Adjuvant Capecitabine Continues as Mainstay in Biliary Tract Cancer, But More Research Is Needed in Neoadjuvant Setting


A long-term analysis of the phase 3 BILCAP study highlighted modest benefit for patients with resected biliary tract cancer who received capecitabine following surgery.

Long-term data support capecitabine’s role as an adjuvant therapy for patients with curatively resected biliary tract cancer (BTC) and should continue to be considered as standard of care (SOC) for this patient population, according to an exploratory analysis of the phase 3 BILCAP study (EudraCT 2005- 003318-13) that was published in the Journal of Clinical Oncology.

At a median follow-up of 106 months (95% CI, 98-108), the median overall survival (OS) in the intention-to-treat (ITT) analysis for patients treated with capecitabine was 49.6 months (95% CI, 35.1-59.1) compared with 36.1 months (95% CI, 29.7-44.2) for those who underwent observation (adjusted HR, 0.84; 95% CI, 0.67-1.06). Moreover, in an analysis adjusted for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59-0.94).

“These long-term data confirm the benefit of capecitabine as adjuvant therapy after surgical resection of BTC, which is now recommended by ASCO guidelines,” lead study author John Bridgewater, MD, PhD, UCL Cancer Institute and coinvestigators, wrote in the study.

Although intrahepatic cholangiocarcinoma is increasing worldwide, BTC remains a rare cancer, and is often linked with poor outcomes. For patients with operable disease, the 5-year survival rate is 25%. Five-year survival rates for those with advanced stage is less than 5%.

BILCAP is a randomized, controlled, multicenter, phase 3 study that enrolled 223 patients with BTC (histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer) resected with curative intent between March 15, 2006 and December 4, 2014. To be eligible for enrollment, patients needed to be at least 18 years old and have an ECOG status of 2 or higher.

Enrolled participants were randomized 1:1 to receive either oral capecitabine at 1250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle for 8 cycles or observation.

OS was the trial’s primary outcome. Key secondary outcomes included a per-protocol (PP) analysis of the data and recurrence-free survival (RFS), as well as toxicity, health economics, and quality of life. Toxicity, health economics, and quality of life data are not yet mature.

The median RFS in the ITT analysis was 24.3 months (95% CI, (18.6-34.6) for patients who received capecitabine and 17.4 months (95% CI, 11.8-23.0) for patients undergoing surveillance. The median RFS in the PP analysis was 25.3 months (18.9-36.7) months with capecitabine and 16.8 months (11.8-20.7) with surveillance. After adjusting for resection, status, performance status, and site of disease, the HR was 0.77 (95% CI, 0.61-0.97). Furthermore, the adjusted HR for RFS was 0.74 (95% CI, 0.57-0.96) for the first 24 months, but data was insufficient beyond this 2-year time period.

At a 5-year analysis, the RFS rate in the ITT population was 34% (95% CI, 28-40) for patients receiving capecitabine and 31% for those undergoing observation.

These data suggest that local recurrence remains a significant issue for up to 50% of all patients after resection, whether the resection is classified as R1. However, local recurrence occurs more frequently in patients in R1, the authors stated.

“The frequency of local recurrence suggests the need to develop novel therapeutic strategies, accepting that more extensive surgery is seldom possible even in the context of expert centers. Neoadjuvant approaches or local therapies such as stereotactic radiotherapy warrant investigation,” the authors concluded.


Bridgewater J, Fletcher P, Palmer DH, et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. Published online March 22, 2022. J Clin Oncol. 2022;JCO2102568. doi:10.1200/JCO.21.02568

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