Phase I evaluation of therapy with four schedules of 5-fluorouracil by continuous infusion combined with recombinant interferon alpha.

Abstract

The purpose of this study was to determine the maximum tolerated dose and dose-limiting toxicities of 5-fluorouracil (5-FU) when administered concurrently with recombinant IFN-alpha using four continuous infusion (CI) dosing schedules of 5-FU. Forty-five patients with advanced or refractory cancers were treated with 5-FU by CI, plus IFN during the infusion only, by one of four schedules: schedule A: 24-h 5-FU infusion repeated weekly, 9 x 10(6) units IFN x 2 doses weekly; schedule B: 48-h 5-FU infusion repeated weekly, 9 x 10(6) units IFN x 4 doses weekly; schedule C: 5-day 5-FU infusion repeated every 3 weeks, 9 x 10(6) units IFN three times weekly; and schedule D: 21-day 5-FU infusion, repeated after 7 days off therapy, 9 x 10(6) units IFN three times weekly. At least three patients were treated at all dose levels. Doses of 5-FU were escalated to the next level if less than one half of the patients at a given level developed grades 2-4 toxicity. The maximum tolerated dose for 5-FU was 2150 mg/m2/week for schedule A (24-h CI), 2350 mg/m2/week for schedule B (48-h CI), 750 mg/m2/day for schedule C (5-day CI), and 175 mg/m2/day for schedule D (21-day CI). Median delivered dose intensities at these levels were 1788 mg/m2/week for schedule A, 2192 mg/m2/week for schedule B, 1250 mg/m2/week for schedule C, and 593 mg/m2/week for schedule D. The dose-limiting toxicities were hematological and gastrointestinal (stomatitis, diarrhea, nausea, anorexia) for schedules A and B and gastrointestinal (mostly stomatitis) for schedules C and D. Severe fatigue due to IFN was rare. Responses correlated with toxicity >/= grade 2, but not with increased dose intensity. Responses were noted in several tumor types on schedules A, B, and D. 5-FU can be combined with IFN using 24- and 48-h high-dose and long-term low-dose CI schedules, with large differences in dose intensity at maximum tolerated dose. Shorter infusions produce less mucosal and more hematological toxicity. Tumor responses were seen on both short- and long-term CI schedules. Future studies can establish the efficacies of these new schedules of 5-FU/IFN administration in specific tumor types.