients:N1&N2DeGramont,A,etalProc.ASCOGIJan.2005661.00.90.80.70.60.50.30.40.20.10.00FOLFOX4–N1LV5FU2–N1FOLFOX4–N2LV5FU2–N2MonthsDFS61218243036424854607.2%11.5%HR:0.76HR:0.72NSABPC-07FU500+LV500weeklyx6every8weeksx3FU500+LV500weeklyx6every8weeksx3+Oxaliplatin85weeks1,3&5ofeach8weekcycleN=2492Primaryendpoint:3-yearDFSRp<0.004HR:0.79[0.67–0.93]21%RiskReductionNSABPC-07Trial(FLOXvs.FU/LV)

3-yearDisease-freeSurvival0.50.60.70.80.9101234Ev#3-yrDFSFLOX27276.5%FU/LV33271.6%NSABPC-07:toxicityandmortality1.0%4.7%1.1%8.0%1.2%2.8%0246810Gr3NCI-sanofineurotoxicityDiarrhea/dehydration*DeathsPercentageofpatientsFU/LVFLOX*Diarrhearequiringhospitalizationand

dehydrationduetobowelthickening0.5%at12monthsWolmarketal.ASCO2005;AbstractLBA3500

3-yrDFS

Δ

HR

C-07

76.5%

4.9%

0.79MOSAIC

77.9%

5.1%

0.77C-07andMOSAIC3-yrDFS:StageIIandIII

Chemo/

radiotherapy-naivestageIIIcolon≤8weekssinceresection

N=1886Primaryendpoint:superiorityofDFSSecondaryendpoints:RFS,OS,tolerabilityn=944

n=942R

A

N

D

OM

I

SA

T

I

O

NAdjuvantXELOXvs5-FU/LV:

NO16968(XELOXA)PhaseIIItrialBolus5-FU/LV(6months)

MayoClinic[n=664]

or

RoswellPark[n=278]XELOX(6months)capecitabine1000mg/m2bidd1–14

oxaliplatin130mg/m2d1q3w

8cyclesBaselinetumourcharacteristicsXELOX

n=9445-FU/LVMayon=6645-FU/LVRoswelln=278Primarytumour(%)T1326T2878T3747376T415189Regionallymphnodes(%)N1656467N2353633Numberoflymphnodesexamined<82326238–12262422>12515055Schmolletal.JCO2007DiarrhoeaNeutropenia/

granulocytopeniaHFS(grade3)Neurosensory

toxicity*Similarratesofgrade3/4AEs(>5%)

inallarms*NotreportedSafetypopulationNausea

vomiting0102030Patients(%)40XELOX (n=938)5-FU/LVMayo (n=657)5-FU/LVRoswell (n=269)Stomatitis*Schmolletal.JCO2007Doseintensity/treatmentmodifications*Ratiodosereceivedvsplanned

5-FU/LV

(n=926)Mayo

(n=657)RP

(n=269)XELOX

(n=938)Mediandoseintensity*85%87%84%Cape84%

Oxal87%Reductions47%49%44%Cape30%

Oxal35%Interruptions15%8%32%Cape14%

Oxal0%Delays37%42%26%Cape56%

Oxal54%5-yearDFS:

benefitwithXELOXmaintainedand

increasedovertimeXELOX 5-FU/LV 1.00.00.20.40.60.80123456YearsITTpopulationΔat4years:6.1%Δat5years:6.3%Δat3years:4.5%70.9%68.4%3-year

DFS66.5%62.3%4-year

DFS5-year

DFS59.8%66.1%Years2460.40.60.81.000.40.60.81.0Years824608Cross-trialcomparisonofMOSAIC

andXELOXA:OSinstageIIIdiseaseXELOX5-FU/LVFOLFOX4LV5FU2XELOXA

(57mo)MOSAIC1

(81.9mo)ITTpopulation1.00.60.81.

Andréetal.JCO200912345678Cross-trialcomparisonofMOSAIC

andXELOXA:OSinstageIIIdiseaseYearsXELOX(n=944)FOLFOX4(n=672)–5-yrOS6-yrOS72.9%77.6%NO16968(XELOXA)*MOSAIC1**–*Medianobservationtime:57.0months**Medianfollow-up:81.9monthsITTpopulation0.40NO16968subgroupanalysis

ofDFSbyage3-yearDFSHazardratio(95%CI)XELOX5-FU/LV<65vs.≥65years

<65years,n=114272%69%0.80(0.65,0.98)≥65years,n=74468%62%0.81(0.64,1.03)<70vs.≥70years

<70years,n=147772%69%0.79(0.66,0.94)≥70years,n=40966%60%0.87(0.63,1.18)ITTpopulationNO16968subgroupanalysis

ofOSbyageITTpopulation5-yearOSHazardratio(95%CI)XELOX5-FU/LV<65vs.≥65years

<65years,n=114280%77%0.87(0.67,1.13)≥65years,n=74473%70%0.90(0.68,1.19)<70vs.≥70years

<70years,n=147780%76%0.86(0.69,1.08)≥70years,n=40969%67%0.94(0.66,1.34)1.Saltzetal.JCO2007

2.VanCutsemetal.JCO2009;3.Ychouetal.AnnOncol2009NR=notreported

TrialDFS

HRDFS∆(%)

pCALGB898031NRNR0.85PETACC-320.902.40.11ACCORD-230.893.10.44Irinotecancombinations:NOsurvivaladvantageinstageIIIOS

HROS∆

(%)

pNRNR0.74NR2.30.091.0910.69IrinotecanasAdjuvantsetting:NoBenefit,moretoxicitiesnoRole24weeks24weeks

NSABPC-08:BevacizumabasAdjuvantSettingPrimaryendpoint:DFSat3yearsSecondaryendpoints:survivalandtolerabilityPatientrecruitmentcompleted10/06mFOLFOX6alonemFOLFOX6+Bevacizumab5mg/kgevery2weeksStageIIIcoloncancer(n=2,710)Bevacizumab5mg/kgevery2weeksObservation

Ev3yDFSmFF6+B29177.4mFF631275.5HR=0.89P=0.15NSABP-08:DFS%YrsRoleofBevacizumabinAdjuvantSetting:-Notshownyet-ShouldNOTbeusedasleastrightnow.

BO17920(AVANT)PhaseIIITrialPrimaryendpoint:DFSat3yearsforstageIIISecondaryendpoints:OSandsafetyAccrualcompletedQ22007SurgeryforhighriskstageII+stageIIIcoloncancer(n=3,450)FOLFOX4FOLFOX4+Avastin(5mg/kgevery

2weeks)XELOX+Avastin(7.5mg/kgevery

3weeks)Avastinalone(7.5mg/kgevery

3weeks)Avastinalone(7.5mg/kgevery

3weeks)ObservationDurationoftreatmentphases24weeks24weeksAVANT:patientrecruitmenttimelineOpened: December2004Closed: June2007Totalaccrual: 3451patientsAveragemonthlyaccrual: 115patientsAccrualtemporarilyonholdduetoDSMBdecision:February–May2006Hoff,etal.ECCO-ESMO2009(abstractNo.6010)AVANT:patientdemographicsHoff,etal.ECCO-ESMO2009(abstractNo.6010)

CharacteristicFOLFOX4

(n=1151)FOLFOX4+Avastin

(n=1155)XELOX+Avastin

(n=1145)Diseasestage,n(%)II(highrisk)IIIN1IIIN2192(17)585(51)

370(32)194(17)590(51)

370(32)187(16)572(50)

380(33)Male,%575155Medianage,years585858ECOGPS,%

0

1

86

14

86

14

86

14AllpatientsrandomisedAVANT:mortality

Deathratea,N(%)FOLFOX4

(n=1126)FOLFOX4+Bev(n=1145)XELOX+Bev(n=1135)60day2(0.18)4(0.35)5(0.44)6month9(0.80)5(0.44)11(0.97)18month15(1.33)11(0.96)17(1.50)aExcludesdeathafterrelapseAVANT:adverseeventsofspecialinterestforAvastin*Hoff,etal.ECCO-ESMO2009(abstractNo.6010)FOLFOX4(n=1126)FOLFOX4+Avastin(n=1145)XELOX+Avastin(n=1135)Category,n(%)aGrade3–5Grade3–5Grade3–5Bleeding/haemorrhage0.61.20.4Hypertension1.110.49.6Proteinuria0.11.01.0Fistula/abscess0.31.40.8GIperforation0.10.70.2Woundhealingcomplication0.40.30.4Venousthromboembolism5.58.34.6Arterialthromboembolism1.01.61.5*AEonsetwithin183daysafterlastdrugintakeAdjuvantTherapy:CetuximabRANDOMIZATIONmFOLFOX66mmFOLFOX6x6m+cetuximab-ComplicatedbecauseofK-Rasmutation&EGFRinhibitorsissue-Studyterminatedin11/09byDSMCbecauseofnoclearbenefitsinthestudyarmandmoredeathonalsoK-RasmutationstatusWTMutation‘Standard’StudyClosedThereisnodifferenceinefficacyTherelikelymoredeathsinthecetuximabarmAllpatientswhointhecetuximabarmwhowerestillontreatmentweretreatedonlywithFOLFOXQUASAR:Adjuvantvs.ObservationinStageIICRC150centersin17countires,3239pts.‘UncertainIndication’Observation16175-FU(370mg/m2)withlowdoseFA,1622-Largerandomizedtrial-PragmatictrialChemoObservationPvalueRelativerisk5-yrsrecurrence22.3%26.2%0.0010.785-yrssurvival80.377.40.020.831.00.80.60.40.20.0Andréet

al.JCO2009YearsStageII

∆=0.1%

p=0.986StageIII

∆=4.2%

p=0.023MOSAIC:nosignificantimprovement

in6-yearOSinstageIIFOLFOX4LV5FU2StageIIHR=1.00

StageIIIHR=0.80123456780E5202:stageIIcoloncancerRiskAssessment18q,MSIRHighRisk(MSSand18qLOHLowRisk(MSIorw/o18qLOH)mFOLFOX6mFOLFOX&BevasucimabObservation(GoalN=3125)AdjuvantTherapy:StageIII

ColonCancer• FOLFOXorFLOXfor6months• XELOXfor6months

• 5-FU/LVfor6-8months -RPMIschedule -MayoClinicschedule -DeGramontinfusionalschedule• Capecitabinemonotherapyfor6monthsRoleforBevacizumabremainsunclear shouldnotbeusedoutsideofclinicaltrialsettingNoroleofEGFRinhibitorsConclusionMetastaticCRC:medianOS2yrs.FOLFOX(XELOX)andFOLFIRIarethebackboneas1stor2ndlineOff-onvs.maintenance(OPTIMOX)BevacizumabshouldbeconsideredwhenitisavailableK-RasstatusshouldbetestedandconsideredcetuximabinWTImportanceofResctabilityAssessment:Pare-operativechemoforptswithlivermets,Timing,Regimens,otherlocaltherapiestode-bulk(RFA,TACE…)Adjuvant:StageIII:FOLFOX/XELOX,5-FUorCapecitabineforthosenotcandidateforoxaliplatinIrinotecan,bevacizumab,cetuximabnorole.StageII:StudiesforsearchingthosewillbebenefitfromStandardtherapy

RespondersandPatientsNotPredisposedtoToxicityAllpatientswithsamediagnosisPersonalizedtherapynon-respondersandtoxicrespondersFuture:‘Personalized’Treatmentvs.‘Optimized’TherapyIndividualizedRiskAssessmentsUsingaRecurrenceNomogramWeiserMR,etal.JClinOncol.2008;26(3):380-385.Locatepatient’sCEAvalueontheCEAaxis.Drawalineuptothe“Poi