Elsevier

The Lancet Oncology

Volume 20, Issue 5, May 2019, Pages 663-673
The Lancet Oncology

Articles
Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study

https://doi.org/10.1016/S1470-2045(18)30915-XGet rights and content

Summary

Background

Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.

Methods

This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1–14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.

Findings

Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37–60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6–59·1) in the capecitabine group compared with 36·4 months (29·7–44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63–1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55–0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30–44) in the observation group (adjusted HR 0·75, 95% CI 0·58–0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6–35·9) in the capecitabine group and 17·5 months (12·0–23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8–46·3) in the capecitabine group and 17·4 months (12·0–23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related.

Interpretation

Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.

Funding

Cancer Research UK and Roche.

Introduction

Biliary tract cancer is an uncommon cancer in high-income countries. There are approximately 1200 and 9000 new cases per year in the UK and the USA, respectively.1, 2 The incidence of biliary tract cancer is increasing, perhaps associated with an increasing incidence of gallstone disease. Potentially curative resection is feasible in 20% of presenting patients,3 and increasing centralisation of often complex surgery in specialist hepatopancreatobiliary centres aims to improve outcomes.4, 5 The postoperative median overall survival is reported to be 18–30 months, with patients with positive lymph nodes and positive resection margins having a worse prognosis.6

The standard of care for patients with unresectable biliary tract cancer has been established as cisplatin and gemcitabine, suggesting that biliary tract cancers are chemosensitive malignancies.7, 8 However, the value of adjuvant chemotherapy has not been investigated in a dedicated randomised trial. A subgroup of the ESPAC-3 trial9 comprising 96 patients with biliary tract cancer and the study by Takada and colleagues, including 133 patients with non-curative biliary tract cancer resections,10 were not sufficiently statistically powered to define a standard of care. More recently, a randomised study11 of gemcitabine compared with surveillance in 225 patients with extrahepatic and perihilar cholangiocarcinoma resected with curative intent showed no difference in overall survival between the groups (hazard ratio [HR] 1·01, 95% CI 0·70–1·44; p=0·97). In addition, a phase 3 trial12 testing adjuvant oxaliplatin plus gemcitabine compared with surveillance has recently been reported. Overall survival was not significantly different between the treatment groups (HR 1·08, 95% CI 0·70–1·66; p=0·74); however, a large effect size was seen (overall survival of 50·8 months in the surveillance group vs 75·8 months in the oxaliplatin plus gemcitabine group; HR 1·08, 95% CI 0·70–1·66).12 A meta-analysis13 of mostly non-randomised series has suggested the potential benefit for chemotherapy as adjuvant therapy in patients with biliary tract cancer and node-positive disease, and of radiation-based adjuvant therapy in resection margin-positive (R1) subgroups, but given the quality of the data included in the analysis, these are still unproven hypotheses.

Capecitabine is an oral fluoropyrimidine prodrug that is effective as adjuvant chemotherapy treatment, either alone or in combination, in colorectal,14 oesophageal and gastric,15 and pancreatic9 malignancies. Fluoropyrimidines have evidence of activity in biliary tract cancer,10 are well tolerated, and used in everyday oncological practice. Although supportive clinical data are scarce, feasibility and compliance with treatment were considered crucial in this study and capecitabine was selected as protocol treatment. The BILCAP trial aimed to compare capecitabine with observation after resection of biliary tract cancer in specialist hepatopancreatobiliary centres in the UK.

Section snippets

Study design and participants

This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK (appendix pp 4–6). Patients aged 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had a macroscopically complete resection with curative intent were eligible. All patients should have had radical surgical treatment, which includes liver resection, pancreatic resection, or, less commonly, both. The Eastern

Results

Between March 15, 2006, and Dec 4, 2014, 447 patients (intention-to-treat population) were enrolled and randomly assigned to the capecitabine group (n=223) or the observation group (n=224; figure 1). The per-protocol population comprised 430 patients (210 in the capecitabine group and 220 in the observation group) following the exclusion of 17 patients, comprising seven (2%) patients (three in the capecitabine group and four in the observation group) who were found to be ineligible after

Discussion

The BILCAP study, which compared capecitabine with observation as an adjuvant in biliary tract cancer resected with curative intent, provides evidence that capecitabine can improve overall survival. Although the overall survival primary endpoint analysed in the intention-to-treat population did not reach statistical significance, the sensitivity analyses of this population, the per-protocol overall survival and recurrence-free survival analyses showed benefit, and the overall survival effect

Data sharing

Data collected for the study, including individual participant data and a data dictionary defining each field in the set, will be made available to others by signed data access agreement.

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