A phase I trial of 5-fluorouracil, leucovorin, and dipyridamole given by concurrent 120-h continuous infusions.
A phase I trial of 5-fluorouracil (FUra) and leucovorin (LV) given with and without dipyridamole (DP) by concurrent 120-h continuous infusion was performed in 27 patients with advanced solid malignancies, 8 of whom had previously received FUra. The LV and DP doses were fixed at 500 mg/m2 daily and 7.7 mg/kg daily, respectively, whereas the FUra dose was escalated. Level 3 (450 mg/m2 FUra daily) represented the maximum tolerated dose for both FUra/LV+DP and FUra/LV. Dose-limiting stomatitis (greater than or equal to grade 3 or grade 2 occurring during the infusion) was encountered in 75% of the first courses given at level 4 (600 mg/m2 daily). Stomatitis was observed in 44/78 (56%) courses. Diarrhea was infrequent and mild. DP infusions were complicated by mild to moderate headache, which was controlled with narcotic analgesics, and mild to moderate nausea/vomiting. FUra-related toxicity was not enhanced by DP administration. Limited pharmacokinetic sampling at levels 3 and 4 revealed mean steady-state FUra concentrations of around 1.0 microM with infusions of FUra/LV+DP. Among three paired courses given with and without DP, no statistically significant difference was found in the total body clearance of FUra (P = 0.44). One partial response was seen in a patient with metastatic gastric carcinoma. For phase II trials, we recommend that concurrent 120-h continuous infusions of FUra (450 mg/m2 daily) and LV (500 mg/m2 daily) be given with and without DP (7.7 mg/kg daily) every 21 days.
Bailey
H
H
University of Wisconsin Clinical Cancer Center, Madison 53792.
Wilding
G
G
Tutsch
K D
KD
Arzoomanian
R Z
RZ
Alberti
D
D
Tombes
M B
MB
Grem
J L
JL
Spriggs
D R
DR
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004176:Dipyridamole / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013274:Stomach Neoplasms / Q000188:drug therapy; D013280:Stomatitis / Q000139:chemically induced
D004176:Dipyridamole; D002955:Leucovorin; D005472:Fluorouracil