Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: A potential role for growth factor as mucosal protectant

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxi city. This study was conducted to determine the maximum tolerated dose (MTD ) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients w ere treated with intravenous LV 500 mg/m(2) plus 5-FU weekly for siv doses followed hy a 2-week rest. GM-CSF 250 mg/m(2) was administered subcutaneous ly 5 days each week. Cohorts were treated with 5-FU at 600, 700 and 800 mg/ m(2) weekly. Twenty-nine patients were treated. The MTD of 5-FU in this sch edule was 700 mg/m(2)/week, with diarrhea dose-limiting. 5-FU delivered dos e intensity at the MTD was 424 +/- 23.7 mg/m(2)/week, including rest period s. 5-FU and LV pharmacokinetics were not altered by concurrent treatment wi th GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5- FU and 5-FU delivered dose Intensity were higher than previously reported w ith 5-FU and LV administered without GM-CSF.