The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary cancer trial found that adjuvant chemotherapy following surgical resection of periampullary adenocarcinoma “was not associated with a significant survival benefit in the primary analysis; however, multivariate analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy.” The phase III randomized controlled trial was conducted in 100 centers in Europe, Australia, Japan, and Canada, and reported in the Journal of the American Medical Association.
“Periampullary carcinomas arise from the head of the pancreas in the region of the ampulla of Vater and apart from pancreatic ductal adenocarcinoma comprise carcinomas of the bile duct, the ampulla itself, and the periampullary duodenum,” according to background information in the article. “The clinical presentation is similar to that of pancreatic ductal adenocarcinoma, and together they represent a major cause of death.” Although adjuvant chemotherapy had been shown to have a survival benefit for pancreatic cancer, there were previously no controlled trials for periampullary adenocarcinomas.
Of the 428 patients included in the primary analysis of the ESPAC-3 trial, 297 had ampullary cancer, 96 had bile duct cancer, and 35 had other cancers. Patients were divided into three groups: (1) 144 to the observation group, (2) 143 to receive leucovorin via intravenous bolus injection followed by fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and (3) 141 to receive intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months.
At the time of analysis, 244 patients (57%) had died—88 (61 %) in the observation group, 83 (58%) in the fluorouracil-plus-leucovorin group, and 73 (52%) in the gemcitabine group. For the primary analysis, median survival was 35.2 months in the observation group, 38.9 months for patients treated with fluorouracil plus leucovorin, and 45.7 months for patients treated with gemcitabine.
“After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI = 0.57–0.98; Wald X2 = 4.53, P = .03),” the investigators reported. The statistically significant survival benefit to chemotherapy was found “specifically for gemcitabine compared with observation, notwithstanding the better safety profile compared with fluorouracil plus leucovorin, but these results should be considered hypothesis generating,” the authors noted. A total of 162 treatment-related serious adverse events were reported by 70 patients (49%) receiving fluorouracil plus leucovorin compared to a total of 81 events reported by 43 patients (30%) receiving gemcitabine.
“Although this study found support for the use of adjuvant chemotherapy to improve survival in patients with periampullary cancers, this effect was modest, indicating a need for further improvements and warranting the testing of combination chemotherapies,” the researchers concluded. ■
Neoptolemos JP, et al: JAMA. 308:147-156, 2012.