Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: Acceptable toxicity and suggestion of improved 1-year disease-free survival

Purpose: (1) To determine the toxicity of an intensified postoperative adju vant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic ) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional exter nal beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. (2) To determine preliminary estima tes of the overall and disease-free survival associated with the use of thi s regimen. (3) To compare the toxicities and early survival results of pati ents treated with the current regimen to those of patients who completed ou r prior trial of concurrent chemoradiation infusion with 5-FU/LV chemothera py and regional nodal and prophylactic hepatic irradiation. Methods: Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m(2)), and LV, (20 mg/m(2), Days 1-3), DPM (75 mg p.o., 4 times per day, Days 0-3, and every 8 weeks), MMC (10 mg/m(2 ); maximum of 20 mg, Day 1 during EBRT). This was followed by 4 months of t he same chemotherapy, beginning 1 month following the completion of EBRT. E BRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned r est after the first 10 fractions (2500 cGy). Results: From 4/96 to 6/99, 45 patients were enrolled and treated. Their ex perience constitutes the basis of this analysis. There were 29 patients wit h pancreatic cancer and 16 with nonpancreatic periampullary cancer. Sevente en patients had tumors of 3 cm or more, and 39 patients had at least 1 hist ologically involved lymph node. Thirteen patients had a histologically posi tive margin of resection. The mean time to start of treatment was 63 days f ollowing surgery. During chemoradiation therapy there were no Grade 3 or wo rse nonhematologic toxicities and 47% Grade 3 or Grade 3 hematologic toxici ties of short duration. Following chemoradiation, during chemotherapy treat ment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission an d no treatment-related mortalities. One patient del eloped a mild case of H US, which responded to standard management. One patient developed persisten t shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of pat ients complained of increased fatigue (Grade 1-2), greatest during the comb ined therapy and improving post all treatment. As of 6/23/99, 20 of 45 pati ents have relapsed, 13 in the liver. Twelve patients have died. Median foll ow-up for surviving patients is 14.3 months. Disease-free survival at 12 mo nths following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8.3 months in our Drier study). Median survival has not yet been reached, but will be se ater than 17 months. Conclusion: With a 14.3-month median follow-up, acute toxicity has been acc eptable and manageable. Observed relapses were seen 9-13 months following s urgical resection. Early survival analysis suggests a trend toward increase d median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma. (C) 2000 Elsevier Science Inc.