The evidence supporting this protocol is based on a single phase III randomised controlled trial (BILCAP).r This was a multicentre trial that randomised 447 patients with histologically confirmed cholangiocarcinoma or muscle invasive gall bladder cancer to receive capecitabine or observation in the adjuvant setting.
Between March 2006 and December 2014, 223 patients were randomised to receive capecitabine 1250 mg/m² twice daily on days 1 to 14 of a 21-day cycle for 8 cycles, and 224 patients were randomised to observation alone.r Adjuvant therapy was commenced within 12 weeks of surgery. Adjuvant radiation therapy was not permitted in the trial protocol. ECOG performance status was 0-1 for 97% of patients. Resection status was R0 (negative resection margins) in 62%, and R1 (microscopic tumour infiltration) in 38%. Tumour site was the gallbladder in 79 of 447 patients (18%).
The primary endpoint of this study was overall survival, and the secondary endpoints were per-protocol analysis of outcomes, relapse free survival, toxicity, quality of life and health economics. The median follow up for all patients was 106 months (95% CI, 98 to 108). The study was powered to detect an 11% improvement in overall survival at 2 years from 60% to 71%, equating to a hazard ratio of 0.69 with a 2-sided significance level of 5% and with 80% power, requiring 410 patients with 234 events.r
Efficacy
Capecitabine was associated with a non-significant trend towards improved overall survival in the intention to treat analysis. The median overall survival in the intention to treat analysis was 49.6 (35.1 to 59.1) months in the capecitabine arm and 36.1 (29.7 to 44.2) months in the observation arm, with a hazard ratio of 0.84(0.67 to 1.06). Capecitabine was associated with an improvement in recurrence-free survival (RFS), on initial analysis at 24 months however the updated RFS data failed to reach statistical significance. There was a RFS of 24.3 (18.6 to 34.6) months for capecitabine and 17.4 (11.8 to 23.0) months for surveillance with a HR of 0.81 (0.65 to 1.01).
However a planned sensitivity analysis which adjusted for prognostic factors such as nodal status, tumour grade, gender, resection margin and performance status showed an OS HR of 0.74 (0.59 – 0.94).
There was no difference in quality of life.r Subgroup analysis showed a benefit of capecitabine in female patients HR of 0.78 (0.61-0.99) and those with duct cholangiocarcinoma HR of 0.88 (0.67 to 1.18) and gallbladder carcinoma HR of 0.88 (0.60 to 1.30). r
Kaplan-Meier curves OS in the ITT population (A) resection status, (B) tumour grade, (C) node status and (D) sexr
© J Clin Oncol 2022
Toxicity
The most common grade 3 side effects were hand-foot syndrome (20%), fatigue (8%) and diarrhoea (8%). At the time of final analysis there were 114 deaths in the capecitabine arm and 131 in the observation arm (51% and 58% respectively).r
Toxicityr |
Grade 3 (n = 213) |
Hand-foot syndrome |
44 (20%) |
Fatigue |
16 (8%) |
Diarrhoea |
16 (8%) |
Nausea |
2 (1%) |
Mucositis/stomatitis |
2 (1%) |
Vomiting |
1 (<1%) |
Neutropenia |
4 (2%) |
Bilirubin |
3 (1%) |
Thrombocytopenia |
1 (<1%) |
© Lancet Oncol 2019