Extended Follow-Up Confirms Survival Advantage of Adjuvant Capecitabine in Resected Biliary Tract Cancer

Adjuvant capecitabine (Xeloda) continued to demonstrate an improvement in overall survival (OS) compared with observation following curative-intent resection in patients with biliary tract cancer (BTC), according to findings from a long-term analysis of the phase 3 BILCAP study (NCT00363584) that were published in the Journal of Clinical Oncology.¹

At a median follow-up of 106 months (95% CI, 98-108) in the intent-to-treat (ITT) population, the results showed a median OS of 49.6 months (95% CI, 35.1-59.1) with capecitabine vs 36.1 months (95% CI, 29.7-44.2) with observation. The hazard ratio (HR) was 0.84 (95% CI, 0.67-1.06), which was adjusted for resection status, performance status, and site of disease.

BTC is rising in prevalence but remains uncommon, often presenting late and producing poor outcomes. Of the 20% of patients with BTC who present with operable disease, the 5-year survival rate is 25%, which lowers to less than 5% for those with advanced disease. The BILCAP study sought to establish capecitabine as the adjuvant standard of care for the BTC population. This subsequent analysis pursued 5-year survival outcomes for the BILCAP study and contributed novel exploratory analyses.

BILCAP enrolled patients aged 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had previously received a macroscopically complete resection with curative intent. All eligible patients underwent radical surgical treatment, including pancreatic or liver resection, or both, to achieve complete microscopic clearance of disease.

Additional eligibility criteria stipulated that patients must have an ECOG performance status (PS) of less than 2, as well as adequate hematologic, renal, and liver function.

Patients were excluded if they had ampullary, pancreatic, or mucosal gallbladder cancer. They were also ineligible if they had unresolved biliary tree obstruction, were not fully recovered from previous surgery, or had received previous chemotherapy or radiotherapy for BTC.

Patients were randomized 1:1 to receive 8 cycles of oral capecitabine at a dose of 1250 mg/m² twice a day on days 1 to 14 of a 3-week cycle or observation within 16 weeks after surgery.

The primary end point of the BILCAP study was OS, defined as the time from randomization until the last date of follow-up for surviving patients or the date of death. Secondary end points included a per-protocol analysis of outcomes, toxicity, recurrence-free survival (RFS), quality of life, and health economics.

The BILCAP study’s ITT population consisted of 447 patients: 223 in the capecitabine group and 224 in the observation group. Between March 15, 2006, and December 4, 2014, 430 per-protocol patients were enrolled in the study and randomly assigned to either the capecitabine group (n = 210) or the observation group (n = 220).

At the start of the follow-up analysis, in the per-protocol population, 65% (n = 145) of patients in the capecitabine group had died compared with 71% (n = 159) of patients in the observation group. Of these deaths, 129 in the capecitabine group and 143 in the observation group were from BTC-related causes.

In the per-protocol population, the median OS was 52.3 (95% CI, 36.5-63.3) months in the capecitabine group vs 36.1 (95% CI, 29.6-42.5) months in the observation group, with an adjusted HR of 0.79 (95% CI, 0.63-1.00).

The median RFS in the ITT population was 24.3 (95% CI, 18.6-34.6) months for capecitabine vs 17.4 (95% CI, 11.8-23.0) months for observation, with an adjusted HR of 0.81 (95% CI, 0.65-1.01). The median RFS in the per-protocol population was 25.3 (95% CI, 18.9-36.7) months in the capecitabine group vs 16.8 (95% CI, 11.8-20.7) months in the observation group, with an adjusted HR of 0.77 (95% CI, 0.61-0.97).

At 5 years, 68% (n = 306) of the ITT population experienced disease recurrence or death from disease: 147 (66%) from the capecitabine group and 159 (71%) from the observation group. The highest risk of recurrence in both groups occurred at 24 months.

Local recurrence at 5 years remains a significant issue for up to 50% of all patients after surgery, with more frequent occurrence in patients in the R1 population who exhibited a poorer survival compared with the R0 population. In the observation group, R1 resections were more likely to have a local recurrence (n = 24/84; 29%) compared with R0 resections (n = 27/140; 19%). Capecitabine did not affect local recurrence rates for either group, as 30% (n = 25/84) of R1 patients on capecitabine and 19% (n = 26/139) of R0 patients on capecitabine still experienced local recurrence.

These data suggest that capecitabine has little effect on local and distant recurrence for both R1 and R0 resections, but that, on average, patients on capecitabine experience recurrence later than those on observation, particularly throughout the first 2 years postrandomization.

This most recent follow-up analysis replicates prior findings from the BILCAP trial.² These long-term data maintain the benefits of adjuvant capecitabine therapy after curative BTC resection, and showcase, a modest, although clinically meaningful, benefit that warrants additional follow-up, the authors concluded.

References

1. Bridgewater J, Fletcher P, Palmer DH, et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. Published online March 22, 2022. doi:10.1200/JCO.21.02568.
2. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 20:663-673. doi:10.1016/S1470-2045(18)30915-X.