胃癌辅助化疗临床试验解读.ppt

Adjuvant Chemotherapy for Gastric Cancer with S-1,an Oral Fluoropyrimidine-ACTS-GC,Introduction,Meta-analyses have shown that adjuvant chemotherapy is effective in treating gastric cancer.However,the effectiveness of specific regimens has not been verified in large clinical trials.,Background,Advanced gastric cancer can respond to S-1,an oral fluoropyrimidine.We tested S-1 as adjuvant chemotherapy in patients with curatively resected gastric cancer.,METHODS,Patients in Japan with stage II or III gastric cancer who underwent gastrectomy with extended(D2)lymph-node dissection were randomly assigned to undergo surgery followed by adjuvant therapy with S-1 or to undergo surgery only.,METHODS,In the S-1 group,administration of S-1 was started within 6 weeks after surgery and continued for 1 year.The treatment regimen consisted of 6-week cycles in which,in principle,80 mg of oral S-1 per square meter of body-surface area per day was given for 4 weeks and no chemotherapy was given for the following 2 weeks.The primary end point was overall survival.,Eligibility Criteria,The criteria for eligibility were histologically proven gastric cancer of stage II,IIIA,or IIIB;D2 or more extensive lymph-node dissection with R0 surgery;no hepatic,peritoneal,or distant metastasis;no tumor cells in peritoneal fluid on cytologic analysis;an age of 20 to 80 years;no previous treatment for cancer except for the initial gastric resection for the primary lesion;and adequate organ function.,Study Design and Treatment,The primary end point was overall survival;secondary end points were relapse-free survival and the degree of safety of S-1.Patients were enrolled,within 6 weeks after surgery and randomly assigned to either the S-1 group or the surgery-only group.,Study Design and Treatment,Patients assigned to the S-1 group received two oral doses of 40 mg of S-1 per square meter of body-surface area per day,for 4 weeks,followed by 2 weeks of no chemotherapy.This 6-week cycle was repeated during the first year after surgery.The surgery-only group received no anticancer treatment after surgery,unless there was a confirmed relapse.Patients in both groups were to be followed up for 5 years postoperatively.,RESULTS,We randomly assigned 529 patients to the S-1 group and 530 patients to the surgeryonly group between October 2001 and December 2004.The trial was stopped on the recommendation of the independent data and safety monitoring committee,because the first interim analysis,performed 1 year after enrollment was completed,showed that the S-1 group had a higher rate of overall survival than the surgery-only group(P=0.002).,RESULTS,Analysis of follow-up data showed that the 3-year overall survival rate was 80.1%in the S-1 group and 70.1%in the surgery-only group.The hazard ratio for death in the S-1 group,as compared with the surgery-only group,was 0.68(95%confidence interval,0.52 to 0.87;P=0.003).,RESULTS,Adverse events of grade 3 or grade 4(defined according to the Common Toxicity Criteria of the National Cancer Institute)that were relatively common in the S-1 group were anorexia(6.0%),nausea(3.7%),and diarrhea(3.1%).,Overall Survival and Relapse-Free Survival,The hazard ratio for death in the S-1 group,as compared with the surgery-only group,was 0.68.The 3-year overall survival rate was 80.1%in the S-1 group and 70.1%in the surgery-only group.The hazard ratio for relapse in the S-1 group,as compared with the surgery-only group,was 0.62.,Overall Survival and Relapse-Free Survival,Overall Survival and Relapse-Free Survival,The rate of relapse-free survival at 3 years was 72.2%in the S-1 group and 59.6%in the surgery-only group.Among eligible patients,the hazard ratio for death in the S-1 group,as compared with the surgery-only group,was 0.66.,Overall Survival and Relapse-Free Survival,Site of First Relapse,Common sites of first relapse were the peritoneum,hematogenous sites,and lymph nodes(Table3).Local relapse occurred in 7 patients in theS-1 group(1.3%)and in 15 patients in the surgery-only group(2.8%).Postoperative treatment with S-1 reduced the frequencies of peritoneal and lymph-node relapses.,Site of First Relapse,In the surgery-only group,84 patients(15.8%)had peritoneal relapse,and 46patients(8.7%)had lymph-node relapse.In the S-1group,59 patients(11.2%)had peritoneal relapse,and 27(5.1%)had lymph-node relapse.,Subgroup Analysis,The overall survival of eligible patients was analyzed according to sex,age,cancer stage,tumor stage,nodal stage,and histologic type.There was no significant interaction between the treatment group and any of the variables studied.,Hazard Ratios for Death and P Values for the Interaction of Treatment Group and Baseline Characteristic among Eligible Patients.,DISCUSSION,1.Few large-scale trials have compared postoperative adjuvant therapy with surgery alone among patients with gastric cancer.Such large trials have been performed by the INT-0116 study and the MAGIC trial.,The INT-0116 study,showed that adjuvant chemoradiotherapy prolonged overall survival and relapse-free survival.Most patients in the INT-0116 study underwent either D0 or D1 surgery,with only 10%undergoing D2 surgery.The characteristics of patients in the INT-0116 study differed from those in our trial.,DISCUSSION,In the MAGIC trial,conducted mainly in the United Kingdom,perioperative and postoperative chemotherapy with epirubicin,cisplatin,and infused fluorouracil significantly prolonged overall survival and relapse-free survival.In that study,D2 surgery was not performed as a standard procedure.,DISCUSSION,2.The survival rate 3 years after surgery was 80.5%in the S-1 group and 70.1%in the surgery-only group.The results may change marginally at the 5-year follow-up.However,the number of events in the surgery-only group has already reached nearly 80%of that initially predicted for 5 years.,DISCUSSION,At the first interim analysis,the predicted probability that overall survival in the S-1 group would be significantly better than that in the surgery-only group at final analysis was estimated to be 99.3%.,DISCUSSION,3.Although it has sometimes been suggested that there may be differences in certain aspects of gastric cancer in Japan and the West,there have been no significant differences identified between Japan and the United Kingdom with regard to possible genetic influences or between Japan and European countries in the distribution of important prognostic factors.,DISCUSSION,Moreover,Italian investigators have reported that pancreas-preserving D2 dissection performed at centers with experience in this procedure can provide a survival benefit.If adequate D2 dissection were performed,we believe that treatment outcomes in Western countries would be similar to those in Japan.We acknowledge that the results of our trial may not be valid in countries where D2 surgery is not considered the standard operation.,DISCUSSION,4.更新数据显示，TS-1组的5年总生存（OS）率和无复发生存（RFS）率分别为71.7%和65.4%，单纯手术组则为61.1%（HR=0.67）和53.1%（HR=0.65），与3年生存数据的总体趋势相似。,DISCUSSION,DISCUSSION,5.对比单药S-1和XELOX对于胃癌术后辅助化疗的比较,DISCUSSION,DISCUSSION,S-1单药辅助化疗在B期胃癌患者中未达到统计学差异，而且还看到单药S-1与单纯手术比较，远处转移发生率也无差异，这说明针对分期较晚、肿瘤负荷量较大的患者，单药尚不足以预防复发和远处转移；而XELOX辅助化疗在预防局部复发、腹膜和远处转移中与对照组比较均有显著差异,DISCUSSION,通过分析ACTS-GC与CLASSIC实验，可以得出结论：分期较晚（IIIB期）、术后复发转移风险高的病人更多考虑联合化疗，II期患者可以考虑XELOX或S-1辅助治疗，同时要结合患者的不良事件及对持续治疗时间的耐受性。,DISCUSSION,6.关于S-1用于胃癌术后辅助化疗的使用期限存在争议，目前有看法认为：术后辅助化疗应用时间不应该长于用于一线姑息化疗同方案的中位PFS，单药S-1在胃癌一线姑息化疗的中位PFS大约4个月，因此S-1用于胃癌术后辅助化疗的合适时间应当为4-6个月，使用时间过长会增加额外的毒性反应并导致生存期缩短，这个需要进一步开展三期临床试验来证实。,DISCUSSION,7.ACTS-GC试验（包括CLASSIC试验）并未设置关于胃癌病理分型（如Lauren分型）的亚组分析，对于恶性程度较高且分期较晚的这部分胃癌术后患者（易于早期复发和转移），如弥漫型III期胃癌患者术后的治疗，仍需进一步设计试验来证实？,DISCUSSION,8.如何避免对化疗原发耐药的患者术后化疗的伤害？,谢谢！,