← Return to [[Biliary Tract Cancer Clinical Trials]] ---- Phase III randomized controlled trial | UK multicenter study | n=447 | Resected biliary tract cancer | Lancet Oncology 2019 **Primrose et al.** Published in Lancet Oncology, 2019 Enrollment: 2006–2014 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/30922733/) --- ### Essential Takeaway BILCAP established adjuvant capecitabine as the practical standard of care following curative-intent resection of biliary tract cancer. Although the trial narrowly missed statistical significance for its primary ITT endpoint, prespecified sensitivity and per-protocol analyses demonstrated meaningful survival benefit with acceptable toxicity. The study became foundational for modern postoperative management of cholangiocarcinoma and gallbladder cancer. --- ### Clinical Question Does adjuvant capecitabine improve survival compared with observation after curative-intent resection of biliary tract cancer? --- ### Background - Only ~20% of patients with biliary tract cancer are candidates for curative-intent resection. - Historical overall prognosis was poor, with 5-year survival <10% overall. - Prior to BILCAP, no adequately powered randomized trial had established an adjuvant standard of care. - Node-positive disease and R1 resection were known adverse prognostic factors. --- ### Population Included: - Intrahepatic cholangiocarcinoma - Perihilar cholangiocarcinoma - Distal cholangiocarcinoma - Muscle-invasive gallbladder carcinoma Eligibility: - Curative-intent macroscopically complete resection - ECOG <2 - Adequate postoperative recovery Excluded: - Pancreatic cancer - Ampullary cancer - Prior chemotherapy or radiation - Persistent biliary obstruction --- ### Study Design #### Arm 1 — Adjuvant Capecitabine - Capecitabine 1250 mg/m² BID - Days 1–14 of a 21-day cycle - 8 cycles total (~6 months) - Initiated within 16 weeks of surgery #### Arm 2 — Observation - Surveillance alone --- ### Endpoints #### Primary Endpoint Overall survival (OS) #### Secondary Endpoints - Recurrence-free survival (RFS) - Toxicity - Quality of life - Cost effectiveness --- ### Key Results ### Intention-to-Treat Overall Survival - 51.1 vs 36.4 months - HR 0.81 - p = 0.097 Technically negative for the primary endpoint, though numerically favorable for capecitabine. --- ### Prespecified Sensitivity Analysis After adjustment for prognostic variables: - HR 0.71 - p = 0.010 This strengthened confidence in treatment benefit. --- ### Per-Protocol Overall Survival - 53 vs 36 months - HR 0.75 - p = 0.028 This analysis became highly influential clinically. --- ### Recurrence-Free Survival #### ITT Analysis - 24.4 vs 17.5 months #### Per-Protocol Analysis - 25.9 vs 17.4 months - HR 0.70 - p = 0.0093 --- ### Toxicity #### Grade 3 Toxicities - Hand-foot syndrome: 20% - Diarrhea: 8% - Fatigue: 8% Additional findings: - 44% experienced at least one grade 3 toxicity - 46% required dose reduction - 55% completed all 8 cycles - No treatment-related deaths Overall toxicity profile was considered manageable. --- ### Additional Findings The study also demonstrated: - improved disease control - delayed recurrence - favorable cost effectiveness - minimal major quality-of-life deterioration Median OS exceeding 50 months after resection was notably better than many historical BTC series. --- ### Interpretation BILCAP is considered the landmark adjuvant biliary tract cancer trial. Although formally negative by strict ITT statistical criteria, the totality of evidence strongly favored adjuvant capecitabine: - clinically meaningful OS improvement - improved RFS - positive sensitivity analyses - positive per-protocol analyses - acceptable toxicity profile The study shifted global practice toward routine postoperative capecitabine after BTC resection. --- ### Important Limitations #### Technically Negative Primary Endpoint - ITT OS narrowly missed significance - Interpretation relies heavily on secondary and sensitivity analyses #### Heterogeneous Disease Group Combined: - intrahepatic CCA - hilar CCA - distal CCA - gallbladder cancer which may have different biology and treatment responsiveness. #### Long Enrollment Period - 2006–2014 - Evolving surgical and oncologic practices during accrual #### Older Systemic Therapy Era Predated: - modern molecular stratification - immunotherapy - contemporary neoadjuvant approaches --- ### Practice Impact BILCAP established: - 6 months of adjuvant capecitabine as the modern standard postoperative therapy after curative-intent resection of biliary tract cancer The trial remains the foundational reference supporting adjuvant systemic therapy in BTC and continues to anchor current guideline recommendations.