Double modulation of 5-fluorouracil with interferon alpha 2a and high-dose leucovorin: a phase I and II study.

Twenty-nine patients with adenocarcinomas of gastrointestinal or unknown primary, and three with advanced neuroendocrine tumours, were entered into a study of bolus plus infusional 5-fluorouracil (FUra) modulated with high-dose leucovorin (LV) and recombinant interferon alpha 2a (IFN-alpha). Successive cohorts of > or = 4 patients received IFN-alpha 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-2 i.v. infusion over 2 h, FUra 400 mg m-2 i.v. bolus then FUra 400 mg m-2 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 > or = 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-alpha was 6 MU on alternate days, with 7/8 patients at 9 MU requiring dose reductions. At 6 MU IFN-alpha, the MTD of FUra was not exceeded at 100% (i.e. 400 mg m-2 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-alpha. The addition of IFN-alpha, 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-alpha to the anti-tumour activity of the combination.