Overall survival was improved by 15 months for patients with macroscopically resected biliary tract cancer who were treated with adjuvant capecitabine compared with observation alone.
John N. Primrose, MD
Overall survival was improved by 15 months for patients with macroscopically resected biliary tract cancer who were treated with adjuvant capecitabine compared with observation alone, according to findings from the phase III BILCAP study released in advance of the 2017 ASCO Annual Meeting.1
The median OS with capecitabine was 51.1 months compared with 36.4 months for observation in the intent-to-treat analysis, which did not pass the bar for statistical significance (HR, 0.81; 95% CI, 0.63-1.04;P= .097). However, in sensitivity analyses that adjusted for nodal status, gender, and stage of disease, capecitabine did show a statistically significant 30% reduction in the risk of death versus observation (HR, 0.70; 95% CI, 0.55-0.91;P= .007).
"Capecitabine compared to surveillance improves median overall survival in resected biliary tract cancer from 36 to 51 months in the intent to treat analysis," said lead study author John N. Primrose, MD, Professor of Surgery at the University of Southampton, United Kingdom. "The toxicities were modest, and based on this, we think that capecitabine should become the standard of care for patients following curative resection of biliary tract cancer."
Seven hundred fifty-three patients were screened for the study, with 447 meeting the criteria for randomization. Overall, there were 224 in the observation arm and 223 in the capecitabine group. Capecitabine was administered at 1250 mg/m2on days 1 to 14 every 21 days for 8 cycles. Greater than 80% of patients were followed for 36 months and all patients had greater than 24 months of follow up.
Patients had completely-resected cholangiocarcinoma (CCA) or gallbladder cancer, with an R0 resection for 62% and R1 for 38%. The median age of patients was 63 years and most had an ECOG performance status of 0 (45%) or 1 (52%). The primary disease sites were hilar (28%), extrahepatic CCA (35%), intrahepatic (19%), and muscle-invasive gallbladder cancers (18%). Approximately half of patients were node negative (46%).
The median relapse-free survival was 25 months in the capecitabine arm versus 18 months for observation (95% CI, 13-28). Overall, there were no deaths attributed to treatment. In the per-protocol assessment, which included 430 patients, the median OS was 53 months with capecitabine versus 36 months for observation (HR, 0.75; 95% CI, 0.58-0.97;P= .028).
Primrose noted that the toxicity associated with capecitabine was modest, with fewer severe adverse events than anticipated. The most common grade 3/4 events were plantar palmar erythema (20.7%), fatigue (7.5%), diarrhea (7.5%), neutropenia (1.9%), bilirubin (1.4%), nausea (0.9%), mucositis/stomatitis (0.9%), and thrombocytopenia (0.5%). There was only a slight difference in quality of life between the two cohorts, Primrose noted.
“Biliary tract cancer is a disease of decidedly unmet need as until recently there has been little research on treating the disease,” Primrose stated. “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.”
Biliary tract cancers are relatively rare in the United States, with greater prevalence in Asia. The study, which enrolled patients in the United Kingdom, began recruiting in March 2006 and was fully accrued by December 2014.
“This study helps resolve long-standing questions about adjuvant treatment for biliary tract cancer, for which there has been no standard of care,” ASCO President Daniel F. Hayes, MD, said in a statement. “This oral chemotherapy is widely available and can offer patients the chance to live more than a year longer.”
In the advanced setting, other studies have shown benefits for the combination of cisplatin plus gemcitabine for patients with advanced biliary tract cancer. In one study, published in the New England Journal of Medicine in 2010,2the median OS with the combination was 11.7 months compared with 8.1 months with gemcitabine alone (HR, 0.64; 95% CI, 0.52-0.80;P<.001).2
A phase III study is looking at gemcitabine plus cisplatin as an adjuvant therapy for patient with resected biliary tract cancer. This study, labeled ACTICCA-1 (NCT02170090), is comparing the combination with observation; however, following the results of BILCAP, the study will be altered to compare cisplatin plus gemcitabine with capecitabine.
"The effect size is dramatic," said senior investigator John A. Bridgewater, MD, PhD, from University College London Hospitals about the BILCAP study. "We really have no doubt that there's an effect here. It's a rare cancer. This is going to be the standard of care from now on…based on these results we've agreed to adjust the ACTICCA study."