Adjuvant S-1 versus observation in curatively resected biliary tract cancer: A phase III trial (JCOG1202: ASCOT).
Masafumi Ikeda, Kohei Nakachi, Masaru Konishi, Shogo Nomura, Hiroshi Katayama, Tomoko Kataoka, Katsuhiko Uesaka, Hiroaki Yanagimoto, Soichiro Morinaga, Hiroshi Wada, Kazuaki Shimada, Yu Takahashi, Toshio Nakagohri, Kunihito Gotoh, Ken Kamata, Yasuhiro Shimizu, Makoto Ueno, Hiroshi Ishii, Takuji Okusaka, Junji Furuse
Abstract
382 Background: Capecitabine is usually used for patients with curatively resected biliary tract cancer (BTC) in EU and US, but no clear survival benefit has been shown in phase III trials. S-1, an oral fluoropyrimidine derivative, has shown promising efficacy, with a mild toxicity profile, in patients with advanced BTC. The aim of this trial was to confirm whether adjuvant S-1 therapy might improve the overall survival (OS) in patients with curatively resected BTC. Methods: This open-label, multicenter, randomized phase III trial was conducted in 38 Japanese hospitals. Eligible patients were aged 20 to 80 years old, had undergone R0/R1 resection for histologically confirmed adeno(squamous) carcinoma of the extrahepatic bile duct, gallbladder or ampulla of Vater (T2-4, N0, M0 or T1-4, N1, M0) or the intrahepatic bile duct (T1-4, N0-1, M0) (7th UICC classification), and had an ECOG performance status (PS) of 0 or 1.The calculated sample size was 440 to detect hazard ratio for OS of 0.74 with one-sided alpha of 5% and a power of 80%. Patients in surgery-alone arm received no further anti-cancer treatment, while those in adjuvant S-1 arm received 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m 2 twice daily for 4 weeks, followed by 2 weeks of rest. Primary endpoint was OS, and secondary endpoints were relapse-free survival (RFS), incidence of adverse events, and proportion of treatment completion. Results: A total of 440 patients (surgery-alone, n = 222; adjuvant S-1, n = 218) were enrolled from September 2013 to June 2018. The data cutoff date was June 23, 2021, and the median follow-up duration was 45.4 months. Of all randomized patients, OS was significantly longer with adjuvant S-1 than surgery-alone (hazard ratio [HR] 0.694, 95%CI, 0.514-0.935; one-sided p = 0.008; the 3-year OS, 67.6% [surgery-alone; 95%CI, 61.0-73.3%] and 77.1% [adjuvant S-1; 95%CI, 70.9-82.1%]). Adjuvant S-1 was also better for RFS (HR 0.797 [95%CI, 0.613-1.035], 3-year RFS, 50.9% [surgery-alone; 95%CI, 44.1-57.2%] and 62.4% [adjuvant S-1; 95%CI, 55.6-68.4%]). All preplanned subgroup analyses (PS, age, cancer type, cancer stage, R factor, and serum CA19-9) revealed favorable OS and RFS for adjuvant S-1 arm. The main grade 3-4 adverse events in adjuvant S-1 arm were biliary tract infection (7.2%), diarrhea (2.9%), appetite loss (2.9%), fatigue (2.9%), and the treatment was well-tolerated. Conclusions: Adjuvant S-1 therapy led to significantly longer survival than surgery alone and becomes the standard of care for resected BTC. Clinical trial information: UMIN000011688.