Double modulation of 5-fluorouracil with interferon α2a and high-dose leucovorin: a phase I and II study

Abstract

Sununa"r Twenty-nine patients with adenocarcinomas of gastrointestinal or unknown primarv, and three with advanced neuroendocrine tumours, were entered into a study of bolus plus infusional S-fluorouracil (FUra) modulated with high-dose leucovorin (LV) and recombinant interferon .2a (IFN-a). Successive cohorts of > 4 patients received IFN-a at 1.5. 3, 4.5. 6 and 9 MU on alternate days throughout the treatment period. The FUra LV regimen consisted of: LV 200 mg m i.v. infusion over 2 h. FUra 400 mg m' i.v. bolus then FUra 400 mg m-' i.v. infusion over 22 h, all repeated on day 2, on a 14-day cycle. FUra was given at 75% dose for the first course. increasing (in the absence of WHO grade > 2 toxicity) to 87.5% for the second and 100% for subsequent courses up to a maximum of 12. The maximum tolerated dose (MTD) of IFN-a was 6 MU on alternate days. with 7 8 patients at 9 MU requiring dose reductions. At 6 MU IFN-a. the MTD of FUra was not exceeded at 100% (i.e. 400mg m2 bolus and infusion. days 1 and 2). and FUra-related toxicities (mucosal, haematological, dermatological) were extremely mild. Twenty-nine patients were assessable for tumour response, among whom WHO criteria partial responses were seen in 7 14 with colorectal. 1 4 with gastric. 0 1 with pancreatic. 1 3 with neuroendocrine and 3 '6 with unknown primaries. Median response duration was 51 weeks. Minor responses and stable disease were seen in a further six patients. Median survival of patients with advanced adenocarcinomas was 9 months, with 33% surviving beyond 18 months. This schedule offers a safe way of co-administering FUra. LV and IFN-a. The addition of IFN-z. while causing significant independent toxicity, does not significantly increase the dose-limiting mucosal toxicities of FUra LV. Further investigation is required to determine the contribution of IFN-a to the anti-tumour activity of the combination.

Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

“…In randomized studies the addition of IFNα, at a dose of 5 and 6 MIU on alternate days, to schedules of 5-FU and folinic acid, does not improve responses. This dose and schedule of IFNα, based on phase I studies, adversely effects the quality of life of patients receiving treatment (Seymour et al, 1994a;Wadler et al, 1990a). We attempted to address whether there was biological evidence in vivo for using alternate day schedules of IFNα compared to those with higher and lower doses of interferon administered at different frequencies.…”