Biliary tract cancers remain associated with a substantial risk of recurrence even after curative-intent surgery, making postoperative treatment an important component of management for eligible patients. Although several randomized studies have evaluated adjuvant chemotherapy in this setting, fluoropyrimidine-based approaches have provided the clearest evidence of benefit.
On September 23, 2026, the Journal of Clinical Oncology published the prespecified 5-year follow-up of the phase III ASCOT trial under the title “Five-Year Follow-Up of the Phase III ASCOT Trial of Adjuvant S-1 After Resection for Biliary Tract Cancer.”
Authors: Masafumi Ikeda, MD, PhD, Kohei Nakachi, MD, Masaru Konishi, MD, Riku Kajikawa, MSc, Hiroshi Katayama, MD, PhD, Yusuke Sano, MD, PhD, Teiichi Sugiura, MD, PhD, Sohei Satoi, MD, PhD, h-MBA, FACS, Masaaki Murakawa, MD, PhD, Akira Tomokuni, MD, PhD, Satoshi Nara, MD, Yu Takahashi, MD, PhD, Ken-ichi Okada, MD, PhD, Naoki Hama, MD, PhD, Keiko Kamei, MD, PhD, Ken Kamata, MD, PhD, Seiji Natsume, MD, PhD, Takuji Okusaka, MD, PhD, Junji Furuse, MD, PhD, and Makoto Ueno, MD, PhD
ASCOT Trial Design
ASCOT, also known as JCOG1202, was a multicenter, open-label, randomized phase III trial conducted across 38 institutions in Japan. The study included patients aged 20 to 80 years with histologically confirmed biliary tract cancer who had undergone curative-intent R0 or R1 resection. Eligible primary tumors included intrahepatic and extrahepatic bile duct cancers, gallbladder cancer, and ampullary carcinoma. Patients were also required to have an ECOG performance status of 0 or 1 and adequate organ function.
Between 2013 and 2018, 440 patients were enrolled and randomly assigned to observation alone or adjuvant S-1, with 222 patients in the observation group and 218 in the S-1 group. S-1 was administered orally at 40 mg/m² twice daily for 4 weeks followed by a 2-week rest period, for four cycles over a total treatment period of 24 weeks. Randomization was stratified according to primary tumor site and lymph node status.
The primary endpoint was overall survival in the intention-to-treat population, while relapse-free survival and safety were secondary endpoints. The current analysis was prespecified and conducted 5 years after completion of accrual, with a data cutoff in June 2023. The earlier ASCOT analysis had already demonstrated an improvement in 3-year overall survival with adjuvant S-1, from 67.6% with observation to 77.1% with S-1. The new analysis examined whether this survival advantage was maintained with longer follow-up.
Survival Benefit Maintained at 5 Years
At a median follow-up of 61.5 months, median overall survival was 8.2 years in the S-1 group compared with 5.9 years in the observation group. Five-year overall survival was 64% with S-1 and 52% with observation, corresponding to a hazard ratio for death of 0.72 (95% CI, 0.55–0.95; one-sided P = .01).
Subgroup analyses generally favored S-1, although the magnitude of benefit appeared attenuated in some groups, including patients with an ECOG performance status of 1 and those who underwent R1 resection. In exploratory multivariable analyses, T3-4 disease, lymph node positivity, and R1 resection were identified as factors associated with poorer overall survival.
Relapse-Free Survival With Adjuvant S-1
Relapse-free survival also favored adjuvant S-1. Median relapse-free survival was 6.1 years with S-1 compared with 3.5 years with observation. The stratified hazard ratio was 0.76 (95% CI, 0.59–0.98; two-sided P = .04).
In the unstratified analysis, the hazard ratio was 0.80 (95% CI, 0.62–1.03; two-sided P = .08). Patterns of recurrence were similar between the two groups, with no statistically significant differences in the distribution of recurrence sites. Across exploratory relapse-free survival subgroup analyses, estimated hazard ratios for S-1 versus observation were 1 or lower in 23 of 24 subgroups.
Multivariable analyses identified T3-4 disease, lymph node positivity, R1 resection, and CA19-9 levels above 37 U/mL as factors associated with poorer relapse-free survival.
Long-Term Patterns and Competing Mortality
The investigators noted that although recurrence generally becomes less frequent beyond 5 years after surgery, the relapse-free survival curves continued to decline and became closer over time. They suggested that this pattern may partly reflect competing causes of mortality. Non–recurrence-related deaths occurred in 15 of 218 patients in the S-1 group (7%) compared with 10 of 222 patients in the observation group (5%).
The authors also noted that age of 70 years or older was associated with poorer overall survival but not with relapse-free survival, suggesting that competing mortality risks may contribute to survival outcomes in older patients.
S-1 in the Adjuvant Biliary Tract Cancer Landscape
The findings add to the evidence supporting fluoropyrimidine-based adjuvant chemotherapy after resection of biliary tract cancer. The BILCAP trial previously evaluated adjuvant capecitabine and contributed to its adoption as a standard postoperative treatment in many regions. ASCOT subsequently demonstrated an overall survival benefit with S-1 in the intention-to-treat population, supporting its use in Japan and other Asian countries.
The authors noted that high treatment adherence, earlier treatment initiation, and favorable baseline characteristics may have contributed to the observed survival benefit. They also suggested that the tolerability profile of S-1 may have supported sustained treatment delivery.
Limitations of the ASCOT Analysis
Several limitations remain important when interpreting the findings. All patients enrolled in ASCOT were Japanese, and the pharmacokinetics and tolerability of S-1 may differ in Western populations. Quality of life was not evaluated.
The trial was also conducted before the widespread use of immune checkpoint inhibitors, and most patients did not receive these agents after recurrence. In addition, although exploratory analyses have examined genes involved in 5-fluorouracil metabolism, comprehensive genomic profiling was not performed.
Looking Ahead
The postoperative treatment landscape for biliary tract cancer continues to evolve. Ongoing studies are evaluating immunotherapy in the adjuvant setting, while neoadjuvant approaches are also being investigated in patients with resectable disease.
Against this changing background, the mature ASCOT results provide long-term randomized evidence for adjuvant S-1 following resection of biliary tract cancer.
The investigators concluded that the 5-year follow-up confirms a durable survival benefit with adjuvant S-1 and supports its role as a standard postoperative treatment for resected biliary tract cancer.
The full article is available in the Journal of Clinical Oncology.
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