There is no standard adjuvant therapy for patients with resectable biliary tract cancer, but that may be about to change based on results of the phase III BILCAP trial.1 Adjuvant capecitabine significantly improved overall survival in the BILCAP trial, and this is the first study to show a benefit in the adjuvant setting.1 These results were presented in advance of the ASCO Annual Meeting in an online press briefing for journalists. Final data are being presented June 4.
There is no standard of care in this setting, and I think oncologists will regard this as a definitive trial.— John Neil Primrose, MD
“The take-home message is patients with resected biliary tract cancer obtain substantial survival benefit from adjuvant capecitabine with a simple single chemotherapy drug, and treatment has no discernible impact on quality of life,” stated lead author John Neil Primrose, MD, of the University of Southampton, UK. “Capecitabine ... should become standard of care,” he added.
Biliary tract cancers comprise about 30% of all primary liver tumors, and few patients present with early disease. Approximately 20% of cases are suitable for surgical resection, and 5-year survival is less than 20%.
In the absence of standardized adjuvant therapy, the BILCAP investigators randomized 447 patients between 2006 and 2014 with completely resected cholangiocarcinoma or gallbladder cancer (including liver and pancreatic resection as appropriate) to receive capecitabine at 1,250 mg/m2 on days 1 to 14 every 8 days for 8 cycles vs observation. Patients enrolled in the trial had adequate biliary drainage; no ongoing infection; adequate renal, hematologic, and liver function; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
The median age was 63 years; 210 patients (45%) had an ECOG performance status of 0, 232 patients (52%) had an ECOG performance status of 1, and 14 patients (3%) had an ECOG performance status of 2. The primary site of the tumor was intrahepatic in 84 patients (19%), hilar in 128 patients (28%), extrahepatic in 156 patients (35%), and muscle-invasive in the gallbladder in 79 patients (18%). Following surgery, 279 patients (62%) had negative margins, and 168 patients (38%) had positive margins. A total of 207 patients (46%) had node-negative disease, and 54% had node-positive disease.
The primary outcome was an intent-to-treat analysis of overall survival. This analysis was performed with at least 24 months of follow-up. Follow-up was at least 36 months in more than 80% of surviving patients.
For the primary outcome, median overall survival was 51 months with capecitabine and 36 months with observation; capecitabine reduced the risk of death by a nonsignificant 20% (P = .09). In the per-protocol analysis, median overall survival was 53 months and 36 months, respectively, representing a 25% reduced risk of death with capecitabine, which was statistically significant (P = .028).
When asked about the difference in significance between the intent-to-treat analysis and the per-protocol analysis, Dr. Primrose responded: “When we set up the study almost a decade ago, we estimated the survival of these patients postoperatively based on the literature. In reality, the patient outcomes were happily much better in the control arm than expected. This meant the study was underpowered. “The data monitoring and ethics committee allowed us to continue recruiting to a higher number but then thought we had done as much as we could with this study so stopped recruitment.”
He continued: “The intent-to-treat analysis escaped statistical significance, but it is clear from the survival curves there is sustained benefit in the experimental arm. As you know, the per-protocol analysis is clearly positive, and the sensitivity analysis—where we corrected for prognostic variables—is strongly positive. We think this is enough!”
In an intent-to-treat analysis, median relapse-free survival was 25 months with capecitabine and 18 months with observation.
Grade 3/4 toxicity was less than anticipated, and no treatment-related deaths were reported. Serious adverse events (grade 3 and higher) among 223 patients in the capecitabine arm follow (in descending order): hand-foot syndrome, 43 (19%); diarrhea, 16 (7%); cardiac, 5 (2%); thromboembolic disease and hyperbilirubinemia, 1 each (0.4% for each), and other, 3.
When asked whether capecitabine should be reserved for high-risk patients, Dr. Primrose said: “The data suggest all. The benefit is not retracted to the high-risk patients. There is no standard of care in this setting, and I think oncologists will regard this as a definitive trial. I think a trial with a no treatment arm would not now be ethical or acceptable to patients.”
The BILCAP investigators collected tissue samples and plan to do further research on these samples. “A lot of translational science can be built on the back of this unique trial,” he stated. ■
The study was funded by Cancer Research UK.
Disclosure: Dr. Primrose reported no conflicts of interest.