Bioavailability and phase II study of oral UFT plus leucovorin in patientswith relapsed or refractory colorectal cancer

Purpose: This study was undertaken to address the influence of concurrent a dministration on the pharmacokinetics of UFT (uracil plus tegafur) and leuc ovorin (LV), and to measure the antitumor activity of a 28-consecutive-day oral regimen of UFT plus LV in patients with relapsed or refractory colorec tal cancer. Methods: Patients with advanced measurable colorectal cancer wh o had failed previous therapy with intravenous bolus 5-fluorouracil (5-FU) were eligible. Patients were treated with UFT 300 mg/m(2) per day plus LV 9 0 mg per day in three divided doses every 8 h for 28 days, repeated at 35-d ay intervals. In addition, a three-treatment by three-period crossover bioa vailability comparison of oral LV 30 mg plus UFT 200 mg versus either LV or UFT alone was scheduled for the 8 days preceding the first cycle of therap y. Results: Of 19 patients enrolled, 18 were assessable for pharmacokinetic s and response. When LV was coadministered with UFT, there were no statisti cally significant effects on tegafur, uracil, or 5-FU C-max, AUG, or T-max, with the exception of a delayed T-max for tegafur (P = 0.03). No statistic ally significant differences were found in LV and 5-methyltetrahydrofolate plasma levels when LV was administered alone or with UFT. However, wide int erpatient variability was observed for all parameters. There were no antitu mor responses seen. Conclusions: Although the T-max for tegafur is delayed with the concurrent administration of LV, there were no differences (P > 0. 05) in any pharmacologic parameters that are of likely clinical significanc e. However, the great interpatient variability observed in UFT and LV pharm acology may have obscured true bioavailability effects in this small patien t population. Daily oral UFT plus LV is inactive as second-line therapy in patients who have failed bolus 5-FU.