辅助 S-1 对比观察用于可切除胆管癌（JCOG1202，ASCOT）：一项多中心、开放标签、随机、对照、III 期临床试验。

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

机构信息

Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, Japan; Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

出版信息

Lancet. 2023 Jan 21;401(10372):195-203. doi: 10.1016/S0140-6736(22)02038-4.

DOI:10.1016/S0140-6736(22)02038-4

PMID:36681415

Abstract

BACKGROUND

S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer.

METHODS

This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688).

FINDINGS

Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]).

INTERPRETATION

Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients.

FUNDING

The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

摘要

背景

S-1 在晚期胆道癌患者中显示出有前景的疗效和轻度毒性特征。本研究的目的是评估辅助 S-1 是否能改善与观察相比切除胆道癌患者的总生存。

方法

这是一项在日本 38 家医院进行的开放性、多中心、随机 3 期临床试验。入组患者年龄 20-80 岁，组织学证实为肝外胆管癌、胆囊癌、壶腹癌或肝内胆管癌，且在切除标本中未进行局部残留肿瘤切除或显微镜下残留肿瘤切除，并随机分配（1:1）接受观察或 S-1 治疗（即根据体表面积给予 40mg、50mg 或 60mg，每日口服 2 次，持续 4 周，然后休息 2 周，共 4 个周期）。随机化采用最小化方法，以机构、原发肿瘤部位和淋巴结转移为调整因素。主要终点是总生存，所有随机分配的患者均进行意向治疗分析。所有合格患者均进行安全性评估。对于 S-1 组，所有开始方案治疗的患者均有资格进行安全性评估。本试验在大学医院医疗信息网络临床试验注册处（UMIN000011688）注册。

结果

2013 年 9 月 9 日至 2018 年 6 月 22 日，共纳入 440 例患者（观察组 222 例，S-1 组 218 例）。数据截止日期为 2021 年 6 月 23 日。中位随访时间为 45.4 个月。在主要分析中，观察组的 3 年总生存率为 67.6%（95%CI，61.0-73.3%），而 S-1 组为 77.1%（95%CI，70.9-82.1%）（调整后的 HR，0.69；95%CI，0.51-0.94；单侧 p=0.0080）。观察组的 3 年无复发生存率为 50.9%（95%CI，44.1-57.2%），S-1 组为 62.4%（55.6-68.4%）（HR，0.80；95%CI，0.61-1.04；双侧 p=0.088）。S-1 组主要的 3-4 级不良事件为中性粒细胞计数减少（29 例[14%]）和胆道感染（15 例[7%]）。