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 toxicity. 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 were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with 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 with 5-FU and LV administered without GM-CSF.
Meropol
N J
NJ
Division of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
Rustum
Y M
YM
Creaven
P J
PJ
Blumenson
L E
LE
Frank
C
C
D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control; D015331:Cohort Studies; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D002955:Leucovorin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D012720:Severity of Illness Index; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000139:chemically induced
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002955:Leucovorin; D005472:Fluorouracil