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1、Adjuvant Chemotherapy for Gastric Cancer with S-1, an Oral Fluoropyrimidine -ACTS-GCIntroductionMeta-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.BackgroundAdvance
2、d 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 as
3、signed 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 pe
4、r 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 CriteriaThe criteria for eligibility were histologically proven gastric cancer of stage II , IIIA, or IIIB; D2 or more ex
5、tensive 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 func
6、tion. 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
7、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 t
8、reatment after surgery, unless there was a confirmed relapse. Patients in both groups were to be followed up for 5 years postoperatively. RESULTSWe randomly assigned 529 patients to the S-1 group and 530 patients to the surgeryonly group between October 2019 and December 2019. The trial was stopped
9、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). RESULTSAnalysis of follow-up da
10、ta 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). RESULTSAdverse events of grade 3 or grade
11、 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 SurvivalThe hazard ratio for death in the S-1 group, as compared with the su
12、rgery-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 SurvivalOverall Survival and Relapse-Free
13、SurvivalThe 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 Rela
14、pse 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 r
15、elapses. Site of First RelapseIn 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 patie
16、nts 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 Characteristi
17、c among Eligible Patients.DISCUSSION1. 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
18、 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 i
19、n 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.DISCUSSION2.The survival rate 3 years after
20、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,
21、 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%.DISCUSSION3.Although it has sometimes been suggested that there may be differences in certain aspects of gastric cancer in J
22、apan 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 reporte
23、d 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
24、 trial may not be valid in countries where D2 surgery is not considered the standard operation.DISCUSSION4.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%，单纯手术组那么为61.1%HR=0.67和53.1%HR=0.65，与3年生存数据的总体趋势类似。 DISCUSSIONDISCUSSION5.对比单药S-1和XELOX对于胃癌术后辅助化疗的比较DISCUSSIONDISCUSSIONS-1单药辅助化疗在B期胃癌患者中未到达统计学差别，而且还
25、看到单药S-1与单纯手术比较，远处转移发生率也无差别，这阐明针对分期较晚、肿瘤负荷量较大的患者，单药尚缺乏以预防复发和远处转移；而XELOX辅助化疗在预防部分复发、腹膜和远处转移中与对照组比较均有显著差别 DISCUSSION 经过分析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思索结合化疗，II期患者可以思索XELOX或S-1辅助治疗，同时要结合患者的不良事件及对继续治疗时间的耐受性。DISCUSSION6.关于S-1用于胃癌术后辅助化疗的运用期限存在争议，目前有看法以为：术后辅助化疗运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适宜时间该当为4-6个月，运用时间过长会添加额外的毒性反响并导致生存期缩短，这个需求进一步开展三期临床实验来证明。DISCUSSION7.ACTS-GC实验包括CLASSIC实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，仍需进一步设计实验来证明？ DISCUSSION8.如何防止对化疗原发耐药的患者术后化疗的损伤？谢谢！
