胃癌的综合治疗现状

胃癌综合治疗的现状马鞍山市人民医院肿瘤科张丰林1中国是胃癌的高发地区2002年世界胃癌的病例分布n=933,937NorthernEurope2%NorthernAmerica3%CentralAmerica1%Others4%WesternAsia1%WesternEurope4%South-EasternAsia3%SouthernEurope4%SouthAmerica6%South-CentralAsia6%Japan11%China41%CentralandEasternEurope10%SouthKorea3%NorthKorea1%Mongolia0%EasternAsia56%2我国Ⅲ/Ⅳ期胃癌患者占总胃癌患者超过60%JSurgConceptsPract2008,Vol.13,No.1：24上海市胃癌发病流行现况3早诊率低治疗水平差异大国内高水平的临床研究少，循证医学依据较少亟待规范治疗行为，统一诊疗标准，特别是综合治疗各期胃癌术后的生存数据USvs.JapanesecentersvsCHApopulationUS(1982–1987)Japan(1971–1985)SH(2002-2004)StageN(%)5yr-SN(%)5yr-SN(%)5yr-SI2004(18.1)50%1453(45.7)91%601(13.2)68%II1976(16.2)29%377(11.9)72%1085(23.9)49%III3945(35.6)13%693(21.8)44%1352(29.8)26%IV3342(30.1)3%653(20.6)9%1504(33.1)7.5%Maruyamaetal.,WorldJSurg1987;11:418-25SHCDCdata,2009中国的胃癌治疗现状介于日本和美国之间在缺乏中国数据的前提下，我们的临床实践是参照日本还是欧美？胃癌治疗中的瓶颈•早期胃癌的诊断率低•局部进展期胃癌的总体疗效差•晚期胃癌的药物治疗疗效欠理想局部进展期胃癌——综合治疗的集中体现新辅助治疗(化疗/放疗)手术(主要的治疗方式)辅助治疗(化疗/放疗)围手术期治疗的三个重要的研究INT-0116术后辅助放化疗2001NEJMMAGIC术前术后ECF2006NEJM•大规模RCT(III期)•对照组：单纯手术•阳性结果ACTS-GC术后辅助S-12007NEJMINT0116(N=503)MAGIC(N=556)ACTS-GC(N=1059)辅助放化疗(N=250)手术(N=253)围手术期化疗(N=282)手术(N=277)辅助化疗(N=529)手术(N=530)入组人群T1/2:31%T3:61%T4:7%N0:16%N+4:41%N+4:43%T1:12%T2:32%T3:50%T4:8%N0:29%N1:48%N2:18%N3:5%T2:54%T3:43%T4:3%N0:10%N1:55%N2:35%国家美国英国日本3年生存率50%41%46%35%80.5%70.1%HR0.76(0.62-0.93)0.75(0.60-0.93)0.68(0.52-0.87)D2术10%45%100%化疗药物5FU/CFECF方案S-1依从性64%术前：86%术后：75.9%65.8%(12个月)77.9%(6个月)87.4%(3个月)局部进展期胃癌的治疗策略•诊断分期是否足够准确(新辅OR姑息？)–远处淋巴结是否有病理诊断？–腹膜转移的诊断•对于手术范围的了解–不局限于R0，更要了解淋巴清扫范围(D0,D1,D2)–D0,D1，术后需要联合放疗•根据病理分期选择术后治疗–D2术后，IB和II期，可选择氟尿嘧啶(S1)单药化疗晚期胃癌的治疗Bestsupportivecare5-FUFAMFAMTXDCF(V325)3–4mo4–5mo4–5mo6.7mo9.2mo10moOxa+HDFL10.5moXPEOX(Real2)11.2moECF9.4mo11.4moTS-1monotherapy13moTS-1+CDDP(SPIRITS)14.4moS-1+CDDP(SP;SC101)1213胃癌治疗有效的化疗药物•OldDrugs–氟尿嘧啶类•5-FU•UFT–铂类•顺铂–蒽环类•阿霉素•表阿霉素–依托泊苷–甲氨蝶呤•NewDrugs–氟尿嘧啶类•卡培他滨•S-1–铂类•草酸铂–紫杉类•紫杉醇•多西紫杉醇–伊力替康14晚期胃癌的化疗•Oxaliplatin+Capecitabine:Noninferior(REAL-2)•Docetaxel+CFCF:toxicity↑↑(TAX325)•Irinotecan+CIV5-FU=CF:toxicity↓↓(V306)•CDDP+Capecitabine=CF:Noninferior(ML17032)OxaliplatinEOXorEOFCapecitabineECXorEOXXPFUFIRIDCFECFPts489513160170221126%RR44%45%41%32%36%45%TTP6.76.55.65.05.6NSOS,mos10.910.410.59.09.28.915Doublets:Fluoropyrimidine-based:+PlatinorIrinotecanTaxane-based:+PlatinorIrinotecan国内晚期胃癌的治疗方案(2006年以前)2002-2006年国内有关胃癌全身化疗的文献（n=274）OXA+CF30.7%PCT13.5%DCT7.7%CAPE4.7%CPT-110.4%其他43%曹妮达等.世界华人消化杂志2008年2月8日;16(4):436-442晚期胃癌III期临床研究草酸铂:REAL-2phaseIII卡培他滨:ML17032phaseIII多西紫杉醇:TAX325phaseIII伊立替康:V306phaseIII草酸铂:FLOvsFLPphaseIIIS-1:JCOG9912phaseIIIS-1:SPIRITSphaseIIIS-1:SC-101phaseIII2009ASCOFLAGSphaseIII2011ASCO-GISTARTphaseIII2009ASCOToGAphaseIII2010ASCOAVAGASTphaseIII17晚期胃癌III期随机临床试验结果Study方案nRR(%)pMSTp-valueV3252006DCFCF10310538.723.2.01210.2m8.5m.0064KangY2006XPFP16015641290.0310.5m9.3m0.27S.Al-Batran2006FLOFP9810234270.0125.7(TTP)3.80.081Wasaburo2008S-1+DDPS-11451505431.00213.0m11.0m.04Cunningham2008ECFECXEOFEOX24924123523940.746.442.447.9NS9.9m9.9m9.3m11.2mNSS-1pIIIstudyinAGC~Asia~StudyRegimenNRR(%)p-valuePFS(m)p-valueOS(m)p-valueJCOG9912S-15-FUcviCPT-11/CDDP17517518128938NS4.22.94.80.0233--0.000111.410.812.30.0233--0.0194SPIRIT(2008)S-1S-1/CDDP15014831540.0024.06.00.000111.013.00.04SC101S-1S-1/CDDP5-FU/CDDP77747324.737.819.20.062--0.0214.2*5.3*2.8*0.008--0.018.914.410.30.01--0.038START(2011)S-1S-1/DOC31331018.430.30.0044.2**5.36**0.000411.113.00.1416TOP002(2009)S-1S-1/CPT-1116015526.941.50.0353.6*4.5*0.158510.512.80.233*TTF,**TTP19(CHN)晚期胃癌化疗模式的变迁•三药联合更多地被两药联合方案所更新•单药也取得不错的疗效•药物联合追求高效、低毒•随着生存期的延长，更多的晚期胃癌患者有机会接受二线治疗Patients:Advanced/relapsegastriccancerRS-1+DOCS-180mg/m2Day1-14Docetaxel40mg/m2Day1q3wS-180mg/m2Day1-28q6wPrimaryendpoint:OSSecondaryendpoints:TTP,Response,Safety.No.ofpatients:639ptsY.H.Kimetal.ASCO-GI2011,Abst#721直至PDMonthLog-rankp=0.1416HR=0.88(95%CI:0.735-1.044)DOC+S-1S-1DOC+S-1S-1No.ofpts310313MST（M）13.011.11yrsurvival52.5%46.0%2yrsurvival23.7%20.6%3yrsurvival13.0%12.3%Estimatedprobability(%)Y.H.Kimetal.ASCO-GI2011,Abst#722月Log-rankp=0.0004HR=0.74DOC+S-1S-1DOC+S-1S-1病例数310313MST(M)5.364.2MonthEstimatedprobability(%)Y.H.Kimetal.ASCO-GI2011,Abst#723Noofpat.ResponseRR(95%CI)CRPRSDPDNEDOC+S-122816869603030.3%(24.4-36.7)S-124444173953118.4%(13.8-23.9)疾病控制率(95%CI)DOC+S-1组：60.5%(53.9-66.9)S-1组：48.4%(41.9-54.8)p=0.010Criteria：RECISTv1.0p=0.004有可测量病灶的病例(N=472)Noofpat.ResponseNon-PD(95%CI)CRPR/SDPDNEDOC+S-181549151266.7%(55.3-76.8)S-16824020661.8%(49.2-73.3)Criteria：RECISTv1.0无可测量病灶的病例(N=149)p=0.607Y.H.Kimetal.ASCO-GI2011,Abst#724DOC+S-1N=310S-1N=313G3/4(≧G3%)G3/4(≧G3%)白细胞59/9(21.9%)6/2(2.6%)嗜中性粒细胞减少44/46(29.0%)11/2(4.2%)血小板2/2(1.3%)2/0(0.6%)血红蛋白30/3(10.6%)20/1(6.7%)发热性中性粒细胞减少8/1(2.9%)0/0(0.0%)AST1/1(0.6%)6/0(1.9%)ALT3/0(1.0%)4/0(1.3%)胆红素3/1(1.3%)4/1(1.6%)血清肌酐值0/0(0.0%)1/1(0.6%)Y.H.Kimetal.ASCO-GI2011,Abst#725DOC+S-1S-1病例数229245MST（M）11.910.9有可测量病灶的病例(N=472)无可测量病灶的病例(N=149)DOC+S-1S-1DOC+S-1S-1Log-rankp=0.7435Log-rankp=0.0389DOC+S-1S-1病例数8168MST（M）17.511.7MonthEstimatedprobability(%)MonthEstimatedprobability(%)Y.H.Kimetal.ASCO-GI2011,Abst#726DOC+S-1S-1病例数8168MST(M)8.45.