ArticlesCapecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study
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.
References (23)
Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States
Hepatology
(2001)- et al.
Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma
J Hepatol
(2014) - et al.
Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial
Lancet
(2017) - et al.
Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial
Lancet Oncol
(2017) - et al.
Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial
Lancet Oncol
(2014) - et al.
Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme
Eur J Cancer
(2014) - et al.
Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998
Gut
(2001) Pancreatic cancer in adults: diagnosis and management
- et al.
Surgeon volume and operative mortality in the United States
N Engl J Med
(2003) - et al.
Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution
Ann Surg
(2007)
Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer
N Engl J Med
Cited by (769)
AI-based digital histopathology for perihilar cholangiocarcinoma: A step, not a jump
2024, Journal of Pathology InformaticsDoes adjuvant treatment improve survival in R1 resected perihilar cholangiocarcinoma? The risk of overtreatment
2024, Journal of Gastrointestinal SurgerySurvival benefit of adjuvant chemotherapy in patients with resected gallbladder adenocarcinoma: An updated retrospective cohort analysis
2024, European Journal of Surgical OncologyPrecision Oncology in Hepatopancreatobiliary Cancer Surgery
2024, Surgical Oncology Clinics of North AmericaSurvival outcome of patient with pT1N0 biliary tract cancer treated with surgery alone
2024, European Journal of Surgical OncologyCompletion of adjuvant S-1 chemotherapy after surgical resection for biliary tract cancer: A single center experience
2024, Asian Journal of Surgery