Patients with locally advanced pancreatic adenocarcinoma who receive conventional therapy with radiation with 5-fluorouracil (5-FU) have median survivals ranging from 8 to 12 months. Here we report our experience with a four-drug chemotherapeutic regimen that resulted in sufficient downstaging of tumor in some patients to justify surgical reexploration and resection. From April 1991 through April 1994, 38 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by intravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response, toxicity, and survival. There were 14 partial responses and one complete response--a 39% response rate. The median survival for all patients was 15.5 months; the 1-year survival rate from time of initial diagnosis was 70%. Six of 15 responding patients had sufficient tumor regression to meet clinical criteria for resectability and reexploration, four of whom underwent a curative resection. The median survival of these six patients was 28 months from the time of original diagnosis. The 1-year survival was 83%, with one patient still alive and free of disease at 53 months. We believe this unique experience from a single institution justifies a prospective multi-institutional trial to evaluate the efficacy of this approach in a larger number of patients.