ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma.

Abstract

LBA4006 Background: The ESPAC-3 trial compared adjuvant GEM with 5-fluorouracil/folinic acid for resected pancreatic cancer. GEM is the standard of care based on similar survival and less toxicity. ESPAC-4 aimed to determine whether combination chemotherapy with GEM/CAP improved survival compared to GEM monotherapy. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4 week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was overall survival; secondary endpoints were toxicity, relapse free survival, 2 and 5 year survival and quality of life. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2 year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumor size was 30 mm, 60% were R1 resections, 80% were node positive and 40% were poorly differentiated. On Dec 11 2015 the Independent Trial Steering Committee requested that the trial proceed to full analysis. The data freeze was on March 2 2016. Median survival (months) for patients treated with GEM/CAP was 28.0 (95% CI, 23.5 – 31.5) and 25.5 (22.7 – 27.9) for GEM. Stratified log-rank analysis revealed an HR=0.82 [95% CI, 0.68 – 0.98]; χ2 (1) = 4.61, P=0.032. 196 out of 366 GEM patients in the safety set reported 481 grade 3/4 adverse events, while 226 out of 359 GEM/CAP patients reported 608 grade 3/4 adverse events ( P=0.242). Conclusions: Adjuvant GEM/CAP for pancreatic cancer had a statistically significant improvement in survival compared to GEM monotherapy. Clinical trial information: ISRCTN96397434.