S1治疗胃癌的国外进展

null替吉奥治疗胃癌的进展替吉奥治疗胃癌的进展 徐建明 军事医学科学院307医院肿瘤中心 试验背景—替吉奥胶囊试验背景—替吉奥胶囊 替吉奥胶囊（S-1），是日本大鹏药品工业株式会社研制的一种口服氟脲嘧啶类衍生物。1999年在日本上市，在日本已取得胃癌、结直肠癌、头颈癌、肺癌、胰腺癌、乳腺癌、胆管癌等7个适应症。 2005年，S-1获得SFDA批准进行胃癌、结直肠癌、头颈癌临床试验，其中胃癌临床试验已完成，将于近日获得进口批准。结直肠癌于2006年－2007年完成I期临床试验，目前将进一步进行II期探索更佳治疗，为III期报批试验做准备。 S-1治疗晚期结直肠癌的疗效： 1994-2001年，单药一线治疗：ORR 16.7%—37.4%，提示S-1单药治疗不亚于奥沙利铂及CPT-11等药（单药疗效7.8～33.3%） 2004-2007年，S-1/LV I/II期临床试验(日本)一线治疗：ORR 57.1%，TTP 203天，疗效良好，值得进一步探索。 nullS-1是一种口服氟尿嘧啶类衍生物，组成：替加氟 (FT; 5-FU前体药物)： 吉美嘧啶(CDHP) ：奥替拉西钾(Oxo) =1：0.4：1 口服亚叶酸钙(LV) 可增强S-1的抗肿瘤活性。 S-1 / LV 的作用null随机 III期临床研究比较 S-1 单药、S-1 + 顺铂 治疗晚期胃癌 (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment of stomach cancerH. Narahara1, W. Koizumi2, T. Hara3, A. Takagane4, T. Akiya5, M. Takagi6, K. Miyashita7, T. Nishizaki8, O. Kobayashi9, S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;1Osaka Medical Center for Cancer and CV Diseases, Osaka, JAPAN, 2Kitasato University East Hospital, Kanagawa, JAPAN, 3Kouseiren Takaoka Hospital, Toyama, JAPAN, 4Iwate Medical University, Iwate, JAPAN, 5Gunma Prefectural Cancer Center, Gunma, JAPAN, 6Shizuoka General Hospital, Shizuoka, JAPAN, 7National Hospital Organization Nagasaki Medical Center, Nagasaki, JAPAN, 8Matsuyama Red Cross Hospital, Ehime, JAPAN, 9Kanagawa Cancer Center, Kanagawa, JAPAN.ASCO 2007: #4514null背景-1 S-1 是: 口服的氟嘧啶类药物，在日本已经广泛用于晚期胃癌. 两个单独的II期临床研究明，单药有效率 44-49 %， MST 207-250 天 1,21: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7ASCO 2007: #4514null背景-2 JCOG92051)1): A. Ohtsu et al. J Clin Oncol 2003; 21:54-59 FP 组比 5FU 组明显更长的 PFS. (P<0.001) 两组的OS无显著差异 In Japan, recommended regimen for AGC was 5-FU aloneASCO 2007: #4514null背景-3 JCOG99125-FU S-1CPT-11+CDDPNon-inferiorityBoku et al. ASCO2007 abstract#: LBA4513 ASCO 2007: #4514null背景-4 S-1+CDDP Phase I/II Study1)S-1 40-60mg BID for 3wksDay 1Day 8Day 15Day 22Day 29Day 36CDDP 60mg/m2 on Day 8S-11: W Koizumi et al. Br J Cancer 2003; 89:2207-2212 S-1 给药剂量是依据患者的体表面积 (BSA) BSA < 1.25 : 40 mg BID 1.25 - < 1.50 : 50 mg BID 1.50 - < BSA : 60 mg BIDASCO 2007: #4514null研究AGC No prior Chemo.RS-1 alone S-1: 40-60 mg BID for 28 days q6wksS-1 + CDDP S-1: 40-60 mg BID for 21 days q5wks CDDP: 60 mg/m2 iv on day 8 Central Randomization (dynamic balancing) Adjustment Factors: Institute PS Unresectable vs RecurrentASCO 2007: #4514null研究终点 Primary Endpoint Overall Survival Estimated OS (S-1/S-1+CDDP) : 8/12 months N=142 in each arm for 90% power to establish superiority in OS (Two-sided log-rank a=0.05). Follow up: 2 years Secondary Endpoints Progression Free Survival Time to Treatment Failure Overall Response Safety142 pts in each armASCO 2007: #4514null入组标准 组织学证实的胃腺癌 (unresectable/recurrent gastric cancer) 以前没有化疗 PS (ECOG scale) 0-2 Age 20-74 预期生存 > 3 months Adequate organ function (bone marrow, liver, renal function) 知情同意ASCO 2007: #4514null患者一般状况 -1 Randomized : 305 pts (S-1/S-1+CDDP : 152/153) between Mar/2002 and Nov/2004 FAS : 298 pts (S-1/S-1+CDDP : 150/148)ASCO 2007: #4514null患者一般状况 -2ASCO 2007: #4514nullMonthsEstimated probability (%) 11.013.0 总生存期Log-rank p-value: 0.0366 HR: 0.774 [ 95% CI: 0.608 – 0.985] Median follow-up time (M): 34.6ASCO 2007: #4514null 无进展生存期Log-rank p-value: <0.0001 HR: 0.567 [ 95% CI: 0.437 – 0.734]Estimated probability (%) Months6.04.0ASCO 2007: #4514null 到治疗失败的时间Log-rank p-value: 0.0089 HR: 0.699 [ 95% CI: 0.536 – 0.912]Estimated probability (%) Months4.83.9ASCO 2007: #4514null疗 效 Criteria : RECIST (Extramural Review)Fisher’s Exact Test p-value: 0.0018ASCO 2007: #4514null药物的副作用-1Criteria : NCI-CTC ver. 2.0ASCO 2007: #4514null药物的副作用-2 No treatment-related death was observedCriteria : NCI-CTC ver. 2.0ASCO 2007: #4514nullAGC的III期临床研究*TTP3) Proc ASCO 2006; Vol 24, No. 18S: LBA40181) J Clin Oncol 2006; 24: 4991 – 4997 2) Proc ASCO 2006; Vol 24, No. 18S: LBA4017ASCO 2007: #4514null结 论 S-1+CDDP 的生存期长于 S-1 单药 S-1 中位生存 11.0 M, S-1+CDDP 13.0 M S-1+CDDP 耐受性好，无治疗相关的死亡 S-1+CDDP 方案可以当作 AGC 的一线治疗方案ASCO 2007: #4514nullN. Boku, S. Yamamoto, K. Shirao, T. Doi, A. Sawaki, W. Koizumi, H. Saito, K. Yamaguchi, A. Kimura, A. Ohtsu Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group 5-FU 单药、 CPT-11 ＋顺铂 (CP) 、 S-1 单药治疗晚期GC的随机 III期临床研究 (JCOG9912)null背 景 晚期胃癌无标准化疗方案. III期临床研究(JCOG9205)并未证明， 5-FU+CDDP 比 5-FU 单药延长生存. II 期研究表明 S-1单药 和 CPT-11+CDDP 疗效好、 毒性反应可以接受. (Sakata, Eur J Cancer 1998; Koizumi, Oncology 2000; Boku, J Clin Oncol 1999) (Ohtsu, J Clin Oncol 2003)nullPrimary endpoint： 总生存 Secondary endpoints： 到治疗失败的时间 (TTF) Non-hospitalized survival (NHS) Adverse Events (NCI-CTC ver.2) Response rate (RECIST, central review) 与 5-FU 持续静滴 (5-FUci)比较 　・ CPT-11+CDDP的优效性 　・ S-1的非劣效性研究目的nullInclusion Criteria 1) 组织学证实的不能手术切除的或复发的胃腺癌 2) 能口服药物 3) Age: > 20, < 75 4) PS (ECOG)： 0, 1, 2 5) 主要脏器功能正常 6) 未接受过放化疗 except adjuvant chemotherapy completed 6 months before 7) 不一定要有可测量的病灶 8) 无严重的腹膜播散 9) Written informed consentnullS-1 40 mg/m2, po, bid, days 1-28 q 6 weeks Stratified by (minimization) ・Institution ・PS 0/1/2 ・Unresectable/ Recurrence with adjuvant Cx/ Recurrence without adjuvant Cx5-FUciCPT-11 + CDDPS-1Randomization800 mg/m2/day, ci, days 1-5 q 4 weeksCPT-11 70 mg/m2, div, days 1&15 CDDP 80 mg/m2, div, day 1 q 4 weeks III 期研究 (JCOG9912)Continued until disease progression, unacceptable toxicities, patient’s refusalBSA < 1.25 80 mg/body/day 1.25 < BSA < 1.5 100 mg/body/day 1.5 < BSA 120 mg/body/daynull患者一般状况Adjuvant Cx - / +Unresectable / Recurrent0 / 1 / 2PSM / FGendermedian (range)AgeNo. of patients233/1188/46151/80/3175/5964 (39-75)234*S-1235/1190/46151/81/4180/5663 (32-75)236CPT-11+CDDP233/1189/45152/79/3176/5863 (24-75)2345-FUci* One patient was ineligible; adenosquamous cell carcinoma.null患者肿瘤情况Target lesion 　- / + intestinal / diffuseHistological type** 0 / 1,2 / 3,4,5Macroscopic type*No. of patientsPeritoneal metastasis165/6959/175110/124***5/68/161234S-1102/101/3155/181102/1345/73/155236CPT-11+CDDP160/76100/105/3159/175111/1215/63/1642345-FUci147/87103/90/41No. of metastatic sites0,1 / 2 / >3- / +* Japanese Classification of Gastric Carcinoma 　　 ** Lauren classification, no data available in 2 pts ** 1 pt with adenosquamous type includednullNo. of patients6个月内 Gr.>3 AE (1)5.63.83.90.941.505.665.01.312.839.315.51.34.70.40.47.7009.40S-1CPT-11+CDDP5-FUci234236234Treatment related death*0.41.30LeukocytesNeutrophilsHemoglobinPlateletsInfection without neutropeniaInfection with Gr.3 or 4 neutropeniaFebrile neutropenia* Judged by Data and Safety Monitoring Committeenull1.703.0Stomatitis5.620.56.9Nausea7.79.00.4Diarrhea12.432.912.5Anorexia5.110.31.7Fatigue4.72.64.7AST3.42.63.4ALT4.31.33.0Bilirubin0.92.10Creatinine5.222.66.5Hyponatremia6个月内 Gr.>3 AE(2)No. of patientsS-1CPT-11+CDDP5-FUci234236234nullPFS和有效率Response rate - in pts with target lesion -CR and PR were confirmed by central reviewnull<0.0010.59-0.850.714.0M234S-10.014-P-value†0.67-0.98-95%C.I.-2.3M2345-FUci0.813.7M236CPT-11+CDDPHRMedian n†: one-sided log-rank test (superiority)到治疗失败的时间null治疗失败的原因OtherDeathRefusal not related to toxicityRefusal related to toxicityToxicitiesDisease progression Continuing at final analysisNo. of patients2108142036S-123491839361430CPT-11+CDDP2366199919915-FUci234nullOverall SurvivalP-value　0.034†0.055†-0.68-1.010.70-1.04-95%C.I.-44.0%10.8M2345-FUci0.8347.9%11.4M234S-10.8552.5%12.3M236CPT-11+CDDPHR1-yrMSTn†: one-sided log-rank test (superiority)non-inferiority <0.001‡: multiplicity adjusted by Holm’s methodSignificance level‡0.050.0250.025null0.0030.62-0.920.769.2M234S-10.027-0.68-1.00-95%C.I.-7.2M2345-FUci0.829.5M236CPT-11+CDDPHRMedian nP-value†　†: one-sided log-rank test (superiority)Non-hospitalized Survival= overall survival time – hospitalized daysnull*　type unknown were excluded from the analysis生存期的亚组 - Hazard Ratio to 5-FUci and 95% Confidence Interval -Hazard ratioAge <65 (n=372) >65 (n=332)PS 0 (n=454)1,2 (n=250)Unresectable (n=567)Recurrent 　 (n=137)Intestinal (n=323)*Diffuse (n=379)(-) (n=173)Target lesion (+) (n=531)No. of met sites 0,1 (n=305)>2 (n=399)Peritoneal mets (-) (n=472)(+) (n=232)All randomized (n=704)CPT-11+CDDPS-1生存期的亚组分析生存期的亚组分析P-value†　S-15-FUci122436 (months)050(%) 1000.0701750.015-175181nP-value†　10.5M9.0M12.1MMST 3.8M2.2M4.8MPFS- Target Lesion (+) -- Target Lesion (-) -0.1818.1M590.54-13.5M5914.4M55MST n†: one-sided log-rank test (superiority)S-15-FUciCPT-11+CDDPCPT-11+CDDP050(%) 100122436 (months)null结 论 S-1 的生存期明显不劣于 5-FUci ，毒性较低 RR, TTF, NHS and PFS 更好 各个亚组的生存期都比5-FUci 组长 CPT-11+CDDP 生存期并不优于 5-FUci ，且毒性大导致更多 的治疗失败 但 RR, TTF, NHS and PFS 更好 在TL (+)亚组的生存比 5-FUci 长 在TL (-) 和腹膜转移 (+)者的生存更短 S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer.nullS-1单药、 S-1/CDDP(SP)、 5-FU/CDDP(FP) 治疗晚期胃癌(AGC) 的随机 III 期临床试验 (SC-101 study)Maolin Jin1, Youjian He2 June 3rd, 2008 1- Beijing Cancer Hospital; 2- Sun Yet-Sen University Cancer Center ASCO 2008, ChicagoAbstract No. #4533; Poster No. #21背 景背 景40% 初次诊断的胃癌患者是晚期, 40％～60％ 术后复发. AGC 无标准治疗方案. S-1治疗 GC有效. 无论是单药还是 SP 在日本广泛用于AGC 治疗*. S-1 在中国无经验, 中国是GC发病率最高的国家之一.*:S-1 is manufactured and supplied by Taiho Pharmaceutical Co., Ltd. Tokyo, Japan研究目标研究目标Primary endpoint: Response Rate (RR)#1 Secondary endpoint: Time to Treatment Failure (TTF) Overall Survival (OS) Toxicity/safety#2#1: RECIST guideline, used IRC evaluation results. #2: NCCN CTCAE version 3.0研究设计研究设计不可切除的晚期或转移性 GCCentral randomization( dynamic balance) Stratification： Performance Status; Number of metastatic sites; Gastrectomy S-15-FU/CDDPS-1/CDDP60 patients60 patients60 patientsIf failed, can switch to S-1治疗方案治疗方案Arm A (S-1): S-1, 42 days/cycleS-1 40 mg/m2, Bid, oralRest 14 daysd1~d28 (4 weeks)d29~d42 (2 weeks)Arm B (SP): S-1 + CDDP, 35 days/cycleS-1 40 mg/m2, Bid, oralRest 14 daysd1~d21 (3 weeks)d22~d35 (2 weeks)CDDP, 60mg/m2, d8, infusion×3hrsArm C (FP) : 5-FU + CDDP, 28 days/cycle (4 weeks)5-FU+CDDPRest 23 daysd1~d5d6~d28CDDP, 20mg/m2, infusion×0.5hr 5-FU, 600mg/m2, infusion×24hrs入组标准入组标准组织学证实的胃腺癌 不可切除, 晚期或转移性病灶 对转移灶既往未放化疗. 辅助和/或新辅助结束6个月以上者可以入选 Age 18 or above ECOG performance status 0 to 2 Adequate hematological, renal and liver function患者分配患者分配230 pts randomized (Jul.2005~Oct.2006)S-1 n=80SP n=76FP n=74FAS n=77FAS n=74FAS n=73Without target lesion, n=1 Inclusion criteria violation n=1Without target lesion n=1Without target lesion n=3一般状况 （FAS=224）一般状况 （FAS=224）There is no significant difference between the three arms in FAS.RR 比较 (FAS)RR 比较 (FAS)Remarks：a) CMH-test, adjusted by stractifications, two-sides significance level= 2.5%. b) Difference compared with S-1/CDDP arm. c) Odds Ratio: FP vs. SP= 0.387(95% CI[0.177~0.847], p=0.0176); d) Odds Ratio: S-1 vs. SP= 0.597(95% CI[0.284-1.256], p=0.1741). S-1 second-line treatment41 of 73 pts switched to S-1 monotherapy after failed in FPOSOS*Until January 15, 2007, 224 patients were followed up, 94 died(42%),115 alive,15 lost follow-up. **: Logrank test* FP’s survival include 41 pts’ contribution who switched to S-1Hazard: S-1 vs. SP=2.262(95%CI[1.327-3.856]) FP vs. SP=1.908(95%CI[1.089-3.341])TTFTTFHazard: S-1 vs. SP=1.709(95%CI[1.145-2.552]) FP vs. SP=2.673(95%CI[1.755-4.071])*: Logrank test.药物主要的副作用药物主要的副作用小 结 小 结 从 2005.7月－ 2006.10月， 80 pts in S-1, 76 pts in SP and 74 pts in FP 入组. 三组患者的一般状况无显著差异. 独立评估委员会评估的结果, RR 24.7% in S-1, 37.8% in SP and 19.2% in FP. SP 有效率优于FP (CMH p=0.021). FP 组41例患者交替到 S-1组 后的RR 14.6%, 说明 S-1 2nd-line 治疗有效. SP 组的生存明显长于FP 组(Log-rank p=0.038) 和 S-1组 (Log-rank p<0.001). S-1/SP/FP 最常见的 3/4 毒性反应(%) : 贫血, 2.5/5.3/5.4; 白细胞下降, 1.3/13.2/9.5; 中性粒减少, 3.8/17.1/16.2; PLT 减少, 0/6.6/12.2; 恶心, 0/2.6/5.4; 呕吐, 1.3/6.6/12.2; 腹泻, 3.8/6.6/0. S-1 和 SP 组均能很好耐受.结 论结 论S-1 和 SP 均有效、耐受性好. SP 有可能成为晚期中国胃癌患者的标准治疗方案.FLAGS Trial: S-1 + CDDP vs 5-FU + CDDPPrimary endpoint: Superiority in OS N = 1000 non-Asian AGC for 1st line palliative chemotherapyFLAGS Trial: S-1 + CDDP vs 5-FU + CDDP5-FU 1,000 mg/m2/d CIV D1-5 Cisplatin 100 mg/m2 iv D1, every 4 weeksS-1 25 mg/m2 po bid D1-21 Cisplatin 75 mg/m2 iv D1, every 4 weeksRAjani, et al. ASCO GI 2009FLAGS: OSFLAGS: OSAjani, et al. ASCO GI 2009% 存活率100 90 80 70 60 50 40 30 20 10 0随机后时间（月）0246810121416182022242628303234Log-rank Test: p=0.1983 相对危险度: 0.92 (95% CI: 0.80, 1.05) 中位总生存时间: CS: 8.6 months CF: 7.9 months CS（顺铂/S1） CF（顺铂/5-Fu）N at risk S-1: 5-FU:52147940234127621217212490694836241464005084523853262501991561167956352619128310FLAGS: PFSFLAGS: PFSAjani, et al. ASCO GI 2009% 无进展生存率100 90 80 70 60 50 40 30 20 10 0Log-rank Test: p=0.9158 相对危险度: 0.99 (95% CI: 0.86, 1.14) CS: 4.8 months CF: 5.5 months CS （顺铂/S1） CF （顺铂/5-Fu）0246810121416182022242628521365237152914124171298510508335235149753622161164N at risk S-1: 5-FU:随机后时间（月）FLAGS: 3/4 度血液学毒性 FLAGS: 3/4 度血液学毒性 Ajani, et al. ASCO GI 2009患者比例 (%)70 60 50 40 30 20 10 0贫血中性粒细胞减少血小板减少白细胞减少中性粒细胞减少性发热*********CS CF**P<0.01FLAGS: 肝肾相关毒性FLAGS: 肝肾相关毒性Ajani, et al. ASCO GI 2009患者比例 (%)50 45 40 35 30 25 20 15 10 5 0肌酐 >1.5 x ULN肌酐清除率 <50 mL/min肾相关不良事件 (所有分级)肾损害胆红素>1.5 x ULN肝相关不良事件 (所有分级)肝功能损害肾毒性肝毒性******CS CF*P<0.05 **P<0.01*FLAGS: 结论FLAGS: 结论与顺铂/5-Fu相比，顺铂/S1并不提高OS 次要终点指标：有效性：顺铂/S1与顺铂/5-Fu 无差异 顺铂/S1 在安全性上比顺铂/5-Fu更好. 然而，顺铂/S1 方案中顺铂剂量是顺铂/5-Fu方案 的75% ，且S-1 剂量也低于日本研究的剂量 Ajani, et al. ASCO GI 2009nullSakuramoto et al. N Engl J Med 2007; 357:1810-20研究目标研究目标探讨II/III 胃癌D2 术后，S-1 单药辅助治疗的有效性 Primary endpoint Overall survival Secondary endpoints Relapse-free survival Safety of S-1 Sakuramoto et al. N Engl J Med 2007; 357:1810-20入组标准入组标准组织学证实的胃癌 D≥2 术后 术后分期II/III (Japanese classification) R0 resection (curability A or B) Negative peritoneal cytology Age 20-80 years 既往未做辅助治疗 Adequate organ function Written informed consentSakuramoto et al. N Engl J Med 2007; 357:1810-20研究设计研究设计Curative gastrectomy (D2)Central Randomization (dynamic balancing) Adjustment factors : stage*(II, IIIA, IIIB), Institutionwithin 6 weeks after surgeryS-1 80-120 mg/day** 4 wks administration with 2wks off in each course for 12 monthsSurgery alone (No further therapy)*Japanese Classification of Gastric Carcinoma, 13th ed,1999** Body surface area (m2) < 1.25 80mg/day 1.25 - < 1.5 100mg/day >= 1.5 120mg/daySakuramoto et al. N Engl J Med 2007; 357:1810-20统计学考虑统计学考虑5-year OS for surgery alone = 70% Improvement by S-1 at a hazard ratio of 0.7 (5y OS:77.9%) Follow up: 5 years Two-sided α= 0.05, statistical power = 80% 485 patients in each group *Calculated by the method of FreedmanTwo interim analyses 1 and 3 years after completion of the enrollment Alpha spending function: O’Brien & Fleming typeSakuramoto et al. N Engl J Med 2007; 357:1810-20AccrualAccrualOpened : October 2001 Closed : December 2004 Randomized : 1059 pts (S-1: 529, Surgery alone: 530) Eligible : 1034 pts (S-1: 515, Surgery alone: 519) Institutions : 109 Japanese institutionsSakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (1)一般状况 (1)Sakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (2)一般状况 (2)Sakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (3)一般状况 (3)Sakuramoto et al. N Engl J Med 2007; 357:1810-20一般状况 (4)一般状况 (4)Sakuramoto et al. N Engl J Med 2007; 357:1810-20依从性 : S-1依从性 : S-1Reasons for discontinuation by 12 months Patient’s withdrawal (adverse events etc.) 71 pts Doctor’s decision (adverse events or complications) 72 pts Relapse or second cancer 27 ptsSakuramoto et al. N Engl J Med 2007; 357:1810-20不良事件 (1)不良事件 (1)Sakuramoto et al. N Engl J Med 2007; 357:1810-20不良事件 (2)不良事件 (2)Sakuramoto et al. N Engl J Med 2007; 357:1810-20第一次中期分析第一次中期分析First interim analysis was carried out on June 2006, using the follow-up data of December 2005 (Median follow-up : 2.0 yrs) O’Brien-Fleming stopping boundary : p=0.0011 Overall survival All randomized : p=0.0016 Eligible : p=0.0008 Relapse-free survival : p=0.0002 Predictive power (OS) : 99.3% Sakuramoto et al. N Engl J Med 2007; 357:1810-20DSMC 推荐DSMC 推荐On June 20th, 2006, after rigorous discussion, the DSMC concluded that the treatment was effective and recommended to the investigators to stop the study and open the survival results using the follow-up data up to June 30th, 2006. O’Brien-Fleming stopping boundary : p=0.0011 Overall survival All randomized : p=0.0016 Eligible : p=0.0008 Relapse-free survival : p=0.0002 The investigators accepted the recommendation. Final analysis was carried out on November 24th, 2006.Sakuramoto et al. N Engl J Med 2007; 357:1810-20总生存总生存 3-year OS - S-1 80.1% - Surgery only 70.1%HR = 0.68 [0.52-0.87] p = 0.003 (stratified log-rank test)012345050100Overall Survival (%) 529 530 515 504 370 352 196 163 46 40Years since RandomizationNo. at risk S-1 Surgery onlySakuramoto et al. N Engl J Med 2007; 357:1810-20(All randomized)无复发生存无复发生存(All randomized)3-year RFS - S-1 72.2% - Surgery only 59.6%HR = 0.62 [0.50-0.77] p < 0.001 (stratified log-rank test)012345050100 529 530 463 437 290 252 145 111 25 21Years since RandomizationNo. at risk S-1 Surgery onlyRelapse-free Survival (%)Sakuramoto et al. N Engl J Med 2007; 357:1810-20亚组分析 (1)亚组分析 (1)(Eligible)Sakuramoto et al. N Engl J Med 2007; 357:1810-20亚组分析 (2)亚组分析 (2)(Eligible)Sakuramoto et al. N Engl J Med 2007; 357:1810-20亚组分析 (3)亚组分析 (3)(Eligible)Sakuramoto et al. N Engl J Med 2007; 357:1810-20首次复发的部位首次复发的部位Sakuramoto et al. N Engl J Med 2007; 357:1810-20小 结小 结S-1 was effective in all stages, showing trends of larger effect in earlier stage. S-1 seems to reduce mainly lymph nodal and peritoneal recurrence. Sakuramoto et al. N Engl J Med 2007; 357:1810-20结 论结 论 S-1作为胃癌术后辅助化疗安全、有效. Single Agent S-1 can be considered as the standard treatment for stage II/III gastric cancer pts after potentially curative D2 dissection. Sakuramoto et al. N Engl J Med 2007; 357:1810-20谢 谢谢 谢