Background
Phase III open-label RCT, N=447 patients with resected biliary tract cancer (cholangiocarcinoma or muscle-invasive gallbladder cancer) after macroscopically complete (R0 or R1) resection. Conducted at 44 specialist HPB centres in the UK. Enrolled Mar 2006–Dec 2014. Randomized 1:1 within 16 weeks of surgery. Stratified by centre, site of disease, resection status, and performance status. Primary endpoint OS (ITT).
Interventions and follow up
Arm A: Capecitabine 1250mg/m² orally twice daily on days 1–14 of a 21-day cycle, for 8 cycles (24 weeks)
Arm B: Observation
Primary endpoint: Overall survival
Median follow up: 60mo
Arm B: Observation
Primary endpoint: Overall survival
Median follow up: 60mo
Results
OS (ITT): 51.1 vs 36.4mo, HR 0.81 (95% CI 0.63–1.04), P=.097 — primary endpoint NOT met
OS (per-protocol): 53 vs 36mo, HR 0.75 (0.58–0.97), P=.028
OS (prespecified sensitivity analysis, adjusted for nodal status, grade, sex): HR 0.71 (0.55–0.92), P=.010
RFS (ITT): 24.4 vs 17.5mo
OS (per-protocol): 53 vs 36mo, HR 0.75 (0.58–0.97), P=.028
OS (prespecified sensitivity analysis, adjusted for nodal status, grade, sex): HR 0.71 (0.55–0.92), P=.010
RFS (ITT): 24.4 vs 17.5mo
Adverse events
Dermatologic/GI: Grade ≥3 toxicities in 44% of capecitabine patients, including hand-foot syndrome 20%, diarrhoea 8%, fatigue 8%.
Serious/cardiac: Serious AEs 47 (21%) capecitabine vs 22 (10%) observation; one grade 4 cardiac ischaemia event; no treatment-related deaths.
Serious/cardiac: Serious AEs 47 (21%) capecitabine vs 22 (10%) observation; one grade 4 cardiac ischaemia event; no treatment-related deaths.
Conclusions
Although BILCAP did not meet its primary ITT endpoint, the prespecified per-protocol and sensitivity analyses both showed statistically significant OS improvement with adjuvant capecitabine. This nuanced result led to capecitabine being widely adopted as the adjuvant standard of care in resected biliary tract cancer in the UK and internationally, supported by ESMO and ASCO guidelines.
Key Limitations
The primary ITT analysis did not meet significance (P=.097); strict per-protocol interpretation would call this a negative trial, and the shift to per-protocol and sensitivity analyses as the basis for guideline adoption is controversial. The open-label design may allow post-surgical surveillance differences between arms. There is no validated biomarker to select patients most likely to benefit. The study was conducted entirely in the UK, limiting generalizability across surgical practices and tumour subtypes (intrahepatic vs extrahepatic cholangiocarcinoma vs gallbladder). Concurrent PRODIGE 12 (GEMOX adjuvant biliary) was negative.
Clinical Context
Despite the negative primary analysis, adjuvant capecitabine is recommended by ESMO and ASCO for resected biliary tract cancer, largely on the strength of the per-protocol analysis and absence of competing evidence. ASCOT/JCOG1202 subsequently showed adjuvant S-1 improves OS in Asian patients (positive ITT result). Together, BILCAP and ASCOT define different regional standards: capecitabine (western) and S-1 (eastern). No platinum-based adjuvant regimen has shown benefit (PRODIGE 12 with GEMOX was negative).