BILCAP
Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study
Phase 3N = 447NCT00363584
- Population
- Adults with resected cholangiocarcinoma or muscle-invasive gallbladder cancer (macroscopically complete resection with curative intent, ECOG performance status below 2); 447 enrolled.
- Design
- Randomised, controlled, multicentre phase 3 study at 44 specialist hepatopancreatobiliary centres in the UK; treatment was not masked. Patients aged 18 or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer, a macroscopically complete resection with curative intent and ECOG performance status below 2 were randomly assigned 1:1, starting within 16 weeks of surgery, to oral capecitabine 1250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle for eight cycles or to observation. Computerised minimisation by surgical centre, site of disease, resection status and performance status. Primary outcome overall survival; analyses prespecified as intention to treat and per protocol. 447 patients enrolled between 15 March 2006 and 4 December 2014. The abstract gives EudraCT 2005-003318-13; The ClinicalTrials.gov record NCT00363584 (which carries the same EudraCT number and the identifier CRUK-BILCAP) lists 360 planned participants.
- Primary endpoint
- OS
- Arms
- Observation (control, n = 224): Observation after surgery
- Capecitabine (experimental, n = 223): Oral capecitabine 1250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle for eight cycles
- People
- Primrose JN, BILCAP study group
OSHR 0.81 (95% CI 0.63–1.04)Δ median OS+14.7 monthsOSHR 0.71 (95% CI 0.55–0.92)OSHR 0.75 (95% CI 0.58–0.97)Δ median OS+17 monthsΔ median RFS+6.9 months
Show the numbers
| Endpoint | Analysis | Capecitabine | Observation | Effect |
|---|---|---|---|---|
| OS | primarymedian follow-up 60 monthsPrimrose 2019 | median 51.1 months (34.6–59.1) | median 36.4 months (29.7–44.5) | HR 0.81 (95% CI 0.63–1.04)P=0.097Adjusted hazard ratio as labelled in the abstract (the adjustment variables are not listed there). The abstract's interpretation is that the study did not meet its primary endpoint of improving overall survival in the intention-to-treat population. Median follow-up for all patients 60 months (IQR 37-60). Adverse events were measured in the capecitabine group only: of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity (hand-foot syndrome 43 [20%], diarrhoea 16 [8%], fatigue 16 [8%]); one patient had grade 4 cardiac ischaemia or infarction. Serious adverse events: 47 (21%) of 223 with capecitabine and 22 (10%) of 224 with observation. No deaths were deemed treatment related. |
| OSProtocol-specified sensitivity analysis (population not stated separately in the abstract) | primaryPrimrose 2019 | — | — | HR 0.71 (95% CI 0.55–0.92)P=0.010Protocol-specified sensitivity analysis adjusting for minimisation factors and for nodal status, grade and gender. No median is given for this analysis in the abstract. |
| OSPer protocol: 210 capecitabine and 220 observation patients | primaryPrimrose 2019 | median 53 months | median 36 months (30–44) | HR 0.75 (95% CI 0.58–0.97)P=0.028Prespecified per-protocol analysis. The capecitabine median is 53 months with a 95% CI of 40 months to not reached (the upper bound is not a number, so the interval is not stored). Adjusted hazard ratio as labelled in the abstract. |
| RFS | primaryPrimrose 2019 | median 24.4 months (18.6–35.9) | median 17.5 months (12.0–23.8) | No hazard ratio or p-value for recurrence-free survival is given in the abstract. |
| RFSPer protocol: 210 capecitabine and 220 observation patients | primaryPrimrose 2019 | median 25.9 months (19.8–46.3) | median 17.4 months (12.0–23.7) | No hazard ratio or p-value for recurrence-free survival is given in the abstract. |
| OS | long term-updatemedian follow-up 106 monthsBridgewater 2022 | median 49.6 months (35.1–59.1) | median 36.1 months (29.7–44.2) | HR 0.84 (95% CI 0.67–1.06)Long-term report (Bridgewater 2022). Adjusted hazard ratio as labelled in the abstract; median follow-up for all patients 106 months (95% CI 98-108); data cutoff 21 January 2021. No p-value is given in the abstract. |
| OSProtocol-specified sensitivity analysis (population not stated separately in the abstract) | long term-updatemedian follow-up 106 monthsBridgewater 2022 | — | — | HR 0.74 (95% CI 0.59–0.94)Protocol-specified sensitivity analysis adjusting for minimisation factors, nodal status, grade and sex. No p-value is given in the abstract. |
| Endpoint | Analysis | Capecitabine | Observation | Effect |
|---|---|---|---|---|
| OS | primarymedian follow-up 60 monthsPrimrose 2019 | median 51.1 months (34.6–59.1) | median 36.4 months (29.7–44.5) | HR 0.81 (95% CI 0.63–1.04)P=0.097Adjusted hazard ratio as labelled in the abstract (the adjustment variables are not listed there). The abstract's interpretation is that the study did not meet its primary endpoint of improving overall survival in the intention-to-treat population. Median follow-up for all patients 60 months (IQR 37-60). Adverse events were measured in the capecitabine group only: of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity (hand-foot syndrome 43 [20%], diarrhoea 16 [8%], fatigue 16 [8%]); one patient had grade 4 cardiac ischaemia or infarction. Serious adverse events: 47 (21%) of 223 with capecitabine and 22 (10%) of 224 with observation. No deaths were deemed treatment related. |
| OSProtocol-specified sensitivity analysis (population not stated separately in the abstract) | primaryPrimrose 2019 | — | — | HR 0.71 (95% CI 0.55–0.92)P=0.010Protocol-specified sensitivity analysis adjusting for minimisation factors and for nodal status, grade and gender. No median is given for this analysis in the abstract. |
| OSPer protocol: 210 capecitabine and 220 observation patients | primaryPrimrose 2019 | median 53 months | median 36 months (30–44) | HR 0.75 (95% CI 0.58–0.97)P=0.028Prespecified per-protocol analysis. The capecitabine median is 53 months with a 95% CI of 40 months to not reached (the upper bound is not a number, so the interval is not stored). Adjusted hazard ratio as labelled in the abstract. |
| RFS | primaryPrimrose 2019 | median 24.4 months (18.6–35.9) | median 17.5 months (12.0–23.8) | No hazard ratio or p-value for recurrence-free survival is given in the abstract. |
| RFSPer protocol: 210 capecitabine and 220 observation patients | primaryPrimrose 2019 | median 25.9 months (19.8–46.3) | median 17.4 months (12.0–23.7) | No hazard ratio or p-value for recurrence-free survival is given in the abstract. |
| OS | long term-updatemedian follow-up 106 monthsBridgewater 2022 | median 49.6 months (35.1–59.1) | median 36.1 months (29.7–44.2) | HR 0.84 (95% CI 0.67–1.06)Long-term report (Bridgewater 2022). Adjusted hazard ratio as labelled in the abstract; median follow-up for all patients 106 months (95% CI 98-108); data cutoff 21 January 2021. No p-value is given in the abstract. |
| OSProtocol-specified sensitivity analysis (population not stated separately in the abstract) | long term-updatemedian follow-up 106 monthsBridgewater 2022 | — | — | HR 0.74 (95% CI 0.59–0.94)Protocol-specified sensitivity analysis adjusting for minimisation factors, nodal status, grade and sex. No p-value is given in the abstract. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.81 | 0.63–1.04 |
| OS | 0.71 | 0.55–0.92 |
| OS | 0.75 | 0.58–0.97 |
| OS | 0.84 | 0.67–1.06 |
| OS | 0.74 | 0.59–0.94 |
- Capecitabine (experimental)
- Observation (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Capecitabine | Observation |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 32 | 64.8% | 54.4% |
| 64 | 42.0% | 29.6% |
| 96 | 27.2% | 16.1% |
| 128 | 17.6% | 8.7% |
- Capecitabine (experimental)
- Observation (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Capecitabine | Observation |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 33 | 64.9% | 53.0% |
| 66 | 42.2% | 28.1% |
| 99 | 27.4% | 14.9% |
| 133 | 17.6% | 7.7% |
Appears in
Sources
Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663-673.
Bridgewater J, Fletcher P, Palmer DH, Malik HZ, Prasad R, Mirza D, et al. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol. 2022;40(18):2048-2057.