In an open-label, phase 3, randomized controlled trial of patients with completely resected pancreatic cancer, researchers found that using gemcitabine did not result in improved overall survival when compared with using fluorouracil plus folinic acid. The results were published in the Journal of the American Medical Association [2010;304(10):1073-1081]. With a 5-year survival rate of <5%, pancreatic cancer is among the major causes of cancer death globally. Patients who undergo surgical resection in specialized centers can achieve resection rates >15%, and the 5-year survival rate after resection improves to 10%. Still, there is a need to improve long-term survival. One such survival benefit has been demonstrated in adjuvant chemotherapy. The authors of the ESPAC (European Study Group for Pancreatic Cancer)-3 trial designed the study to compare the survival benefit of adjuvant fluorouracil plus folinic acid with gemcitabine. During the ESPAC-1 trial, gemcitabine was established as the standard of care for advanced pancreatic cancer. The ESPAC-3 trial was the largest adjuvant trial conducted in pancreatic cancer and featured 1088 patients. The last of the 1088 patients recruited was randomized on January 8, 2007, and the database was locked on March 18, 2009. ESPAC-3 initially included an observation group based on the survival uncertainty of adjuvant chemotherapy, but that group was removed after the definitive results of ESPAC-1. The authors ceased randomization into the control group on June 20, 2003. Thus, the trial design of ESPAC-3 (version 2) removed the control group from the original ESPAC-3 (version 1) trial design. The study was conducted at 159 centers in 17 countries: Australia and New Zealand (26), Canada (15), Czech Republic (1), Finland (1), France (15), Germany (13), Greece (3), Hungary (2), Ireland (2), Italy (3), Japan (7), Poland (1), Serbia (1), Sweden (8), Switzerland (1), and the United Kingdom (60). To be eligible, patients had to have undergone complete macroscopic (R0 or R1) resection for ductal adenocarcinoma of the pancreas with histologic confirmation and with no evidence of malignant ascites, peritoneal metastasis, or spreading to the liver or other distant abdominal or extra-abdominal organs. Patients also had to be fully recovered from the surgery, with a World Health Organization performance score of ≤2 and a life expectancy >3 months. Patients were excluded if they previously used neoadjuvant chemotherapy or other concomitant chemotherapy or if they had pancreatic lymphoma, macroscopically remaining tumor (R2 resection), or Classification of Malignant Tumors stage IVb disease. The authors randomly assigned patients to each treatment group on a 1:1 basis according to a computer-generated variable-size blocked randomization method. Patients were stratified at randomization by country and resection margin status (R0 vs R1). They received either fluorouracil plus folinic acid (folinic acid, 20 mg/m2, intravenous bolus injection, followed by fluorouracil, 425 mg/m2, intravenous bolus injection given 1-5 days every 28 days; n=551) or gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks; n=537) for 6 months. Of the 1088 patients in the study, 551 were randomized to receive fluorouracil plus folinic acid, and 537 were randomized to receive gemcitabine. There were 2 ineligible patients in each group, and they were included in the analysis on an intention-to-treat basis. Four hundred eighty-six patients (88%) received 2326 cycles of fluorouracil plus folinic acid and 478 (89%) received 2464 cycles of gemcitabine. Sixty-five patients (12%) in the fluorouracil plus folinic acid group and 59 (11%) in the gemcitabine group did not start treatment. At the time of the analysis, 753 patients (69%) had died, including 388 in the fluorouracil plus folinic acid group and 365 in the gemcitabine group. The 355 remaining patients had a follow-up time of 34.2 months (interquartile range, 27.1-43.4; range, 0.4-86.3), which was equal across treatment groups. The median survival was 23.0 months (95% confidence interval [CI], 21.1-25.0) for patients treated with fluorouracil plus folinic acid and 23.6 months (95% CI, 21.4-26.4) for patients treated with gemcitabine. Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, while 40 patients (7.5%) receiving gemcitabine had 52 events (P<.001). The results indicated no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.