Capecitabine Plus Oxaliplatin Versus Gemcitabine Plus Oxaliplatin as First-Line Therapy for Advanced Biliary Tract Cancers: A Multicenter, Open-Label, Randomized, Phase Three, Non-Inferiority Trial

Background: Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase two trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase two and three trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. Methods: In this open-label, randomized, phase three, non-inferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling 8 cycles. The primary endpoint was to prove the non-inferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. Findings: In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5·3 months for the GEMOX group and 5·8 months for the XELOX group. The 6-month PFS rate was 44·5% for the GEMOX group and 46·7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for non-inferiority of XELOX to GEMOX. There was no difference in objective response (p=0·171) and median overall survival (p=0·131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (p<0·001). Interpretation: XELOX showed significant non-inferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment for BCTs. Trial registration Number: This study was registered in ClinicalTrials.gov (number NCT01470443) Funding Information: None. Competing interest declaration: We declare no competing interests. Ethical approval statement: The institutional review board or ethics committee of each study site reviewed and approved the study protocol. All patients provided written informed consent according to institutional guidelines before study entry. This study was conducted in accordance with the Declaration of Helsinki.