Study Finds Addition of Adjuvant Capecitabine to Gemcitabine Improves Survival in Resected Pancreatic Cancer
In the European phase III ESPAC-4 trial reported in The Lancet, Neoptolemos et al found that adding adjuvant capecitabine to gemcitabine significantly improved overall survival in patients with resected pancreatic cancer.
Study Details
In the open-label trial, 730 patients from 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden were randomized between November 2008 and September 2014 within 12 weeks of surgery to receive 6 cycles of either 1,000 mg/m² of gemcitabine alone given once a week for 3 of every 4 weeks in each cycle (n = 366) or 1,660 mg/m² of oral capecitabine given for 21 days followed by 7 days off in each cycle (n = 364). Patients had undergone complete macroscopic resection (R0 or R1) for ductal adenocarcinoma of the pancreas. Randomization was stratified by resection margin and country. The primary endpoint was overall survival in the intention-to-treat population.
For the combination vs gemcitabine groups: 55% vs 58% were male; median age was 65 years in both; World Health Organization performance status was 0 or 1 in 97% vs 98%; 40% vs 41% were never smokers; 75% vs 73% had no history of diabetes; 39% vs 40% had a negative resection margin status; 57% vs 60% had a well or moderately differentiated tumor grade; 79% vs 82% had positive lymph nodes; maximum tumor size was 30 cm in both; median postoperative CA 19-9 concentration was 17.6 vs 20.5 kU/L; and 70% of patients in both groups were from England.
Improved Overall Survival
The Independent Data and Safety Monitoring Committee requested that results be reported based on a clear signal of efficacy when 458 (95%) of the target of 480 deaths had occurred. Median follow-up was 43.2 months.
Median overall survival was 28.0 months (95% confidence interval [CI] = 23.5–31.5 months) in the combination group vs 25.5 months (95% CI = 22.7–27.9 months) in the gemcitabine group (hazard ratio [HR] = 0.82, P = .032). Estimated overall survival was 84.1% vs 80.5% at 12 months and 53.8% vs 52.1% at 24 months. Among patients with positive resection margins, median overall survival was 23.7 months vs 23.0 months; among those with negative margins, median overall survival was 39.5 months vs 27.9 months (P = .0001 for trend).
Hazard ratios consistently favored combination therapy in the subgroups examined. In a multivariate model including treatment, resection margin, country, postoperative CA 19-9, tumor grade, lymph node status, and maximum tumor size, combination treatment had a significant treatment effect (HR = 0.79, P = .016). Other significant factors included resection margin, postoperative CA 19-9, tumor grade, lymph node status, and maximum tumor size.
Median relapse-free survival was 13.9 vs 13.1 months, with 3-year relapse-free survival of 23.8% vs 20.9% and 5-year relapse-free survival of 18.6% vs 11.9%. Among patients with relapse, 33% and 39% of patients received additional treatment. These treatments included chemotherapy (31%), chemoradiotherapy (4%), and surgery (3%) in the combination group and chemotherapy (32%, including capecitabine in 16%), chemoradiotherapy (4%), and surgery (5%) in the gemcitabine group.
Adverse Events
The most common grade 1 or 2 adverse events in the combination group were anemia (56% vs 58% in the gemcitabine group), fatigue (64% vs 66%), and neutropenia (49% vs 40%). Grade 3 or 4 adverse events occurred in 63% vs 54%, with the most common in the combination group being neutropenia (38% vs 24%), decreased white blood cell count (10% vs 8%), and hand-foot syndrome (7% vs 0%). Grade 3 or 4 fever occurred in 2% in both groups, and infection occurred in 3% vs 7%. Treatment-related serious adverse events occurred in 24% vs 26% of patients. Adverse events led to discontinuation of treatment before the end of cycle 6 in 47% vs 41% of patients.
The investigators concluded: “The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.” They noted: “Patients with R0 resections…had better survival than those with R1 resection margins, but a substantial survival benefit with adjuvant chemotherapy was still observed in those with R1 resection margins.”
The study was funded by Cancer Research UK.
John P Neoptolemos, MD, of Liverpool Clinical and Cancer Research UK Trials Unit, University of Liverpool, is the corresponding author of The Lancet article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
