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CHICAGO -- Patients with biliary tract cancer gained more than a year of additional life if they received chemotherapy after surgery as compared with having surgery alone, a randomized trial showed.

Median overall survival after surgical resection increased from 36.4 months with surgery alone to 51.1 months with the addition of adjuvant capecitabine. The chemotherapy was generally well tolerated, consisting primarily of skin irritation on the hands and feet, John Primrose, MD, of the University of Southampton in England, reported at the American Society of Clinical Oncology (ASCO) annual meeting.

"Our trial is the first to enroll a sufficient number of patients to show that chemotherapy after surgery can have a significant improvement in survival, with modest side effects," Primrose said during a press briefing held prior to the meeting, which begins here June 2. "Capecitabine should become the standard of care for patients following curative resection of biliary tract cancer."

Noting that biliary cancer remains relatively rare outside of Asia, ASCO President Daniel Hayes, MD, said the applicability of the results to Asian populations will likely be at the center of discussions after the data are presented to a roomful of GI cancer specialists at the annual meeting.

"Otherwise, this is an impressive study that required an enormous amount of work, and this is a very important finding," said Hayes, of the University of Michigan in Ann Arbor.

The required 10 years to conduct, reflecting the low prevalence and incidence of the disease in many parts of the world. Primrose said new approaches are needed to recruit and enroll patients in trials of biliary cancer, given the rapid pace of development for new therapies and treatment strategies.

"One of the major benefits of our trial is the fact that we now have a tumor tissue collection associated with very robust clinical data, which will be used for genomic exploration," said Primrose. "Since we started planning this trial at the start of this century, a number of new agents have become available, including several that treat cancer based on its genetic profile. This is where our tumor tissue repository will play an important role."

The trial investigated a longstanding controversy in the treatment of biliary tract cancer, which includes the liver, bile ducts, and gallbladder: namely, whether adjuvant chemotherapy improves results over surgery alone. Limited data existed regarding use of chemotherapy in bile duct cancer, leaving primary surgery as the only effective option. Most patients eventually die of the disease, even with seemingly complete and successful resection, said Primrose.

The prospective, multicenter involved 447 patients with macroscopically resected biliary tract cancer with Eastern Cooperative Oncology Group performance status ≤2. Eligibility criteria allowed enrollment of patients whose surgery included the liver or pancreas. Following surgery, patients were randomized to observation or eight cycles of oral capecitabine.

The trial had a primary endpoint of overall survival, and key secondary endpoints included relapse-free survival, toxicity, and quality of life.

The 15-month overall survival advantage translated into an unadjusted 19% reduction in the survival hazard, which proved not to be statistically significant (HR 0.81, 95% CI 0.63-1.04, P=0.097). However, investigators prespecified a sensitivity analysis that adjusted for differences between the treatment groups with respect to nodal status, disease grade, and sex. That analysis yielded a 30% reduction in the hazard, which did achieve statistical significance (95% C 0.55-0.91, P=0.007).

A safety analysis limited to the capecitabine group showed that grade 3/4 toxicity included a 20.7% incidence of plantar/palmar erythema, as well as fatigue in 7.5% of patients, and diarrhea in 7.5% of patients. No chemotherapy-associated deaths occurred.

The trial protocol included several prespecified subgroup analyses. Primrose said investigators are evaluating the effects of capecitabine in patients representing the four distinct subtypes of biliary tract cancer, three of which involve the liver and associated ducts and one involving the gallbladder.

Despite the unresolved issue about applicability of the results to non-Western patients, Hayes said the study "helps resolve long-standing questions about adjuvant treatment for biliary tract cancer, for which there has been no standard of care. This oral chemotherapy is widely available and can offer patients the chance to live more than a year longer."

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