晚期胃癌化療策略

晚期胃癌化療策略,晚期胃癌治療現(xiàn)狀,局部進展期治愈：手術(shù)與化療的結(jié)合復(fù)發(fā)或轉(zhuǎn)移不能治愈：化療為主的綜合治療，但手術(shù)或其它局部治療手段的作用加強化療：新藥、新方案高效低毒，近期療效增加而生存期延長不滿意，但近3年進展迅速,胃癌化療,新輔助化療輔助化療晚期胃癌的化療,生存目標(biāo),新輔化,輔化,根治、延長PFS,手術(shù),姑息化療,手術(shù),化,療,化,療,延長生存期改善生活質(zhì)量,化療,手術(shù)局部治療,晚期胃癌化療臨床問題,藥物、方案的選擇療程及后續(xù)治療化療與手術(shù)或局部治療的合理應(yīng)用（新輔助化療）手術(shù)后輔助化療,藥物、方案的選擇,所有的選擇:5FU/CAPE/S-1DDP+5FUECF/LFEP多西紫杉醇/紫杉醇CAPE/DDP+5FUOXA+CAPE/5FUCPT-11+5FU/CAPE/S-1分子靶點藥物,RandomizedPhaseIIIStudy:1990-2000,歐洲實踐標(biāo)準(zhǔn),AjaniJA,etal.Oncology.1998;12:179-223.GoldbergR,etal.Proceedingsofthe38thAnnualMeetingoftheAmericanSocietyofClinicalOncology.2002;21:128a,abstract511.,亞洲實踐標(biāo)準(zhǔn),晚期胃癌化療現(xiàn)狀,在轉(zhuǎn)移性胃癌的治療中沒有公認(rèn)的治療“金標(biāo)準(zhǔn)”“FP，F(xiàn)LP,ECF在晚期胃癌中不被當(dāng)作標(biāo)準(zhǔn)治療方案”，但是常用的試驗對照方案新藥臨床試驗活躍，近年大樣本量、III期隨機、對照試驗增多個體化治療少（普遍性與特意性）,VanhoeferU,etal.JClinOncol.2000;14:264857.,新世紀(jì)初的選擇,紫杉烷類順鉑5-Fu/CAPEOXACAPE/5-FuCAPEDDP伊立替康5-Fu/CAPE/S-1/-DDP分子靶點藥物,Docetaxel,5-FUandCisplatin:V325PhaseIII,StratificationFactors:,LiverInvolvement,PriorGastrectomy,MeasurablevsEvaluableDisease,WeightLoss(5%)inPrior3Months,Centers,Responseassessmentevery8weeksindependentoftreatmentschedule,Cisplatin100mg/m2IVD1,Cyclesrepeatedevery4weeks,Docetaxel75mg/m2IVD1,Cisplatin75mg/m2IVD1,5-FU750mg/m2CIVD1-5,Cyclesrepeatedevery3weeks,5-FU1000mg/m2CIVD1-5,vs,胃癌III期臨床-TAX325隨訪結(jié)果,TCFvsCFp,N227230RR37%25%0.0106TTP5.6m3.7m0.00042Y18%9%0.0201G3/481%75%,2005ASCO，abs4002,TAX325:increasedfebrileneutropeniawithTCF,%patientswithgrade3/4,0,20,40,60,80,100,TCF,FP,MoiseyenkoVMetal.ProcAmSocClinOncol2005;(Abst4002).,TAX325研究結(jié)果,TCF(多西紫杉醇、順鉑、5FU)是用于預(yù)后較好的患者的一項新的治療選擇,Moiseyenkoetal,ASCO2005,Abstract4002,*34級毒性包括：81的非血液學(xué)毒性反應(yīng)，75的血液學(xué)毒性反應(yīng)中30伴有中性粒細(xì)胞減少性發(fā)熱,CPT-11forAGC期多中心臨床研究（2003ASCO）FFCD9803法國,BoucheOetal.JClinOncol2004;22:431927,CPT-11聯(lián)合5-FU治療AGC-III期臨床試驗（2005ASCO）,N=170CPT-1180mg/m2CF500mg/m25FU2000mg/m2civ1/Wx6w,N=163CDDP100mg/m2d15FU1000mg/m2/dd1-5Q4W,N=333AGC,RR54（31.8%）42（25.8%）TTP5.0m4.2m(p=0.088)TTF4.0m3.4m(p=0.002)OS9.0m8.7mp0.53,M.Dank2005ASCOabs4003,新世紀(jì)初的選擇：問題！,多西紫杉醇（Docetaxel）聯(lián)合DDP/5-FU：高效！生存期延長！不良反應(yīng)性大！CPT-11聯(lián)合5-FU/CF:RR改善、安全性提高、TTF延長,OS無延長如何改變？更合理的選擇？,新的探索和循證醫(yī)學(xué)證據(jù),OXADDPCAPE5-FU重新設(shè)定劑量強度或改變劑量密度增、減藥物聯(lián)合續(xù)慣。,REAL2randomisedmulticentrephaseIIIstudycomparingcapecitabinewith5-FUandoxaliplatinwithcisplatininpatientswithadvancedoesophagogastriccancer,DCunninghametal.2006ASCOAbstractLBA4017,REAL-2:randomized,phaseIIItrialingastricandGEJcancer,EpirubicinCisplatin5-FU,EpirubicinCisplatinXeloda,EpirubicinEloxatin5-FU,EpirubicinEloxatinXeloda,21-daycyclePlanneddurationoftreatment:24weeks(8cycles),Targetrandomizationn=600,Eloxatin130mg/m2day1CAPE625mg/m2twicedailydays121Eprirubucin50mg/m2day1;Cisplatin60mg/m2day1;5-FU200mg/m2/day,REAL2:研究目標(biāo),Primaryendpointofnon-inferiorityinoverallsurvivalXelodavs.5-FUoxaliplatinvs.cisplatinSecondaryendpointsORRandresponsedurationPFSsafetyQoL,SumpterKetal.BrJCancer2005;92:197683.,REAL2interimanalysis:goodresponsewithoxali-vs.cisplatin,D.CunninghamMdASCO2006,REAL2:survivaloutcomes,Updatedresultsforfourregimens,D.CunninghamMdASCO2006,REAL2:safetyoutcomes,TherewaslessneutropeniaintheEloxatin-containingarmscomparedwiththecisplatin-containingarms,REAL2:conclusions,Theprimaryobjectiveofthetrialwasmet:Capecitabineisnotinferiorto5-FUOxaliplatinisnotinferiortocisplatinInthesetripletregimensCapecitabinecouldreplace5-FUOxaliplatincouldreplacecisplatinTheuseofEOXisassociatedwithimprovedefficacyoverECF,以EPI為基礎(chǔ)的三藥聯(lián)合可行！EOX有明顯生存優(yōu)勢！,Oxaliplatin聯(lián)合EPI、5-FU/CF治療晚期胃癌的臨床多中心研究china,用藥方法樂沙定100mg/m2d1EPI50mg/m2d1CF200mg/m2d1-35-FU500mg/m2CIVd1-3每3周重復(fù)，治療至少3個周期評價療效及毒性反應(yīng),CR2例（5.6%）PR13例（36.1%）SD17例（47.2%）總有效率41.7%。其中初治患者9/20（45%）復(fù)治患者6/16（37.5%）,主要不良反應(yīng)：骨髓抑制：-OANC7/36（19.4%），OPLT3/36（8.3%），OHb4/36（11.1%），O神經(jīng)末梢毒性4/36（11.1%），,first-linechemotherapywithfluorouracil,leucovorinandoxaliplatin(FLO)versusfluorouracil,leucovorinandcisplatin(FLP),FLOF2600mg/m224hinfusion,L200mg/m2,oxaliplatin85mg/m2q2w,FLPF2000mg/m224hinfusion,qwL200mg/m2,qwcisplatin50mg/m2,q2w.,Total220ptsMedianage64yrsAdvancedand/ormetastaticgastriccancer(AGC),RANDOMIZATION,S.Al-Batran,J.Hartmann,ASCO2006,SuperiorPerformancewithFLOvs.FLP,S.Al-Batran,J.Hartmann,ASCO2006,奧沙利鉑5FU作為一線治療,1.DeVitaetal.BrJCancer2005;92:164449.2.Al-Batranetal.JClinOncol2004;22:65863.3.Al-Batrametal,ASCO2005,Abstract4014.,Oxaliplatin/CF/5-FUvspaclitaxel/CF/5-FUinpatswithadvancedgastriccancerAphaseIIclinicaltrial,T.LinASCO2006Abstr14014,PhaseIImulticentertrialofdocetaxel+oxaliplatininstageIVgastroesophagealand/orstomachcancer,PATIENTPROFILE:Medianage=59.4years72%malepatients,76%whiteECOGPSscores:0(45%);1(49%);2(6%)32.8%ofpatientshaddistalgastriccancer,N=71Eligibility:Patientswithmetastatic(StageIV)AGEJ/S,ENDPOINTS:Primary:ORR,Secondary:timetoresponse,durationofresponse,TTP,toxicity,1-and2-yearsurvival,Docetaxel,60mg/m21hIVD1;q3w,Oxaliplatin,130mg/m22hIVD1;q3w,+,RichardsDAetal.2006ASCOAbstract4071,Results:efficacy,RRof38%similartoTAX325;OSof9.2monthssimilartoTAX325,Results:toxicity,ML17032:CAPEvs5-FUtrialdesign,FPCisplatin80mg/m23-houri.v.infusion5-FUc.i.800mg/m2/day;d15q3w,XPCisplatin80mg/m23-houri.v.infusionCapecitabine1000mg/m2twicedaily;d114q3w,KPS70%1875yearsAdvancedand/ormetastaticgastriccancer(AGC)1measurablelesionNopriortreatmentforAGC,RANDOMIZATION,SuperiorresponseratewithXPvs.FP,ML17032:XPvsFPprogression-freesurvivalHR0.81,Estimatedprobability,HR=0.81(95%CI:0.631.04)ComparedtoHRupperlimit1.25,p=0.0008,1.0,0.8,0.6,0.4,0.2,0.0,Perprotocolanalysis,Similarall-gradeshematologicadverseevents:XPvs.FP,APhaseIITrialofCapecitabineandDDPinAGCChina,2002.6-2003.5,N=145,Cape1000mg/m2Bidd1-14DDP20mg/m2ivd1-5q3W130ptsevaluable:98M/32FAge:53.7ys,Results,CR10(8%)PR48(37%)SD51(39%)PD21(16%)OS12m,Safety：grade3-4adverseevent5%,-2005,2006ASCO,SummaryofCombinationChemotherapywithCAPEinAGC,RegimenXXPTXDXDX(weekly)ECXDXP,N44424542555440,RR(%)34554960405968,TTP(mo)7.8,OS(mo)9.510.111.410.512.09.616.9,Neut(%)G3/40324715*366063,NeutFever(%)000791910,TxDeath-11,X;Xeloda,P;Cisplatin,T;Taxol,D;Docetaxel,E;Epirubicin,C;Cisplatin*notbasedonweeklyCBC,CAPEvs5-FUindoubletregimensforAGC,1.Al-BatranSProcAmSocClinOncol2005;(Abst4015);2.ParkYBrJCancer2006;94:95963;3.DankMProcAmSocClinOncol2005;(Abst4003);4.BaekJBrJCancer2006Apr25;5.ParkS.AnticancerDrugs2006;17:2259;6.Kang.H.ProcAmSocClinOncol2004;(Abst4051,posterupdate);7.Thuss-PatiencePJClinOncol2005;23:494501;8.ParkYBrJCancer2004;90:132933,新的探索和循證醫(yī)學(xué)證據(jù),CAPE5-FUOXADDP重新設(shè)定劑量強度或改變劑量密度增、減藥物聯(lián)合續(xù)慣。,伊立替康聯(lián)合5-FU/LV、CDDP治療胃癌,降低5FU劑量強度改變給藥間隔增加DDP,伊立替康聯(lián)合奧沙利鉑治療胃癌,中性粒細(xì)胞減少癥,貧血,3級腹瀉,神經(jīng)毒性,3級虛弱,發(fā)熱性中性粒細(xì)胞減少癥,不良反應(yīng)發(fā)生率,SouglakosJ,etal.AnnOncol.2004;15(8):1204-9,N=32,CPT:200mg/m2iv30md1,OXA:85mg/m2iv2hd1Q3W,有效率提高！生存期延長不滿意！,irinotecanpluscapecitabineinpatientswithAGC,N=38/40/41，Cape1000mg/m2BIDday1-14irinotecan100mg/m2d1，8Q3WRR46.3%.TTP5.1OS8.6m,Grade3/4neutropeniain4patsgrade3febrileneutropeniain2pats.grade3diarrheagrade2HFSin6patients,J.BaekASCO2006，ABSTR14037,Iri80mg/m2ond1,8,and15cape625mg/m2BIDD1-14;Q4w29/31ptswereevaluableforresponsePR38.5%.SD29%,TTP5.8monthsOS10.5monthsnogradeIII-IVtoxicity,F.FarhatASCO2006Abstr14030,S-180mgm2d1-14q28dCPT-1170-100mgm2d1,8q4weeks,phaseI:MTD:CPT-1190mg/m2RD80mg/m2.phaseII:42patsThemediantreatmentcoursewas5(range:113).RR62%(95%confidenceinterval:47.276.6%),Themediansurvivaltimewas444days.grade34haematological19%;nonhaematologicaltoxicities10%,伊立替康聯(lián)合S1治療胃癌臨床I/II期試驗,MInokuchBritishJCancer(2006)94,11301135,N=45/48irinotecan150mg/m2d1oxaliplatin85mg/m2d1lv100mg/m2/d5-FU2000mg/m248-hcid1,Q2wRR73.3%（2CRsand31PR）.SD9%PD18%estimatedmOS14.0mestimatedmTTP8.9mgrade3/4toxicitieswereneutropenia(11%ofallcycles)andemesis(12%),FOLFOXIRIcombinationchemotherapyinmetastaticorrecurrentgastriccancer,J.LeeASCO2006Abstr4076,AphaseIstudyofS-1plusweeklydocetaxelinpatientswithmGC,MTDforthisregimenwasS-190mg/m2/d+docetaxel35mg/m2d1,8RDwasS-180mg/m2/d(D1-14)+docetaxel35mg/m2(D1,8).DLT:diarrheaandfebrileneutropenia,S.R.Park,H.K.KimASCO2006Abst14005；T.Ozaki,ASCO2006Abst14108,MTDS1:80mg/m2d1-21+docetaxel25mg/m2D1,8,15RDS180mg/m2d1-21anddocetaxel:20mg/m2day1,8and15DLT:febrileneutropenia,Grade3stomatitisandcontinuousGrade4neutropenia.,3周方案,5周方案,Capecitabineanddocetaxelforadvancedgastriccancer,partI：Docetaxel75mg/m2d1,capecitabine2000mg/m2d1-14,q3w.CR2.6%,PR52.6%,NC36.8%,PD7.9%,RR:55.3%InpartII：furtherimprovetolerability：reducedthedoseofdocetaxelto60mg/m2andcapecitabineto1600mg/m2to,P.C.Thuss-Patience,2006ASCOAbstr:4068,Taxanes+5-FU或CDDP二聯(lián)治療AGC,方法：PCT175mg/m2/3w,DCT75-85mg/m2/3w5-FU750mg/m2civ,d1-5/3w或200-300mg/m2/3wciv2w/3wCDDP20mg/m2I.V.d1-5/3w或75mg/m2I.V./d1/3w,AphaseI/IIstudyofoxaliplatin,docetaxel,andcapecitabineinadvancedcarcinomaoftheesophagusandstomach.,DLT：Grade3/4diarrhea,nausea,andfebrileneutropeniaRD：Oxaliplatin50mg/m2anddocetaxel35mg/m2day1and8capecitabine750mg/m2BID10daysQ21day,D.L.EvansASCO2006Abstr14046,AphaseIIstudyofalternatingchemotherapywithCDDP/5FU/FAandepirubicin(E)/docetaxel(T)(CF-ETregimen)asfirstlinetherapyforptswithMGC,N=34CDDP35mg/m2d1,2,15and16,5FU2000mg/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.KirchnerASCO2006Abstr14021,續(xù)貫,靶向治療,EGFR,EGFR在66的胃癌中過表達(dá)（Roid2001）吉非替尼（酪氨酸激酶抑制劑）胃癌：緩解率為1，N75（ASCO2003）食管腺/鱗細(xì)胞癌：緩解率為1012，N=56（ASCO2004）Erlotinib（Tarceva）食管腺/鱗細(xì)胞癌：緩解率為16，N=17（ASCO2004）胃或胃食管交接部癌：N2644，緩解率為012（1例完全緩解）（ASCO2005）,VEGFR,Bevacizumab抑制VEGFR在轉(zhuǎn)移性病變中順鉑和伊立替康（MSKCC）輔助ECF方案（MAGIC-2實驗）,胃癌靶向治療,Bevacizumab（BEV）聯(lián)合PT-11+DDP一線治療AGC-II期臨床試驗（ASCO2005）,BEV15mg/kgd1CPT65mg/m2d1，8DDP30mg/m2d1，8q3w,N=243mPFS89%6mPFS76%16例可評價近期療效PR（12/16）75%MR3，SD1,不良反應(yīng)（24例）：級白細(xì)胞減少、惡心嘔吐、腹瀉8%血栓（4肺和2深靜脈）：6例（20%）；2例胃穿孔，2例幾近穿孔（腫瘤部位）,M.A.ShAhetal:ASCO2005abstr4025,CPT-11、DDPBevacizumabinAGC,僅進行了初步的治探索正在進行或準(zhǔn)備之