Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial
Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial
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DOI：
10.1016/s1470-2045(18)30132-3
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发表时间：
2018-05-01
期刊：
影响因子：
51.1
通讯作者：
Verheij, Marcel
中科院分区：
文献类型：
--
作者：
Cats, Annemieke;Jansen, Edwin P. M.;Verheij, Marcel
围手术期化疗和术后放化疗均能提高欧洲和北美可切除胃癌患者的生存率。据我们所知，这些治疗策略尚未进行头对头比较研究。我们的目的是比较围手术期化疗与术前化疗和术后放化疗在可切除的胃腺癌患者中的作用。方法在这项由化疗药物启动的、开放标签的、随机的3期试验中，我们招募了18岁或以上的IB-IVA期可切除的胃腺癌或胃食管腺癌患者（如美国癌症联合委员会第六版所定义），WHO体能状态为0或1，心脏、骨髓、肝脏和肾脏功能良好。患者从荷兰、瑞典和丹麦的56家医院入组，并使用计算机化最小化程序随机（1：1）分配至围手术期化疗（化疗组）或术前化疗+术后放化疗（放化疗组）。在患者接受任何术前化疗治疗之前进行随机分组，并根据组织学亚型、肿瘤定位和医院进行分层。患者和研究者对治疗分配不设盲。手术包括原发肿瘤的根治性切除和至少D1+淋巴结清扫。术后4-12周内开始术后治疗。化疗包括术前3个21天周期和术后3个静脉外照射周期（第1天50 mg/m2），顺铂（第1天60 mg/m2）或奥沙利铂（第1天130 mg/m2）和卡培他滨（1000 mg/m2，口服片剂，每日两次，持续14天，与表阿霉素和顺铂联合，或625 mg/m2，口服片剂，每日两次，持续21天，与表阿霉素和奥沙利铂联合），每三周收到一次。放化疗包括45戈伊，分25次，每次1.8戈伊，共5周，每周5次，联合卡培他滨（575 mg/m2，放疗日口服，每日2次）和顺铂（20 mg/m2，每5周放疗第1天静脉注射）。CRITICS试验注册于ClinicalTrials.gov，编号NCT 00407186; EudraCT，编号2006-004130-32;和CKTO，2006- 02。结果2007年1月11日至2015年4月17日，788例患者入组，随机分配至化疗组（n=393）或放化疗组（n=395）。术前化疗后，化疗组393例患者中的372例（95%）和放化疗组395例患者中的369例（93%）进行了手术，化疗组393例患者中的310例（79%）和放化疗组395例患者中的326例（83%）进行了潜在治愈性切除。术后，393例患者中的233例（59%）开始化疗，395例患者中的245例（62%）开始放化疗。中位随访时间为61.4个月（IQR 43.3-82.8），化疗组的中位总生存期为43个月（95% CI 31-57），放化疗组为37个月（30-48）（分层分析的风险比为1.01（95% CI 0.84-1.22 ;p=0.90）。术前化疗后，在781例患者的总安全性人群中（一起评估），有368例（47%）3级不良事件; 130例（17%）4级不良事件和13例（2%）死亡。术前治疗期间的死亡原因为腹泻（n=2）、二氢嘧啶缺乏症（n=1）、猝死（n=1）、心血管事件（n=8）和功能性肠梗阻（n=1）。术后治疗期间，化疗组233例患者中分别有113例（48%）和22例（9%）发生3级和4级不良事件，放化疗组245例患者中分别有101例（41%）和10例（4%）发生3级和4级不良事件。术后化疗期间非发热性中性粒细胞减少症的发生率（79/233 [34%]）高于术后放化疗期间（11/245 [4%]）。在术后treatment.Interpretation中没有观察到死亡，与术前化疗和手术充分治疗的可切除胃癌患者的术后化疗相比，术后放化疗并不能提高总生存率。鉴于两个治疗组的术后患者依从性较差，未来的研究应侧重于优化术前治疗策略。(c)2018爱思唯尔有限公司版权所有。
Background Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma.Methods In this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB-IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1: 1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m(2) on day 1), cisplatin (60 mg/m(2) on day 1) or oxaliplatin (130 mg/m(2) on day 1), and capecitabine (1000 mg/m(2) orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m(2) orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1.8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m(2) orally twice daily on radiotherapy days) and cisplatin (20 mg/m(2) intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.Findings Between Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61.4 months (IQR 43.3-82.8),median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1.01 (95% CI 0.84-1.22 ;p=0.90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment.Interpretation Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies. (c) 2018 Elsevier Ltd. All rights reserved.