Clinical trial of weekly intensive therapy with 5-fluorouracil on two different schedules combined with interferon alpha-2a and filgrastim in patients with advanced solid tumors: Eastern Cooperative Oncology Group Study P-Z991.

PURPOSE: The hematopoietic growth factor filgrastim has been shown to reduce both chemotherapy-induced myelosuppression and mucosal toxicities. The aim of this study was to conduct four separate pilot trials to determine the maximum-tolerated doses at which interferon alpha (IFN alpha) followed by 5-fluorouracil (5-FU) could be administered in combination with filgrastim support.

PATIENTS AND

METHODS

Patients were required to have a histologically documented solid tumor with either measurable or evaluable lesions. All patients were fully ambulatory; had adequate bone marrow, renal, and hepatic function; had recovered from surgery; and gave informed consent. Trials were conducted sequentially. In parts A and B, patients received 5-FU as a continuous intravenous infusion daily for 5 days, followed by weekly bolus therapy at the same dose. In parts C and D, patients received 5-FU as a weekly high-dose, 24-hour infusion. Interferon was administered immediately before the 5-FU three times a week. Filgrastim was administered at 5 micrograms/kg subcutaneously either four (parts A, B) or five (parts C, D) times a week. In part A, the starting doses were as follows: 5-FU, 750 mg/m2, and IFN alpha, 3 MU subcutaneously, and the IFN alpha was escalated between patient cohorts to a maximum of 9 MU. Part B used the dose of IFN alpha established from part A, and the 5-FU was escalated to the maximum-tolerated dose between patient cohorts. In part C, the starting dose of IFN alpha was 3 MU subcutaneously, and that of 5-FU, 2.6 g/m2, and the dose of IFN alpha was escalated to a maximum of 9 MU. In part D, the dose of IFN alpha was determined from part C, and the dose of 5-FU was escalated. The maximum tolerated dose was the highest dose at which three of three or five of six patients were able to tolerate therapy.

RESULTS

There were 71 patients entered into the four parts of this trial. In part A (12 patients), the dose of IFN alpha, was escalated to 9 MU subcutaneously three times a week with only one patient experiencing dose-limiting toxicity. In part B (13 patients), the dose of 5-FU could not be escalated beyond 750 mg/m2 because of sepsis (one patient) and gastrointestinal hemorrhage (one patient). The predominant toxicities were diarrhea (46%), vomiting (23%), and mucositis (31%). In part C (24 patients), two patients experienced dose-limiting toxicities (staphylococcal sepsis [one patient] and neuropsychiatric [one patient]). The dose of IFN alpha was escalated to 9 MU. In part D (21 patients), the dose of 5-FU was escalated to 3.4 g/m2 administered weekly. No patients at this dose level experienced serious toxicities. At the next highest dose level, 3.6 g/m2, one patient each experienced gastrointestinal hemorrhage and diarrhea. There were no additive constitutional symptoms resulting from the combination of IFN alpha and filgrastim. In parts C and D, filgrastim could be administered 6 hours after the end of the 5-FU infusion without excessive myelosuppression.

CONCLUSIONS

The addition of filgrastim allowed escalation of the dose of 5-FU on the weekly, high-dose schedule, but not on the weekly bolus schedule. IFN alpha and filgrastim can be administered without additive toxicities. Filgrastim can be safely administered < 24 hours after completion of the weekly, high dose 5-FU infusion.