晚期胃癌化疗进展北京

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,晚期胃癌化疗进展北京,新发病数 死亡数,Stomach - 934,000,Liver - 626,000,Stomach - 700,000,Liver - 598,000,Colon & rectum 529,000,Breast 411,000,Parkin DM, CA Cancer J Clin. 2005,全球胃癌负荷,(2002):,发病率位居第,4,位,死亡率第,2,位,男女性都包括在内,胃癌流行病学趋势,近,70,年来全球范围内呈下降趋势,远端胃癌发生率下降，但食管,-,胃结合部癌发生率仍在上升,弥漫型和低分化癌比例增加,男性,女性,Ahmedin, et al. CA, Cancer J Clin, 2008,58:71-96,美国,1930-2004,胃癌死亡率变化,美国,总体发病率和死亡率显著下降,中国上海胃癌流行病学趋势,Yang, et al. WJG,2005,2005,年中国胃癌发病率居第三位,Yang et al, WJG, 2005,*,ASR: Age-standardized incidence rate (per 100,000) using world standard population,胃癌,胃癌,新发病例,:,40,万,死亡,: 30,万,东西方胃癌生物学行为显著差异,亚裔,n=4446,白种人,n=15870,p,远端胃癌比例,92%,68%,0.001,平均淋巴结检出数目,(,个,),14.9,10.9,0.001,中位生存,(,月,),36,23,0.001,远端胃癌,(,月,),38,24,0.001,近端胃癌,(,月,),22,21,0.02,I-III,期,亚裔显著好于白种人,0.001,IV,期,无显著差异,0.14,A. Artinyan, et al. ASCO, 2008, abstr 4540,1988-2004,年,美国,局限性手术后胃癌,回顾性病例对照研究,:,亚裔,vs,白种人,胃癌术后,5,年生存率,Cancer 2000, 88:921-32,AJCC stage,U.S.,Japan,China,IA,78%,95%,93.70%,IB,58%,86%,80.20%,II,34%,71%,65.70%,IIIA,20%,59%,44.80%,IIIB,8%,35%,23.10%,IV,7%,17%,10.80%,Overall,28%,61.4,40%,转移性,/,晚期胃癌的化疗,5-FU/PDD,Taxane,Oxaliplatin,Xeloda,S-1,Irinotecan,BSC,1970,1980,1990,2000,2009,ECF, ELF, EAP,个体化治疗,分子靶向治疗？,晚期胃癌化学治疗演变,FAMTX/FAM,传统联合化疗方案的疗效,Response Rate,Median Survival,FAM(5FU+ADM+MMC),25-40%,6.9 months,FAMTX(5FU+ADM+MTX),20-30%,7.7 months,EAP(VP-16+EPI+DDP),40-60%,6.1 months,ELF(VP16+CF +5FU),21%,7.0 months,CF(DDP+CF),29%,7.0 months,ECF(EPI+DDP+5FU),45%,8.9 months,ECF,在欧洲被推荐为一线化疗方案,CF,在美国被推荐为一线方案,III,期试验中联合方案的疗效,CF,方案,DDP 80-100mg/m2, iv, d1,5-FU 1000mg/m2, civ, d1-5,4,周重复,ECF,方案,EPI 50mg/m2, iv, d1,DDP 60mg/m2, iv,d1,5-FU 200mg/m2, civd1-21,21,天为一周期,CF,和,ECF,方案的不足之处：,大剂量,DDP,的肾毒性,消化道反应,5FU,持续静脉输注,:,中心静脉置管,血栓,感染,方便性问题,CF,方案较低的客观有效率,;,中位生存,顺铂,+5FU (TAX325),初治晚期胃癌患者,随机,DCF:,多西他赛,75 mg/m2 IV 1 hr ,d1,顺铂,: 75 mg/m2 IV 1-3 hrs, d1,5-FU 750 mg/m2/day,持续静注,5,天,q3w,CF:,顺铂,100 mg/m2 IV over 1-3 hrs d1,5-FU 1000 mg/m2/day,持续静注,5,天,q4w,N=227,N=230,DCF,CF,缓解率,37%,25% (p=0.011),TTP,5.6,3.7 (p=0.0004),OS,9.2,8.6 (p=0.02),结果,结果,:DCF,严重的毒性反应,3/4,级毒性反应,DCF,CF,胃炎,21%,27%,腹泻,20%,8%,恶心,/,呕吐,16%,19%,中性粒细胞减少,82%,57%,中性粒细胞减少发热,30%,14%,毒性反应死亡,3.6%,5.4%,结论,:,缓解率, TTP(1.9,月,月,),毒性,代价,Van Cutsem et al. J C.O ,2006,24:4991,其它的联合方式,n,ORR,PFS,OS,CPT-11+L-OHP,43,58%,5.3,9.5,Docetaxel+L-OHP,42,40.5,6.1,NA,XELOX,68,54.4,5.7,10.5,Taxol+xeloda,45,48.9,5.6,11.3,E. Woell, et al. J.CO,2006,24(18S):abstr4070,J. Kim, et al. JCO,2007,25(18S):abstr15026,Liu C, et al. Anticancer Drugs, 2008,19:825,晚期胃癌,III,期随机临床试验结果,Study,方案,n,RR (%),p,MST,p-value,V325,2006,DCF,CF,103,105,38.7,23.2,.01,2,10.2m,8.5m,.00,6,4,Kang Y,2006,XP,FP,160,156,41,2,9,0.03,10.5m,9.3,m,0.27,S. Al-Batran,2006,FLO,FP,98,102,34,27,0.012,5.7(TTP),3.8,0.081,Wasaburo,2008,S-1+PDD,S-1,1,45,1,50,54,31,.002,13.0,m,11,.,0,m,.0,4,Cunningham 2008,ECF,E,CX,EOF,EOX,24,9,241,235,239,40.7,46.4,42.4,47.9,NS,9.9,m,9.9,m,9.3m,11,.2 m,NS,胃癌新药一线化疗,多西他赛,+ CF CF:,但毒性大,伊立替康,+ 5-FU,持续静注,= CF:,毒性更低,奥沙利铂,+,卡培他滨,vs DDP+5FU :,非劣效,EOX ECF,中位生存未超过,1,年,!,S-1 +,顺铂,vs S1,转移性胃癌,n=305,S1,单药,: 40mg/m2, bid,连,4,周休,2,周,S1:,40mg/m2, bid,d1-21,DDP: 60mg/m2, iv, d8,DDP+S1,n=152,S1,n=153,p,ORR,54%,31%,PFS(,月,),6,4,0.0001,OS(,月,),13,11,0.04,度粒细胞减少,39.9%,10.7%,贫血,25.7%,4.0%,度恶心,11.5%,1.3%,结果,:,Koizumi W,ASCO,2008,S1+DDP+,紫杉类,:II,期临床试验,2008,年, ASCO,会议上日本报告,一线治疗转移性胃癌,:,S1 :80mg/m2,或,70mg/m2,DDP: 60mg/m2,多西紫杉醇,: 60mg/m2,或紫杉醇,160mg/m2,21,天为一周期,结果,:,作者,n,CR,ORR,OS(,月,),PFS(,月,),粒细胞,减少,Y.Sato,31,3%,87.1%,19.1,7.4,51.6%,H.Iwase,42,10%,65%,15.2,8.0,47.5%,Y Sato, et al. ASCO, 2008, abstr 4537,H I wase, et al. ASCO, 2008, abstr 4539,S1,联合其它药物,n,ORR,PFS(,月）,OS,（月）,S1,S1+CPT-11,1,162,164,26.9%,41.5%,10.1 P=0.23,12.9,DDP+Docetaxel,2,S1+Docetaxel,2,39,41,43.6%,24.3%,6.2,4.7,S1+paclitaxel,3,53,49%,7.7,14.6,S1+paclitaxel,4,44,64.4%(CR4.4%),NA,NA,1H. Imamura,，,2008,，,GI ASCO , Abstr5,2 H. Jeung, et al.,J Clin Oncol, 2008, 26; abstr 4534),3 J. J. Lee, et al. J Clin Oncol, 2007,25(18s):4634,4 Y. Ueda, et al. J Clin Oncol,2006,24(18s):14033,胃癌二线化疗,无标准的二线方案,CPT-11+DDP,治疗,S1,失败的转移性胃癌，共入组,35,例,CPT-11 60mg/m2, iv,DDP 30mg/m2, iv,14,天重复,结果：,ORR,；,28.4%,个月,S. R. Park,J Clin Oncol,2008, 26: , abstr 4558,未来方向,:,靶向药物,血管生成抑制剂,:,- VEGF,单克隆抗体,:,贝伐单抗,-,血管内皮素抑制剂,:,恩度,EGFR,拮抗剂,- TKI,s:,吉非替尼,埃罗替尼,-,单克隆抗体,:,西妥昔单抗,帕尼单抗, matuzimab,多靶点药物,-,索拉非尼,-,舒尼替尼,EGFR,拮抗剂单药治疗晚期胃,/,胃,-,食管交界癌,研究对象,病例数,缓解率,%,吉非替尼,Doi,等,胃癌,75,1%,Janmaat,等,胃食管交界,癌,26,0%,埃罗替尼,Tew,等,胃食管交界,癌,17,0%,Dragovich,等,胃,/,胃食管交界,癌,78,0% (25,胃,),9% (43,胃食管交界,),C225,Gold,等,食管腺癌,/,胃癌,63,0%,西妥昔单抗联合化疗治疗胃癌,: II,期临床研究,F.Lordick, ASCO 2007,abstr4526,2009, ASCO GI meeting, Aabstr 89,2009, ASCO GI meeting, LBA 39,Han, ASCO, 2008,作者,方案,n,ORR,TTP,（月）,OS,（月）,F. Lordick,FUFOX+C225,52,65.2%,7.6,9.5,C.kim,XELOX+C225,44,52.3%,6.6,11.7,X Zhang,DDP+XELOX+C225,54,48.1%,NA,NA,Han,FOLFOX6+C225,40,50%,5.5,月,9.9,月,贝伐单抗治疗晚期胃癌,（一）贝伐单抗,+,伊立替康,/,顺铂治疗晚期胃癌,胃食管交界癌,23,例,胃癌,24,例,治疗方案,:,贝伐单抗,15 mg/kg day 1 +,伊立替康,65/mg/m2 +,顺铂,30,mg/m2 day 1, 8,，每,3,周一次,结果,: - 34,例可评估 ，,缓解率,65% ,TTP 8.3,月,中位生存,12.3,月,不良反应,: - 2,例胃穿孔（贝伐组,), 1,例接近穿孔,-15%,胃肠道出血,- 25%,出现血栓栓塞事件,Shah JCO 24: 5201, 2006,（二）贝伐单抗,+,多西紫杉醇,+,奥沙利铂,治疗转移性胃癌,n=8,4l,例有效，,ORR :50%,2,例胃肠道穿孔,，原发灶均未切除，但,1,例穿孔发生在非肿瘤部位，,1,例穿,孔部位不明。,J.CO.2008,26S: abs,靶向药物联合化疗的,III,期随机对照临床试验：,进行之中,DDP+,卡培他滨,贝伐单抗,DDP+,卡培他滨,赫赛汀,奥沙利铂,+,卡培他滨, lapatinib,紫杉醇,lapatinib (,二线）,总结和展望,晚期胃癌目前仍缺乏全球公认的一线方案,CR,率低,缓解时间短,新药虽然提高有效率,但总体上中位生存未取得突破性进展,缺乏标准的二线方案,期待靶向药物带来突破性进展,个体化治疗,-,肿瘤化疗靶点,的表达,(TS, ERCC-1),遗传药理学,-,分子标志物,筛选优势人群和预测疗效,-,药物基因组学,谢 谢,!,谢谢观赏！,2020/11/5,33,