Patients who underwent radical surgery for BTC and who were diagnosed pathologically were eligible if they met the following inclusion criteria: those with BTCs classified into either intrahepatic, hilar/perihilar, or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary of Vater carcinomas according to the WHO classification 2010;(17) Moreover, patients were included, if the eligible pathological stage ranged from Stage IB to Stage III according to the 6th edition of the UICC/AJCC staging system (18) without macroscopic residual tumors; if no distant metastases and no peritoneal dissemination was observed; if no prior chemotherapy or radiation for BTC was administered; patients who were able to start chemotherapy within 10 weeks after surgery; age ≥20 years; Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 0 or 1; adequate oral intake; adequate bone marrow function (white blood cells ≥3500/mm3, neutrophils ≥2000/mm3, platelet ≥100000/mm3, hemoglobin ≥9.0 g/dL), adequate liver function [aspartate aminotransferase (AST) ≤100 IU/L (or 150 IU/L under biliary drainage), alanine aminotransferase (ALT) ≤100 IU/L (or 150 IU/L under biliary drainage)] serum total bilirubin ≤2.0 mg/dL (or ≤3.0 mg/dL under biliary drainage), adequate renal function [serum creatinine ≤1.2 mg/dL and creatinine clearance or estimated glomerular filtration rate (GFR) by Cockcroft-Gault formula ≥60 mL/min], and serum albumin ≥3.0 g/dL; normal EKG findings within 28 days before registration; and written informed consent.
The exclusion criteria were as follows: previous history of S-1 administration; uncontrollable diarrhea; history of flucytosine, phenytoin, or warfarin potassium treatments; accumulated pleural effusion or ascites; presence of active infection without viral hepatitis; presence of other cancer except carcinoma in situ within 3 years; severe organ dysfunction (such as heart failure, renal failure, liver failure, intestinal paralysis, uncontrollable diabetes mellitus); presence of pulmonary fibrosis or interstitial pneumonitis; presence of severe mental disorder; presence of severe drug allergy; transfusion within 14 days before registration; women who were pregnant or nursing; women who may have been pregnant or were willing/trying to get pregnant; and unsuitable candidates for this study as judged by the physician.
Study design (Single-arm, non-randomized, open, historical control)
This study was designed by the Keio Surgery Research Network (KSRN) and was conducted at the Keio University Hospital. This study was registered with University Hospital Medical Information Network (UMIN) center (unique trial number: UMIN000009029). Patient registration and data management were conducted at an independent center at Keio University School of Medicine. All laboratory tests required to assess eligibility were completed within 28 days before the start of protocol treatment.
S-1 (tegafur, gimeracil, oteracil potassium; Taiho Pharmaceutical, Tokyo, Japan) was administered within 10 weeks after the surgery. An oral dose of 80 mg/m2 S-1 was given every day on days 1 to 28 of a 6-week cycle for a year. The total dose was based on the patient’s body surface area as follows: <1.25 m2, 80 mg; 1.25–1.5 m2, 100 mg; >1.5 m2, 120 mg. After a-year of chemotherapy, additional chemotherapy was not given unless the patient was diagnosed with recurrence.
The protocol permitted dose modifications and cycle interruptions were as follows: white blood cells < 2000/mm3, neutrophils < 1000/mm3, platelet < 75000/mm3, hemoglobin < 8.0 g/dL, adequate liver function (AST >150 IU/L, ALT >150 IU/L), serum total bilirubin > 3.0 mg/dL, serum creatinine > 1.5 mg/dL, and adverse events associated with gastrointestinal symptom ≥ Grade 3. In cases for which the S-1 dose was reduced, the dose was decreased by 20 mg/body weight while maintaining a minimum dose of 60 mg/body weight, and it was not subsequently increased for any reason. When dose interruptions were prolonged for longer than 4 weeks or if dose reductions below 60 mg/m2 were required, the patient was considered for medication discontinuation. Patients had the option to withdraw from the trial or during follow-up at any stage. Furthermore, criteria for treatment discontinuation included factors such as the physician’s decision, recurrence, and development of other cancers.
Follow up after surgery
Postoperative follow-up CT scanning were performed at 3, 6, 12 months for the first year and every 6 months following that. Tumor marker tests were conducted every 3 months for 2 years.
Evaluation of toxicity
Toxicity was categorized according to the Common Terminology Criteria for Adverse Events, version 4.0. Toxicity was recorded during treatment continuously.
The primary outcome was completion rate at 1 year after first administration of S-1. Secondary outcomes included relative dose intensity (RDI), toxicity, overall survival rate, and disease-free survival rate at two years, which was defined as the time from registration until the event. RDI was defined as the proportion of actual dose intensity received to the planned dose intensity.
The expected treatment completion rate was set at 50% based on the data of the ACTS-GC trial, of which completion rate was 65.8%. (10) The sample size was calculated as 43 patients with a 95% confidence interval for the completion rate of treatment within 30%. Therefore, the target number of patients was set to be 50 for possible ineligible patients.