晚期胃癌化疗策略专家讲座

晚期胃癌化疗策略北京大学临床肿瘤学院消化内科沈琳－8晚期胃癌化疗策略第1页晚期胃癌治疗现实状况局部进展期－－治愈:手术与化疗结合复发或转移－－不能治愈:化疗为主综合治疗，但手术或其它局部治疗伎俩作用加强化疗:新药、新方案高效低毒，近期疗效增加而生存期延长不满意，但近3年进展快速晚期胃癌化疗策略第2页胃癌化疗新辅助化疗辅助化疗晚期胃癌化疗生存目标新辅化辅化根治、延长PFS手术姑息化疗手术化疗化疗延长生存期改进生活质量化疗＋手术局部治疗晚期胃癌化疗策略第3页晚期胃癌化疗临床问题药品、方案选择疗程及后续治疗化疗与手术或局部治疗合理应用（新辅助化疗)手术后辅助化疗晚期胃癌化疗策略第4页药品、方案选择全部选择:5FU/CAPE/S-1DDP+5FUECF/LFEP多西紫杉醇/紫杉醇＋CAPE/＋DDP+5FUOXA+CAPE/5FUCPT-11+5FU/CAPE/S-1分子靶点药品晚期胃癌化疗策略第5页RandomizedPhaseIIIStudy:1990-StudyRegimenNRR(%)p-valueMSTp-valueEORTC1991FAMFAMTX103105941<.000129w42w.004MSKCC1992FAMTXEAP30303320NS7.3m6.1mNSMRC1997FAMTXECF1081112145.0025.7m

8.9m.009EORTCFAMTXELFFP92939812920NS6.7m7.2m7.2mNS晚期胃癌化疗策略第6页欧洲实践标准FLP甲酰四氢叶酸500mg/m2每七天1次5-氟尿嘧啶2gm2/24h每七天1次顺铂50mg/m2每2周1次ECF表阿霉素50mg/m2每4周1次顺铂60mg/m2每4周1次5-氟尿嘧啶200mg/m2连续静脉泵入3周AjaniJA,etal.Oncology.1998;12:179-223.GoldbergR,etal.Proceedingsofthe38thAnnualMeetingoftheAmericanSocietyofClinicalOncology.;21:128a,abstract511.晚期胃癌化疗策略第7页亚洲实践标准FLP甲酰四氢叶酸100－300mg/m2/dd1-5每3-4周5-氟尿嘧啶375－600mg/m2/dd1-5每3-4周顺铂50-75mg/m2d1or10mg/m2d1-5每3-4周LFEP表阿霉素50mg/m2每3-4周1次顺铂60mg/m2每3-4周1次5-氟尿嘧啶375－600mg/m2/dd1-5连续静脉泵入每3-4周晚期胃癌化疗策略第8页晚期胃癌化疗现实状况在转移性胃癌治疗中没有公认治疗“金标准”“FP，FLP,ECF……在晚期胃癌中不被看成标准治疗方案”，不过惯用试验对照方案新药临床试验活跃，近年大样本量、III期随机、对照试验增多个体化治疗少（普遍性与特意性)VanhoeferU,etal.JClinOncol.;14:2648–57.晚期胃癌化疗策略第9页新世纪初选择…紫杉烷类＋顺铂＋5-Fu/CAPEOXA＋CAPE/5-FuCAPE＋DDP伊立替康＋5-Fu/CAPE/S-1＋/-DDP分子靶点药品晚期胃癌化疗策略第10页Docetaxel,5-FUandCisplatin:V325PhaseIIIRANDOMIZEStratificationFactors:LiverInvolvementPriorGastrectomy

Measurablevs

EvaluableDiseaseWeightLoss(>5%)in

Prior3MonthsCentersResponseassessmentevery8weeksindependentoftreatmentschedule

Cisplatin100mg/m2IVD1Cyclesrepeatedevery4weeksDocetaxel75mg/m2IVD1Cisplatin75mg/m2IVD1

5-FU750mg/m2CIVD1-5Cyclesrepeatedevery3weeks5-FU1000mg/m2CIVD1-5vs

晚期胃癌化疗策略第11页胃癌III期临床----TAX325随访结果TCFvsCFp

N227230RR37%25%0.0106TTP5.6m3.7m0.00042Y18%9%0.0201G3/481%75%ASCO,abs4002晚期胃癌化疗策略第12页TAX325:increasedfebrileneutropeniawithTCF%patientswithgrade3/4NeutropeniaAnemiaPlateletsFebrileneutro-

penia,infection020406080100TCFFPMoiseyenkoVMetal.ProcAmSocClinOncol;(Abst4002).82573014晚期胃癌化疗策略第13页TAX325研究结果TCF(多西紫杉醇、顺铂、5FU)是用于预后很好患者一项新治疗选择Moiseyenkoetal,ASCO,Abstract4002例数总体缓解疾病进展时间（月）总生存期（月）3—4级毒性TCF221/22737%5.69.2腹泻，感染，中性粒细胞降低症*p=0.01p=0.0004p=0.02CF224/23025%3.78.6胃炎，肾毒性*3－4级毒性包含:81％非血液学毒性反应，75％血液学毒性反应中30％伴有中性粒细胞降低性发烧晚期胃癌化疗策略第14页CPT-11forAGC——Ⅱ期多中心临床研究

（ASCO)FFCD9803法国BoucheOetal.JClinOncol;22:4319–27例数RRmTTPmOSLV5FU24513%3.2m6.8mLV5FU2-DDP4427%4.9m9.5mLV5FU2-CPT-114540%6.7m11.3m晚期胃癌化疗策略第15页CPT-11联合5-FU治疗AGC

----III期临床试验（ASCO)N=170CPT-1180mg/m2CF500mg/m25FUmg/m2civ1/Wx6wN=163CDDP100mg/m2d15FU1000mg/m2/dd1-5Q4WN=333AGCRR54（31.8%)42（25.8%)TTP5.0m4.2m(p=0.088)TTF4.0m3.4m(p=0.002)OS9.0m8.7mp＝0.53M.DankASCOabs4003晚期胃癌化疗策略第16页新世纪初选择：问题!…多西紫杉醇（Docetaxel)联合DDP/5-FU：

高效！生存期延长！不良反应性大！CPT-11联合5-FU/CF:RR改进、安全性提升、TTF延长,OS无延长怎样改变？更合理选择？晚期胃癌化疗策略第17页新探索和循证医学证据OXA→DDPCAPE→5-FU重新设定剂量强度或改变剂量密度增、减药品联合续惯。。。晚期胃癌化疗策略第18页REAL2

randomisedmulticentrephaseIIIstudy

comparingcapecitabinewith5-FUand

oxaliplatinwithcisplatininpatientswithadvancedoesophagogastriccancerDCunninghametal.ASCOAbstractLBA4017晚期胃癌化疗策略第19页REAL-2:randomized,phaseIIItrialingastricandGEJcancer

Epirubicin

Cisplatin5-FUEpirubicinCisplatinXeloda

Epirubicin

Eloxatin5-FUEpirubicinEloxatin

Xeloda21-daycyclePlanneddurationoftreatment:24weeks(8cycles)Target

randomizationn=600Eloxatin

130mg/m2day1CAPE

625mg/m2twicedailydays1–21Eprirubucin

50mg/m2day1;Cisplatin60mg/m2day1;5-FU200mg/m2/day晚期胃癌化疗策略第20页REAL2:研究目标Primaryendpointofnon-inferiorityinoverallsurvivalXelodavs.5-FUoxaliplatinvs.cisplatinSecondaryendpointsORRandresponsedurationPFSsafetyQoLSumpterKetal.BrJCancer;92:1976–83.晚期胃癌化疗策略第21页REAL2interimanalysis:goodresponsewithoxali-vs.cisplatin%%%%%%%%%%%%%%%D.CunninghamMdASCO2006晚期胃癌化疗策略第22页1-yearS

(%)MedianOS(months)HR2x2comparisons5-FU:ECF+EOF39.49.61Capecitabine:ECX+EOX44.610.90.86Cisplatin:ECF+ECX40.110.11Oxaliplatin:EOX+EOF43.910.40.92REAL2:

survivaloutcomes晚期胃癌化疗策略第23页Updatedresultsforfourregimens1yearOS(95%CI)MedianOSHR(95%CI)ECFn=26337.7%(31.8-43.6)9.9mths1EOFn=24540.4%(34.2-46.5)9.3mths0.95(0.79-1.15)ECXn=25040.8%(34.7-46.9)9.9mths0.92(0.76-1.11)EOXn=24446.8%(40.4-52.9)11.2mths0.80(0.65-0.97)D.CunninghamMdASCO2006晚期胃癌化疗策略第24页ECFEOFECXEOXGrade3/4non-haematologicaltoxicity,%36423345Grade3/4neutropenia,%42305128p-value0.0080.0080.00430.001REAL2:safetyoutcomesTherewaslessneutropeniaintheEloxatin-containingarmscomparedwiththecisplatin-containingarms晚期胃癌化疗策略第25页REAL2:conclusionsTheprimaryobjectiveofthetrialwasmet:Capecitabineisnotinferiorto5-FUOxaliplatinisnotinferiortocisplatinInthesetripletregimensCapecitabinecouldreplace5-FUOxaliplatincouldreplacecisplatinTheuseofEOXisassociatedwithimproved

efficacyoverECF以EPI为基础三药联合可行!EOX有显著生存优势!晚期胃癌化疗策略第26页Oxaliplatin联合EPI、5-FU/CF治疗

晚期胃癌临床多中心研究——china用药方法乐沙定100mg/m2d1EPI50mg/m2d1CF200mg/m2d1-35-FU500mg/m2CIVd1-3每3周重复,治疗最少3个周期评价疗效及毒性反应CR2例（5.6%)PR13例（36.1%)SD17例（47.2%)

总有效率41.7%。其中初治患者9/20（45%)复治患者6/16（37.5%)]主要不良反应：骨髓抑制：Ⅲ-ⅣOANC7/36（19.4%)，ⅢOPLT3/36（8.3%)，ⅢOHb4/36（11.1%)，ⅢO神经末梢毒性4/36（11.1%)，晚期胃癌化疗策略第27页first-linechemotherapywithfluorouracil,leucovorinandoxaliplatin(FLO)versusfluorouracil,leucovorinandcisplatin(FLP)FLO

F2600mg/m224hinfusion,L200mg/m2,oxaliplatin85mg/m2q2wFLPFmg/m224hinfusion,qwL200mg/m2,qwcisplatin50mg/m2,q2w.Total220ptsMedianage64yrs

Advancedand/or

metastaticgastriccancer(AGC)R

A

N

D

OM

I

ZA

T

I

O

NS.Al-Batran,J.Hartmann,ASCO晚期胃癌化疗策略第28页SuperiorPerformancewithFLOvs.FLPConfirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)S.Al-Batran,J.Hartmann,ASCO晚期胃癌化疗策略第29页奥沙利铂＋5FU作为一线治疗1.DeVitaetal.BrJCancer;92:1644–49.2.Al-Batranetal.JClinOncol;22:658–63.3.Al-Batrametal,ASCO,Abstract4014.方案例数缓解率疾病进展时间/总生存期3-4度神经病变FOLFOX416138%7.1/11.25%FOLFOX624143%---/9.60改良FOLFOX6vs5-Fu(AIO)

＋顺铂3105（80例可评价）39.1%24.2%---54.5%19.4%晚期胃癌化疗策略第30页Oxaliplatin/CF/5-FUvspaclitaxel/CF/5-FUinpatswithadvancedgastriccancer

AphaseIIclinicaltrial

T.LinASCOAbstr14014armAFOLFOX6armBFOLFPa

PTX80mg/m2病例数4643CR+PR37.0%47.2%CR+PR+SD76.1%69.4%TTP6.0m3.2m?OS13.4m13.8m晚期胃癌化疗策略第31页PhaseIImulticentertrialofdocetaxel+oxaliplatininstageIVgastroesophageal

and/orstomachcancerPATIENTPROFILE:Medianage=59.4years72%malepatients,76%whiteECOGPSscores:0(45%);1(49%);2(6%)32.8%ofpatientshaddistalgastriccancerN=71Eligibility:Patientswithmetastatic(StageIV)AGEJ/SENDPOINTS:Primary:ORR,Secondary:timetoresponse,durationofresponse,TTP,toxicity,1-and2-yearsurvivalDocetaxel60mg/m21hIVD1;q3wOxaliplatin130mg/m22hIVD1;q3w+RichardsDAetal.ASCOAbstract4071晚期胃癌化疗策略第32页Results:efficacyN%BestresponsePartialresponse2538Stabledisease(SD≥6months;3patients)3452Progressivedisease711Clinicalbenefitrate2842Timetoresponse(months)Median1.3Range1.1–4.4Durationofresponse(months)Median4.6Range2.7–18.3EstimatedoverallsurvivalrateMediasurvivaltime[95%CI]9.2months[6.5–11.2]RRof38%–similartoTAX325;OSof9.2months–similartoTAX325晚期胃癌化疗策略第33页

Adverseevents(Grade3/4)Total(%)HaematologicalLeukopeniaNeutropeniaThrombocytopeniaFebrileneutropenia177077Non-haematologicalDehydrationDiarrhoeaFatigueNauseaVomiting1313131617Results:toxicity晚期胃癌化疗策略第34页ML17032:CAPEvs5-FU

trialdesignFP

Cisplatin

80mg/m23-houri.v.infusion5-FUc.i.

800mg/m2/day;d1–5q3wXPCisplatin

80mg/m23-houri.v.infusionCapecitabine

1000mg/m2twicedaily;d1–14q3wKPS≥70%18–75yearsAdvancedand/or

metastaticgastriccancer(AGC)≥1measurablelesionNopriortreatmentforAGCR

A

N

D

OM

I

ZA

T

I

O

N晚期胃癌化疗策略第35页SuperiorresponseratewithXPvs.FPConfirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)Confirmedresponse

%(95%CI)晚期胃癌化疗策略第36页ML17032:XPvsFP

progression-freesurvivalHR0.81

EstimatedprobabilityHR=0.81(95%CI:0.63–1.04)ComparedtoHRupperlimit1.25,p=0.00080Months24681012141618202224261.00.80.60.40.20.0PerprotocolanalysisXP(n=139)FP(n=137)MedianPFS

months(95%CI)5.6(4.9–7.3)5.0(4.2–6.3)晚期胃癌化疗策略第37页Similarall-grades

hematologicadverseevents:

XPvs.FP

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients

%ofpatients晚期胃癌化疗策略第38页APhaseIITrialofCapecitabineandDDPinAGC－－China.6-.5,N=145,Cape1000mg/m2Bidd1-14DDP20mg/m2ivd1-5q3W130ptsevaluable:98M/32FAge:53.7ysResultsCR10(8%)PR48(37%)SD51(39%)PD21(16%)OS12mSafety：grade3-4adverseevent<5%-----,ASCO晚期胃癌化疗策略第39页SummaryofCombinationChemotherapywithCAPEinAGCRegimenXXPTXDXDX(weekly)ECXDXPN44424542555440RR(%)34554960405968TTP(mo)3.26.35.75.24.56.07.8OS(mo)9.510.111.410.512.09.616.9Neut(%)G3/40324715*366063NeutFever(%)000791910TxDeath-----11X;Xeloda,P;Cisplatin,T;Taxol,D;Docetaxel,E;Epirubicin,C;Cisplatin*notbasedonweeklyCBC晚期胃癌化疗策略第40页CAPEvs5-FUindoubletregimensforAGCStudiesnRR(%)PFS/TTP

monthsOS

monthsOxaliplatin+5-FU1

Oxaliplatin+X244

2040

655.8

7.59.3

tooearlyIrinotecan+5-FU3

Irinotecan+X4172

3832

465.0

5.19.0

8.6Paclitaxel+5-FU5

Paclitaxel+X638

4042

504.3

6.89.9

13.6Docetaxel+5-FU7

Docetaxel+X843

3838

60

5.5

5.29.5

10.51.Al-BatranSProcAmSocClinOncol;(Abst4015);2.ParkYBrJCancer;94:959–63;3.DankMProcAmSocClinOncol;(Abst4003);4.BaekJBrJCancerApr25;5.ParkS.AnticancerDrugs;17:225–9;6.Kang.H.ProcAmSocClinOncol;(Abst4051,posterupdate);7.Thuss-PatiencePJClinOncol;23:494–501;8.ParkYBrJCancer;90:1329–33

晚期胃癌化疗策略第41页新探索和循证医学证据CAPE→5-FUOXA→DDP重新设定剂量强度或改变剂量密度增、减药品联合续惯。。。

晚期胃癌化疗策略第42页伊立替康联合5-FU/LV、CDDP治疗胃癌方法nRR(%)中位生存期（月）研究者CPT-11:80mg/m2,5-FU:mg/m2,FA：500mg/m2,CDDP：20-50mg/m2每2周1次1770NASchleucheretal（）降低5－FU剂量强度改变给药间隔增加DDP晚期胃癌化疗策略第43页伊立替康联合奥沙利铂治疗胃癌CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)CR(%)中性粒细胞降低症贫血3级腹泻神经毒性3级虚弱发烧性中性粒细胞降低症不良反应发生率SouglakosJ,etal.AnnOncol.;15(8):1204-9

N=32CPT:200mg/m2iv30md1,OXA:85mg/m2iv2hd1Q3W有效率提升!生存期延长不满意!晚期胃癌化疗策略第44页irinotecanpluscapecitabineinpatientswithAGCN=38/40/41，Cape1000mg/m2BIDday1-14irinotecan100mg/m2d1，8Q3WRR46.3%.TTP5.1OS8.6m,Grade3/4neutropeniain4patsgrade3febrileneutropeniain2pats.grade3diarrheagrade2HFSin6patientsJ.BaekASCO,ABSTR14037

Iri80mg/m2ond1,8,and15cape625mg/m2BIDD1-14;Q4w29/31ptswereevaluableforresponsePR38.5%.SD29%,TTP5.8monthsOS10.5monthsnogradeIII-IVtoxicityF.FarhatASCOAbstr14030晚期胃癌化疗策略第45页S-180mgm2d1-14q28dCPT-1170-100mgm2d1,8q4weeks,phaseI:MTD:CPT-1190mg/m2RD80mg/m2.phaseII:42patsThemediantreatmentcoursewas5(range:1–13).RR62%(95%confidenceinterval:47.2–76.6%),Themediansurvivaltimewas444days.grade3–4haematological19%;nonhaematologicaltoxicities10%,伊立替康联合S－1治疗胃癌临床I/II期试验MInokuchBritishJCancer()94,1130–1135晚期胃癌化疗策略第46页N=45/48irinotecan150mg/m2d1oxaliplatin85mg/m2d1lv100mg/m2/d5-FUmg/m248-hcid1,Q2wRR73.3%（2CRsand31PR).SD9%PD18%estimatedmOS14.0mestimatedmTTP8.9mgrade3/4toxicitieswereneutropenia(11%ofallcycles)andemesis(12%)FOLFOXIRIcombinationchemotherapyinmetastaticorrecurrentgastriccancerJ.LeeASCOAbstr4076晚期胃癌化疗策略第47页AphaseIstudyofS-1plusweeklydocetaxelinpatientswithmGCMTDforthisregimenwasS-190mg/m2/d+docetaxel35mg/m2d1,8RDwasS-180mg/m2/d(D1-14)+docetaxel35mg/m2(D1,8).DLT:diarrheaandfebrileneutropeniaS.R.Park,H.K.KimASCOAbst14005;T.Ozaki,ASCOAbst14108MTDS1:80mg/m2d1-21+docetaxel25mg/m2D1,8,15RDS180mg/m2d1-21anddocetaxel:20mg/m2day1,8and15DLT:febrileneutropenia,Grade3stomatitisandcontinuousGrade4neutropenia.

3周方案5周方案晚期胃癌化疗策略第48页CapecitabineanddocetaxelforadvancedgastriccancerpartI：Docetaxel75mg/m2d1,capecitabinemg/m2d1-14,q3w.CR2.6%,PR52.6%,NC36.8%,PD7.9%,RR:55.3%InpartII：furtherimprovetolerability：reducedthedoseofdocetaxelto60mg/m2andcapecitabineto1600mg/m2toP.C.Thuss-Patience,ASCOAbstr:4068晚期胃癌化疗策略第49页Taxanes+5-FU或CDDP二联治疗AGC方法:PCT175mg/m2/3w,DCT75-85mg/m2/3w 5-FU750mg/m2civ,d1-5/3w或200-300mg/m2/3wciv×2w/3w CDDP20mg/m2I.V.d1-5/3w或75mg/m2I.V./d1/3w晚期胃癌化疗策略第50页AphaseI/IIstudyofoxaliplatin,docetaxel,andcapecitabineinadvancedcarcinomaoftheesophagusandstomach.DLT:Grade3/4diarrhea,nausea,andfebrileneutropeniaRD:Oxaliplatin50mg/m2anddocetaxel35mg/m2day1and8capecitabine750mg/m2BID×10daysQ21dayD.L.EvansASCOAbstr14046晚期胃癌化疗策略第51页AphaseIIstudyofalternatingchemotherapywithCDDP/5FU/FAandepirubicin(E)/docetaxel(T)(CF-ETregimen)asfirstlinetherapyforptswithMGCN=34CDDP35mg/m2d1,2,15and16,5FUmg/m2cid1,8,15and22,FA200mg/m2ivd1,8,15and22E60mg/m2d29and43,T60mg/m2d29and43q8WRR64.5%.Themedianresponsedurationwas6.1months.OS11.4months。Grade3/4toxicities：leukopenia41/37.5%,neutropenia16/82%,thrombocytopenia23.2/0%,H.H.KirchnerASCOAbstr14021续贯晚期胃癌化疗策略第52页靶向治疗靶点Ⅰ－Ⅱ期Her-2HerceptinVEGFBevacizumab(Avastin)EGFR西妥昔单抗（C225）多靶点Sutent(Sunitinib)晚期胃癌化疗策略第53页EGFREGFR——在66％胃癌中过表示（Roid)吉非替尼（酪氨酸激酶抑制剂)胃癌：缓解率为1％，N＝75（ASCO)食管腺/鳞细胞癌：缓解率为10％－12％，N=56（ASCO)Erlotinib（Tarceva)食管腺/鳞细胞癌：缓解率为16％，N=17（ASCO)胃或胃食管交接部癌：N＝26＋44，