Clinical trialPhase 3Bile duct and gallbladder cancer (biliary tract cancer)

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

Lancet Oncol · 2019447 patients (223 capecitabine, 224 observation)

Primrose JN, Fox RP, Palmer DH, et al. Lancet Oncol. 2019. 20:663-673

Study type: Clinical trial
Study name: BILCAP
Phase: Phase 3
Design: Randomised, controlled, multicentre, open-label trial in 44 specialist hepatopancreatobiliary centres in the UK; 1:1 randomisation by computerised minimisation (EudraCT 2005-003318-13)
Sample size: 447 patients (223 capecitabine, 224 observation)
Source: Lancet Oncol · 2019

In plain words

People with bile duct or gallbladder cancer who had complete surgery either took capecitabine tablets for 6 months or were only followed up. The capecitabine group lived longer and their cancer came back later; this difference did not reach a definite result in the main analysis, but it was also seen in more detailed analyses and with longer follow-up. The most common severe side effect was redness and pain of the palms and soles. Based on this study, capecitabine after surgery became the standard treatment.

Key results

Median 51.1 vs 36.4 months

Overall survival (intention to treat)

Adjusted HR 0.81 (95% CI 0.63–1.04); P=0.097; primary endpoint not met

HR 0.71

Overall survival (protocol-specified sensitivity analysis)

95% CI 0.55–0.92; P=0.010

Median 53 vs 36 months

Overall survival (per protocol, 430 patients)

Adjusted HR 0.75 (0.58–0.97); P=0.028

Median 24.4 vs 17.5 months

Recurrence-free survival (intention to treat)

Per protocol: 25.9 vs 17.4 months

Median 49.6 vs 36.1 months

Long-term follow-up (JCO 2022; median 106 months)

Adjusted HR 0.84 (0.67–1.06); sensitivity analysis HR 0.74 (0.59–0.94)

Drugs in this study:Capecitabine (Xeloda)

Dose and schedule cards

Adjuvant capecitabine (BILCAP)

Cholangiocarcinoma (intrahepatic, perihilar or distal) or muscle-invasive gallbladder cancer after macroscopically complete resection; ECOG below 2; start within 16 weeks of surgeryCycle length: Every 21 daysOn the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After surgery (adjuvant treatment)

Cholangiocarcinoma (intrahepatic, perihilar or distal) or muscle-invasive gallbladder cancer after macroscopically complete resection; ECOG below 2; start within 16 weeks of surgery

Drug	Dose	Route	Schedule
Capecitabine	1250 mg/m² twice daily	Oral	Days 1–14

Cycle length: Every 21 days
Duration: 8 cycles (24 weeks)

Dose source: BILCAP. ASCO: 6 months; the dose may follow institutional or regional practice. Grade 3 toxicity in 44% (hand-foot syndrome 20%, diarrhoea 8%, fatigue 8%). DPYD testing before starting; reduce the dose by 25% with creatinine clearance 30–50 and no dose established below 30; tablets swallowed whole with water within 30 minutes after a meal. In ACTICCA-1, adjuvant gemcitabine–cisplatin was not significantly better than capecitabine.

On the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After surgery (adjuvant treatment)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Capecitabine (223 patients)

Oral capecitabine 1250 mg/m² twice daily on days 1–14 of each 21-day cycle for 8 cycles (24 weeks), starting within 16 weeks of surgery.

2Observation (224 patients)

No adjuvant treatment; follow-up only.

Source of the regimen details: Abstracts of the Lancet Oncol 2019 and JCO 2022 papers (capecitabine dose and schedule)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had a macroscopically complete resection with curative intent (liver resection, pancreatic resection or, rarely, both) and ECOG performance status below 2. Patients who had not fully recovered from surgery or had previous chemotherapy or radiotherapy for biliary tract cancer were excluded. Treatment started within 16 weeks of surgery; stratification by surgical centre, disease site, resection status and performance status.

Endpoints

Primary endpoint: overall survival. As planned, analyses were by intention to treat and per protocol, with a protocol-specified sensitivity analysis adjusted for minimisation factors, nodal status, grade and sex. Other reported outcomes: recurrence-free survival and adverse events (recorded in the capecitabine group only).

Safety and side effects

Adverse events were recorded in the capecitabine group only. Of 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity; the most frequent were hand-foot syndrome (43 patients, 20%), diarrhoea (16 patients, 8%) and fatigue (16 patients, 8%). One patient (less than 1%) had grade 4 cardiac ischaemia or infarction. Serious adverse events occurred in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 in the observation group. No deaths were deemed treatment related.

Clinical significance and place in guidelines

BILCAP was the first phase 3 trial to show a benefit of adjuvant therapy in biliary tract cancer and made 6 months of capecitabine the standard adjuvant treatment. ASCO 2019 recommends 6 months of adjuvant capecitabine for resected patients, and ESMO 2023 endorses it [II, A]. Long-term follow-up (JCO 2022) supported the original result. In ACTICCA-1 (Ann Oncol 2026), adjuvant gemcitabine–cisplatin was not significantly better than capecitabine, which remains the standard.

Limitations

The primary endpoint was not met in the intention-to-treat analysis, and the positive result rests on the sensitivity and per-protocol analyses. The trial was open label and adverse events were recorded in the capecitabine group only. All patients were from the UK, different tumour sites were analysed together, and recruitment took a long time (2006 to 2014).

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.