S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial
S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial
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DOI：
10.1016/s2468-1253(17)30072-9
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发表时间：
2017-06-01
影响因子：
35.7
通讯作者：
Okusaka, Takuji
中科院分区：
文献类型：
--
作者：
Kudo, Masatoshi;Moriguchi, Michihisa;Okusaka, Takuji
背景：不能切除的晚期肝细胞癌是一种异质性疾病，索拉非尼是被批准用于一线治疗的第一靶向药物，而对索拉非尼耐药的晚期肝细胞癌患者的治疗选择有限。我们评估了以氟尿嘧啶为基础的化疗药物S-1在索拉非尼耐药的晚期肝癌患者中的疗效和安全性。方法我们在日本57个地点进行了一项随机、双盲、安慰剂对照的3期研究。不能接受手术或局部区域治疗且对索拉非尼无效的晚期肝癌患者(即曾接受索拉非尼治疗或因不良反应而停用索拉非尼)的患者，随机分为两组(2：1)口服S-1(体重80 mg/m(2)[80~120 mg/d])或安慰剂，每日2次，连续28天，之后至少停药14天。重复这个循环，直到疾病进展或患者对研究治疗变得不耐受。根据部位和是否有肝外转移或血管侵犯对患者进行分层。主要终点是总存活率，在完整的分析集中进行评估(即，所有接受研究药物治疗的患者，除了被发现没有患上肝细胞癌或被发现患有活动性双重癌症的任何个人)。患者、医务人员、调查人员和赞助商都被蒙面接受治疗任务。即使在研究治疗结束后，失明仍保持不变。这项研究在JAPICCTI注册，编号JAPICCTI-090920，并已完成。65例患者因不符合标准(n=61)、拒绝参加(n=3)或其他原因(n=1)而被排除。334例患者随机分为S-1号组(n=223)和安慰剂组(n=111)。S-1组中有1名患者没有接受治疗，因此被排除在分析之外。在数据截止时，S-1组的中位随访期为32.4个月(IQR24.0-34.7)，安慰剂组为32.9个月(23.7-39.5)。S-1组和安慰剂组的中位总生存期分别为11.1个月(95%CI 9.7-13.1)和11.2个月(9.2-12.8)(风险比0.86，95%CI 0.67-1.10；p=0.20)。最常见的不良事件是皮肤色素沉着(S-1组222名患者中123名[55%]比安慰剂组111名患者中9名[8%])、食欲下降(104名[47%]比21名[19%])、乏力(102名[46%]比20名[18%])、腹泻(77名[35%]比14名[13%])和血液胆红素升高(77名[35%]比14名[13%])。S-1组和安慰剂组分别有90例(41%)和24例(22%)出现严重不良反应。在S-1组中报告了5例与治疗相关的死亡。解释S-1并不能延长索拉非尼耐药的晚期肝细胞癌患者的总体生存时间。需要进一步的研究来确定可能受益于S-1的患者亚群。
Background Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma.Methods We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m(2) [80-120 mg per day]), or placebo, twice per day for 28 days consecutively, followed by a minimum 14 day drug-free period. This cycle was repeated until disease progression or the patient became intolerant to the study treatment. Patients were stratified by site and presence or absence of extrahepatic metastasis or vascular invasion. The primary endpoint was overall survival, assessed in the full analysis set (ie, all patients who were treated with study drug except any individuals who were found not to have hepatocellular carcinoma or who were found to have active double cancer). Patients, medical staff, investigators, and the sponsor were masked to treatment assignment. Blinding was maintained even after study treatment concluded. This study is registered with JapicCTI, number JapicCTI-090920, and has been completed.Findings Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32.4 months (IQR 24.0-34.7) in the S-1 group and 32.9 months (23.7-39.5) in the placebo group. Median overall survival was 11.1 months (95% CI 9.7-13.1) in the S-1 group and 11.2 months (9.2-12.8) in the placebo group (hazard ratio 0.86, 95% CI 0.67-1.10; p=0.20). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group.Interpretation S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1.