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Phase I-II Study of 5-Fluorouracil, Leucovorin, Doxorubicin, Methotrexate, and Long-Term Oral Etoposide (FLAME) in Unresectable or Metastatic Gastric Cancer

Bjarnason, Georg A. M.D.; Cripps, Christine M.D.; Goel, Rakesh M.D.; Fine, Sheldon M.D.; Oza, Amit M. M.D.; Skillings, Jamey R. M.D.; Kerr, Ian M.D.; Germond, Colin J. M.D.; Moore, Malcolm J. M.D.; Maroun, Jean A. M.D.; Franssen, Edmee M.Sc.; Dulude, Helene Ph.D.

American Journal of Clinical Oncology: December 1998 - Volume 21 - Issue 6 - p 537-542

The objective of this phase I-II study was to determine the efficacy and toxicity of combination chemotherapy with 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and oral etoposide (FLAME) in patients with measurable unresectable or metastatic gastric cancer. Starting doses on the phase I study were as follows: methotrexate 50 mg/m2 intravenous bolus day 1; leucovorin 20 mg/m2 intravenous bolus days 2 through 4, starting 24 hours after the methotrexate dose; 5-fluorouracil 325 mg/m2 intravenous bolus 15 minutes after leucovorin days 2 through 4; doxorubicin 25 mg/m2 intravenous bolus day 8; and oral etoposide 50 mg/day for 14 days, starting on day 8. A new cycle started on day 28. A total of 42 patients were treated-10 patients in the phase I study and 32 patients in the phase II study. Dose-limiting toxicity was encountered in the phase I study on the second escalation step, when doxorubicin was escalated to 30 mg/m2 and 5-fluorouracil was escalated to 350 mg/m2. In the phase II study 28 patients (109 courses) were evaluable for toxicity. Neutropenia grade 3 or more was dose limiting and was documented in 12 patients (43%) during 22 treatment courses (20%). Neutropenia was associated with febrile neutropenia requiring hospitalization in four patients during five courses of therapy. Grade 3 stomatitis and grade 3 diarrhea was infrequent, documented in two patients (two courses) and three patients (four courses), respectively. All other toxicity was grade 1 and grade 2. The combined objective response rate in 38 evaluable patients entered in both studies was 23.3% (six partial responses and one complete response). Stable disease was documented in 15 patients (39.5%). The median survival for the 42 patients entered in both trials was 6.9 months (95% confidence interval, 5.9-8.5 months). The objective response rate and median survival for the combined group is comparable with that reported for the etoposide, leucovorin, and 5-fluorouracil (ELF), and 5-fluorouracil and methotrexate (FMTX) regimens in a recently reported, multicenter, phase III study.

From the Toronto-Sunnybrook Regional Cancer Centre (G.A.B., I.K., E.F.), Toronto, Ontario; The Ottawa Regional Cancer Centre (C.C., R.G., J.A.M.), Ottawa, Ontario; The Credit Valley Hospital (S.F.), Toronto, Ontario; The Princess Margaret Hospital (A.M.O., M.J.M.), Toronto, Ontario; The Nova Scotia Cancer Treatment and Research Foundation (J.R.S.), Halifax, Nova Scotia; The Northeastern Ontario Regional Cancer Centre (C.J.G.), Sudbury, Ontario; and Bristol-Myers Squibb Canada Inc. (H.D.), Montreal, Quebec, Canada.

Supported by a grant from Bristol-Myers Squibb Canada Inc., Montreal, Quebec, Canada.

Address correspondence and reprint requests to Dr. Georg A. Bjarnason, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

© 1998 Lippincott Williams & Wilkins, Inc.