A Phase Ii Study of Weekly Methotrexate, Cisplatin, and 24-Hour Infusion of High-Dose 5-Fluorouracil and Leucovorin (Mp-Hdfl) in Patients with Metastatic and Recurrent Esophageal Cancer-Improving Toxicity Profile by Infusional Schedule and Double Biochem

Background: Patients with advanced esophageal cancer are frequently not indicated for intensive chemotherapy due to aero-digestive tract complications. In order to improve the therapeutic index of systemic chemotherapy for these patients, we designed a weekly MP-HDFL protocol, which took advantage of the low toxicity of the infusional dosing schedule for cisplatin and 5-fluorouracil (5-FU), and double biochemical modulation of 5-FU by methotrexate and leucovorin. Patients and Methods: Between April 1997 and April 2001, a total of 26 patients (M: F= 22: 4) with a median age of 59.5 (range: 43-81) years were enrolled into this phase II clinical trial prospectively. There were 12 patients with de novo , metastatic disease, 13 with recurrent disease (including 7 relapsed from previous concurrent chemoradiotherapy incorporating cisplatin and 5-FU), and one with locally advanced disease. The weekly MP-HDFL protocol 2 was composed of methotrexate 40 mg/m(2), i.v., on days 1, 8, 15; cisplatin 35 mg/m(2) 24-hour IVF, on days 2, 9, 16; and 5-FU 2,600 mg/m(2) and leucovorin 300 mg/m(2), 24-hour IVF, on days 2, 9, 16; repeated every 28 days. Results: A total of 97 courses were given with an average of 3.7 courses per patient (range: 1-19). All of the patients were assessable for evaluation of toxicity. Grades 314 leukopenia and thrombocytopenia were noted in 13 (14%) and 17 (18%) of the treatment courses, respectively. There were 3 episodes of febrile neutropenia in 2 patients, and lethal sepsis in one patient. The Grades 3/4 non-hematological toxicities were infrequent. Among 25 patients with recurrent or metastatic disease, 7 had partial response and 12 had stable disease. The response rate for the intent-to treat group was 28% (95% CI:12%- 49%). The median survival was 5 months( range: 1-28 months). Conclusion: Weekly MP-HDFL combination chemotherapy is associated with mild and acceptable toxicity, and has modest palliative activity in a portion of advanced esophageal cancer patients. However, a more active and better tolerated anticancer drug combination is needed to improve the outcome of these patients