The long-term (5-year) survival data from the BILCAP study confirm the benefit of capecitabine as adjuvant therapy after surgical resection of biliary tract cancer and it should be considered as the standard of care. The benefit of improved overall survival (OS), although clinically meaningful, is modest and patients and investigators are encouraged to participate in adjuvant studies aimed at improving outcomes further according to Prof. John Bridgewater of the UCL Cancer Institute in London, UK and colleagues from the BILCAP study group, who published the study findings on 22 March 2022 in the Journal of Clinical Oncology.
The BILCAP study is a randomised, multicentre phase III study that was originally published in 2019. It compared oral capecitabine with observation alone after curative resection of biliary tract cancer and established capecitabine as the adjuvant standard of care in the context of other negative studies. Although negative for the primary endpoint, the previously presented data were accepted as sufficient to support a recommendation as the standard of care by the oncology community. The study group now presents the prespecified long-term, 5-year survival outcomes and novel exploratory analyses.
This randomised, controlled, multicentre, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an ECOG performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine or observation. The primary outcome was OS.
Between 15 March 2006 and 4 December 2014, the study group enrolled 447 patients of whom 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cut-off of 21 January 2021, the median follow-up for all patients was 106 months (95% confidence interval [CI] 98 to 108).
In the intention-to-treat (ITT) analysis, the median OS was 49.6 months (95% CI 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI 29.7 to 44.2) in the observation group (adjusted hazard ratio [HR] 0.84; 95% CI 0.67 to 1.06).
In the ITT analysis, the median recurrence-free survival (RFS) was 24.3 months for capecitabine and 17.4 months for surveillance, with a HR of 0.81. The 5-year RFS proportion for the ITT population was 34% for capecitabine and 31% for observation.
In a protocol-specified sensitivity analysis, adjusting for minimisation factors, nodal status, grade, and sex, the OS HR was 0.74 (95% CI 0.59 to 0.94).
The study group observed a significantly poorer survival in the R1 population compared with R0 (HR 1.60), positive node status compared with negative (HR 2.22), poorly differentiated tumours compared with well-differentiated (HR 1.90), and better survival in female compared with male (HR 0.78). There was no evidence that either site of disease or ECOG performance status was associated with differential survival.
In the observation arm, R1 resections are more likely to have a local recurrence alone (24 of 84, 29%) compared with R0 resections (27 of 140, 19%). Capecitabine did not appear to have any impact on the local recurrence rate for either R0 (26 of 139, 19%) or R1 (25 of 84, 30%) resections.
The recent advances in the management of advanced biliary tract cancer have been in the targeted therapy of actionable alterations including FGFR, IDH1, and BRAF, among others. The molecular description of the BILCAP study is currently underway and may provide further insights into the biology of individual subgroups and other prognostic variables such as the R status. Even in this large study, the analysis will be limited by the number of patients in each subgroup emphasizing the importance of cross-study collaboration.
The authors commented that the BILCAP data represent the single largest prospectively assembled data set of patients after curatively resected biliary tract cancer. The long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected biliary tract cancer when used as adjuvant chemotherapy after surgery. Capecitabine remains the adjuvant standard of care after curatively resected biliary tract cancer and the control arm of future randomised studies. The need to continue clinical studies activity, in particular, the continuous collection of material for translational analysis, is critical.
The study was funded by Cancer Research UK. An unrestricted educational grant was given by F. Hoffmann-La Roche AG.
Bridgewater J, Fletcher P, Palmer DH, et al. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. Journal of Clinical Oncology; Published online 22 March 2022. DOI: 10.1200/JCO.21.02568