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A recent phase III trial showed that adding adjuvant gemcitabine and oxaliplatin chemotherapy to surgical resection did not improve survival in patients with biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI; NEJM JW Oncol Hematol May 2019 and J Clin Oncol 2019; 37:658).
To test the potential benefit of adding adjuvant capecitabine to surgical resection in this setting, investigators from the U.K. conducted an industry-supported, multicenter, open-label, randomized phase III trial (BILCAP) involving 447 biliary tract cancer patients. After surgery, patients were assigned to 6 months of capecitabine (2500 mg/m2 daily for 14 days of a 21-day cycle) or observation. Among these patients, 28%–29% had hilar cholangiocarcinoma, 18%–19% had intrahepatic primaries, 17%–18% had gallbladder primaries, 61%–64% were stage II, 8%–13% were stage III, 46%–48% were node positive, and 38% had R1 resection.
At a median follow-up of 60 months, overall survival (OS) in the intent-to-treat population (the primary endpoint) trended longer with adjuvant capecitabine than with observation (51.1 vs. 36.4 months; hazard ratio, 0.81; P=0.097). In the per-protocol analysis of 430 patients who received ≥1 cycle of capecitabine, OS was significantly longer with adjuvant capecitabine (53 vs. 36 months; HR, 0.75; P=0.028). Completion of all eight cycles was achieved in 55% of patients. Frequent grade 3 adverse events in treated patients were hand-foot syndrome (20%), diarrhea (8%), and fatigue (8%).
Primrose JN et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): A randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019 Mar 25; [e-pub]. (https://doi.org/10.1016/S1470-2045(18)30915-X)
Comment
These findings of improved OS after resection of biliary cancer with adjuvant capecitabine have established a new standard of care. Although the benefit did not reach statistical significance in the intent-to-treat population, a benefit was seen when patients actually received treatment in the per-protocol population. The contrast with the negative results from the prior PRODIGE 12-ACCORD 18-UNICANCER GI study reinforces the observation that regimens such as gemcitabine and oxaliplatin that are potentially active in metastatic disease are not necessarily effective as adjuvant therapy.