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Patients who received capecitabine chemotherapy after undergoing resection of biliary tract cancer lived more than a year longer than patients whose disease was managed with observation only after surgery, according to results from the phase III BILCAP study.

The 223 patients with biliary tract cancer assigned to adjuvant capecitabine had a median overall survival of 51.1 months compared with 36.4 months for the 224 patients in the observation group, a 14.7-month difference. This survival difference was seen with minimal adverse effects, reported John N. Primrose, FMedSci, of the University of Southampton in England, and colleagues in .

However, this difference was not statistically significant (adjusted HR 0.81, 95% CI 0.63-1.04, P=0.097), causing the trial to fail to meet its primary endpoint of overall survival in the intention-to-treat analysis.

"Although the overall survival primary endpoint analyzed 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," wrote Primrose and colleagues, who previously presented the results at the American Society of Clinical Oncology's 2017 annual meeting.

In the protocol-specified sensitivity analysis, which adjusted for nodal status, grade, and gender, the HR improved to 0.71 (95% CI 0.55-0.92, P=0.010) in favor of capecitabine. The researchers also conducted a prespecified per-protocol analysis, which did not include 17 patients assigned to, but not treated with, capecitabine. In this comparison, the difference in median overall survival was statistically significant, improving from 36 months for surgery alone to 53 months for capecitabine (HR 0.75, 95% CI 0.58-0.97, P=0.028).

In the intention-to-treat analysis, the median recurrence-free survival was also significantly improved with capecitabine compared with observation (24.4 vs 17.5 months). In the first 24 months, patients assigned to capecitabine had significantly better recurrence-free survival (HR 0.75, 95% CI 0.58-0.98, P=0.033). However, the recurrence-free survival did not differ between the two study groups from 24 months through 60 months -- which suggested "that deferred recurrence occurred in the capecitabine group," the researchers said.

Median recurrence-free survival in a per-protocol analysis was 25.9 months for capecitabine compared with 17.4 months for observation.

Attempts to Answer Unresolved Question

Writing in an , David Malka, MD, PhD, of Universite Paris-Saclay in Villejuif, France, and Julien Edeline, MD, of Centre Eugene Marquis, Rennes, France, said the data from Primrose and colleagues attempts to answer the "unresolved" question of adjuvant treatment for biliary tract cancer.

The editorial also pointed out that the researchers had to adjust the BILCAP study protocol several times in an attempt to circumvent the fact that it was underpowered due to the fact that "2-year overall survival in the observation group (60%) was considerably higher than originally thought (20%)."

Although the results were statistically negative, BILCAP is still a clinically meaningful study, Malka and Edeline wrote, with a large overall survival effect and a convenient, affordable, and tolerable treatment regimen.

They suggested that capecitabine be proposed to patients "after curative-intent resection of biliary tract cancer, and should be considered the control group for future studies," given the negative results of two recent randomized studies of gemcitabine and gemcitabine plus oxaliplatin that failed to show a significant benefit in this treatment area.

Study Details

The multicenter study included patients ages 18 or older enrolled across 44 sites in the U.K. Eligible patients had confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer and had undergone resection of the disease with curative intent. Patients were enrolled from March 2006 through December 2014 and randomly assigned to oral capecitabine (1,250 mg/m² twice daily on days 1-14 of a 21-day cycle) or observation.

Adverse events were monitored only in patients assigned to capecitabine. Of patients who received a dose of the study drug, 44% had at least one grade 3 or worse adverse event. The most common event was hand-foot syndrome (20%), followed by diarrhea (8%) and fatigue (8%). One patient had a grade 4 cardiac ischemia or infarction; no treatment-related deaths occurred.