This study will conduct a phase II study of gemcitabine and S-1 as first-line chemotherapy in patient with advanced biliary tract cancer

Biliary-tract cancer (BTC) is invasive carcinoma that originates from the epithelial lining of the gallbladder and bile ducts. BTC include cholangiocarcinoma (intrahepatic, perihilar, and distal biliary-tree tumor) and carcinoma arising from the gallbladder.

Surgical resection of the primary tumor is potentially curative for BTC, but less than a quarter of patients are eligible for resection at presentation. Systemic chemotherapy is the principal treatment method for patients with unresectable or metastatic BTC.

Gemcitabine is a promising agent, which has shown efficacy in biliary tract cancer. As a single-agent therapy, gemcitabine shows response rates of 8-36% in BTC[4]. In phase II trials with patients in advanced BTC, gemcitabine in combination with capecitabine or platinum analogues produced objective response rates of 26-50%.

The ABC-02 study reported a significant survival advantage for gemcitabine and cisplatin over gemcitabine alone in patients with advanced BTC (median overall survival 11.7 vs. 8.1 months; P < 0.001).

Oral anticancer drug S-1 consists of the 5-FU prodrug tegafur with two biochemical modulators, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo). S-1 monotherapy is active against advanced BTC with objective response rates of 21-35%, and phase II trials of S-1 in combination with gemcitabine reported objective response rates of 20-36%. Differences between trials in the doses and administration schedules of gemcitabine and S-1 may be reflected in the ranges of efficacy, dose-intensity, and rates of toxicity observed.

Even though the efficacy of gemcitabine and S-1 combination is evident for patients with advanced BTC in previous phase II trials, there was no clinical study investigating the efficacy of gemcitabine and S-1 combination for patients with advanced BTC when this study was started. Therefore, we conducted a phase II study to evaluate gemcitabine and S-1 combination as first-line chemotherapy for patients with advanced BTC.

Inclusion Criteria:

• Unresectable, locally advanced, metastatic adenocarcinoma arising from the intra- and extrahepatic biliary ducts or gallbladder
• Initially diagnosed or recurred
• At least one bidimensionally measurable lesion, defined as at least 1x1cm with clearly defined margins on physical examination, on 3-dimentional CT, MRI, or PET-CT
• Age ≥18 and ≤70 years
• Estimated life expectancy ≥3 months
• ECOG performance status ≤2
• Adequate bone marrow function (WBCs ≥4,000/µL or absolute neutrophil count ≥1,500/µL, platelets ≥100,000/µL),
• Adequate kidney function (creatinine ≤1.4 mg/dL)
• Adequate liver function (bilirubin ≤1.8 mg/dL, transaminase levels ≤100mg/dL)
• Written informed consent

Exclusion Criteria:

• Other tumor type than adenocarcinoma
• Previous history of chemotherapy (exception : adjuvant chemotherapy)
• Presence of CNS metastasis, psychosis, or seizure
• Obvious bowel obstruction
• Evidence of serious gastrointestinal bleeding
• Past or concurrent history of neoplasm other than biliary adenocarcinoma, except for curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix uteri
• Pregnant or lactating women, women of childbearing potential not employing adequate contraception
• Other serious illness or medical conditions