SEQUENTIAL PHASE-II TRIALS OF FLUOROURACIL AND INTERFERON BETA(SER) WITH OR WITHOUT SARGRAMOSTIM IN PATIENTS WITH ADVANCED COLORECTAL-CARCINOMA

BACKGROUND Preclinical and early clinical trials suggested that the bi ologic agent interferon beta(ser) (IFN beta(ser)) may augment the anti cancer activity of 5-fluorouracil (5-FU). The current studies were und ertaken to explore the optimal schedule of IFN beta(ser) and to determ ine whether the hematopoietic growth factor sargramostim (granulocyte- macrophage colony-stimulating factor) could reduce the hematologic and gastrointestinal toxicities of the chemotherapy. METHODS Three sequen tial, single-institution phase II trials using different regimens were initiated. Patients were required to have advanced, histologically do cumented colorectal carcinoma with no prior chemotherapy; to have adeq uate bone marrow, renal, and hepatic function; to be fully ambulatory; and to give informed consent. All patients received 5-FU, 750 mg/m(2) intravenously as an infusion daily for 5 days, followed by 5-FU, 750 mg/m(2), as an intravenous bolus every week beginning day 15. Patients in arm A received IFN beta(ser), 9 MU subcutaneously, three times a w eek Patients in arm B received IFN beta(ser), 9 MU subcutaneously ever y day. Patients in arm C were treated exactly as in arm B but also rec eived sargramostim, 250 mu g subcutaneously on days they did not recei ve 5-FU. Beginning day 15, all patients received IFN beta(ser) exactly 10 minutes before receiving the 5-FU bolus. RESULTS There were 81 pat ients enrolled: 19 in arm A; 40 in arm B; and 22 in arm C. Myelosuppre ssion and diarrhea were the most common toxicities. Increasing the fre quency of IFN beta(ser) administration in arm B resulted in a doubling of the rate of diarrhea from 11% to 22%, and the addition of sargramo stim in arm C failed to reduce this. Sargramostim did reduce the incid ence of grade 3 to 4 leukopenia, but this did not allow intensificatio n of dosing or result in improved response or survival among patients in arm C. IFN-mediated fatigue was also common, occurring in 37% to 43 % of patients. Patients receiving IFN beta(ser) on the intermittent sc hedule tolerated full-dose therapy longer than those on the daily sche dule (10 weeks versus 5 weeks, P < 0.01). The response rates in the th ree arms were 21%, 35%, and 27%; there was no difference in median sur vival (15 months for all three arms). a CONCLUSIONS The combination of 5-FU and IFN beta(ser) was active in patients with advanced colorecta l carcinoma, and survival with this regimen was comparable to or bette r than that with other modulating regimens. The intermittent schedule of IFN beta(ser) was better tolerated than the daily schedule.