title: A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin in patients with advanced cancer.
abstract: A phase I and pharmacokinetics study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer. Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, and 350 mg/m2 of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at 350 mg/m2 UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously untreated patients, UFT at 350 mg/m2 was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m2) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide interpatient variations. Plasma levels of 5-FU (Cmax 1.4 +/- 1.9 microM) were comparable to those achieved with protracted venous infusions, and folate levels (Cmax 6.1 +/- 3.6 microM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs.
authors.affiliation: Division of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
authors.forename: N J
authors.initials: NJ
authors.lastname: Petrelli
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Bigas
authors.forename: C
authors.initials: C
authors.lastname: Frank
authors.forename: D H
authors.initials: DH
authors.lastname: Ho
authors.forename: M
authors.initials: M
authors.lastname: Kurowski
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D002955:Leucovorin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D005641:Tegafur / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013763:Tetrahydrofolates / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D013763:Tetrahydrofolates; D005641:Tegafur; D014498:Uracil; D002955:Leucovorin; C005984:5-methyltetrahydrofolate