Adjuvant chemotherapy with S-1 as a novel standard of care for curatively resected biliary tract cancer
Thus far, no standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer (BTC). The Japanese ASCOT trial now demonstrated that adjuvant chemotherapy with the oral fluoropyrimidine derivative S-1 improves overall survival and relapse-free survival, while being well-tolerated. Therefore, study investigators recommend adjuvant S-1 as a novel standard of care for curatively resected BTC.
In Europe and the United States, capecitabine is often used for patients with curatively resected biliary tract cancer (BTC), although no clear survival benefit has been shown in phase III trials. S-1, an oral fluoropyrimidine derivative, has demonstrated promising efficacy, with a mild toxicity profile, in patients with advanced BTC. Adjuvant S-1 therapy has been established as a standard therapy for patients with resected pancreatic cancer and gastric cancer in Japan. The aim of the phase III JCOG1202, ASCOT study was to confirm whether adjuvant S-1 therapy might improve the overall survival (OS) in patients with curatively resected BTC.
ASCOT Study Design
This open-label, multicentre, randomised 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 of 0 or 1. Patients in the surgery-alone arm received no further anti-cancer treatment, while those in the adjuvant S-1 arm received 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m2 twice daily for 4 weeks, followed by 2 weeks of rest. Primary endpoint of the trial was OS, and secondary endpoints were relapse-free survival (RFS), incidence of adverse events, and proportion of treatment completion.
A total of 440 patients (surgery-alone, N= 222; adjuvant S-1, N= 218) were enrolled from September 2013 to June 2018. Patient characteristics were well balanced between both study arms. Patients receiving S-1 had a median age of 68 years compared with 70 years for surgery alone, and most patients in either group were male (74% vs. 68%) and had an ECOG performance score of 0 (88% vs. 87%). The primary tumour site was most likely extrahepatic (57% vs. 55%), followed by ampulla of Vater (17% vs. 16%), gallbladder (14% vs. 15%), and intrahepatic (12% vs. 14%) in the S-1 and surgery-alone arms, respectively. Most patients in the S-1 and surgery groups had a resection status of R0 (86% vs. 85%, respectively) and stage II disease (58% vs. 59%). Most patients had no lymph node involvement (N0; 61% vs. 59%).
At the data cut-off on June 23, 2021, the median follow-up duration was 45.4 months.
Of all randomised patients, OS was significantly longer with adjuvant S-1 than surgery-alone (HR[95%CI]: 0.694[0.514-0.935]; one-sided p= 0.008). The 3-year OS rate improved from 67.6% in the surgery alone arm to 77.1% in the adjuvant S-1 arm. In addition, adjuvant S-1 also improved the RFS (HR[95%CI]: 0.797 [0.613-1.035], with 3-year RFS rates of 50.9% and 62.4% for surgery alone and adjuvant S-1, respectively, although this difference was not statistically significant. All pre-planned subgroup analyses (performance status, age, cancer type, cancer stage, R factor, and serum CA19-9) revealed favourable OS and RFS for the adjuvant S-1 arm. The most common adverse events upon treatment with S-1 were myelosuppression, gastro-intestinal toxicity and skin hyperpigmentation. The main grade 3-4 adverse events in adjuvant S-1 arm were biliary tract infection (7.2%), diarrhoea (2.9%), appetite loss (2.9%), fatigue (2.9%). Overall, adjuvant S-1 was well-tolerated.
In the ASCOT study, adjuvant S-1 therapy led to significantly longer survival than surgery alone in patients with resected BTC. As such, study investigators consider adjuvant S-1 therapy as the new standard of care for resected BTC.
Ikeda M, Nakachi K, Konishi M, et al. Adjuvant S-1 versus observation in curatively resected biliary tract cancer: A phase III trial (JCOG1202: ASCOT). Presented at ASCO GI 2022; Abstract 382.