Liver and Bile
Lancet. 2023;401(10372):195–203
Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): A multicenter, open-label, randomized, controlled, phase 3 trial
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 (OS) compared with observation for resected biliary tract cancer.
Methods: This open-label, multicenter, randomized 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 tumor resection or microscopic residual tumor resection were randomly assigned (1:1) to undergo observation or to receive S-1 (i.e., 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 4 cycles). Randomization was performed by the minimization method, using institution, primary tumor site, and lymph node metastasis as adjustment factors. The primary end point was OS 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.
Findings: Between September 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n = 222 and S-1 group n = 218). The data cut-off date was June 23, 2021. Median duration of follow-up was 45.4 months. In the primary analysis, the 3-year OS was 67.6% (95% confidence interval [CI]: 61.0–73.3%) in the observation group compared with 77.1% (95% CI: 70.9–82.1%) in the S-1 group (adjusted hazard ratio [HR] = 0.69, 95% CI: 0.51–0.94; 1-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% (95% CI: 55.6–68.4%) in the S-1 group (HR = 0.80, 95% CI: 0.61–1.04; 2-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.