Sequential phase II trials of fluorouracil and interferon β(ser) with or without sargramostim in patients with advanced colorectal carcinoma

BACKGROUND: Preclinical and early clinical trials suggested that the biologic agent interferon beta(ser) (IFN β(ser)) may augment the anticancer activity of 5-fluorouracil (5-FU). The current studies were undertaken to explore the optimal schedule of IFN β(ser) and to determine whether the hematopoietic growth factor sargramostim (granulocyte-macrophage colony- stimulating factor) could reduce the hematologic and gastrointestinal toxicities of the chemotherapy. METHODS: Three sequential, single- institution phase II trials using different regimens were initiated. Patients were required to have advanced, histologically documented colorectal carcinoma with no prior chemotherapy; to have adequate bone marrow, renal, and hepatic function; to be fully ambulatory; and to give informed consent. All patients received 5-FU, 750 mg/m² intravenously as an infusion daily for 5 days, followed by 5-FU, 750 mg/m², as an intravenous bolus every week beginning day 15. Patients in arm A received IFN β(ser), 9 MU subcutaneously, three times a week. Patients in arm B received IFN β(ser), 9 MU subcutaneously every day. Patients in arm C were treated exactly as in arm B but also received sargramostim, 250 μg subcutaneously on days they did not receive 5-FU. Beginning day 15, all patients received IFN β(ser) exactly 10 minutes before receiving the 5-FU bolus. RESULTS: There were 81 patients enrolled: 19 in arm A; 40 in arm B; and 22 in arm C. Myelosuppression and diarrhea were the most common toxicities. Increasing the frequency of IFN β(ser) administration in arm B resulted in a doubling of the rate of diarrhea from 11% to 22%, and the addition of sargramostim in arm C failed to reduce this. Sargramostim did reduce the incidence of grade 3 to 4 leukopenia, but this did not allow intensification of dosing or result in improved response or survival among patients in ann C, IFN-mediated fatigue was also common, occurring in 37% to 43% of patients. Patients receiving IFN β(ser) on the intermittent schedule tolerated full-dose therapy longer than those on the daily schedule (10 weeks versus 5 weeks, P < 0.01). The response rates in the three arms were 21%, 35%, and 27%; there was no difference in median survival (15 months for all three arms). CONCLUSIONS: The combination of 5-FU and IFN β(ser) was active in patients with advanced colorectal carcinoma, and survival with this regimen was comparable to or better than that with other modulating regimens. The intermittent schedule of IFN β(ser) was better tolerated than the daily schedule.