a-Interferon (IFN-ä) enhances the activity of 5-fluorouracil in patients with advanced colorectal carcinoma. Preclinical evidence suggests a similar potential role for IFN-ä combined with cyclophosphamide, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) in advanced adenocarcinoma of the breast. To determine a maximum tolerated dose of IFN-ä that could be combined with CAF and that did not compromise CAF dose intensity and to determine the effect of IFN-ä on the pharmacokinetics of doxorubicin, a phase I study of IFN-ä plus CAF was performed by the Eastern Cooperative Oncology Group. Nine patients with advanced breast cancer received CAF (cyclophosphamide at 100 mg/m2/day p.o. on days 1-14, doxorubicin at 30 mg/m2 and 5-fluorouracil at 500 mg/m2 i.v. bolus on days 1 and 8) plus IFN-ä (1 milliunit/m2, n = 6, or 2 milliunits/m2, n = 3) given s.c. on days 1,3,5, and 8 (1 h prior to the doxorubicin and 5-FU injection on days 1 and 8) of each cycle every 28 or more days. Escalation of the IFN-ä dose occurred in cohorts of 3-6 patients if a dose-limiting toxic event (neutropenic fever, platelet nadir of < 25,000/ul, > 2-week treatment delay, or a <50% dose reduction in day 8 CAF) occurred during the first two cycles in 0 of 3 or 1 of 6 patients. During cycle 1, IFN-ä was omitted on day 1, and multiple plasma samples were drawn on day 1 (without IFN-ä) and day 8 (with IFN-ä) after each doxorubicin injection and were analyzed for plasma doxorubicin concentration. The maximum tolerated dose of IFN-ä by our criteria was 1 milliunit/m2, and neutropenia was the predominant toxic effect that precluded IFN-ä dose escalation. The dose intensity of CAF achieved with IFN-ä was identical to that for CAF alone observed in prior studies. IFN-ä had no significant effect on the pharmacokinetics of doxorubicin, although 3 of 7 patients studied had reduced doxorubicin clearance, ranging from 32% to 69%. Alternative CAF drug delivery schedules (all drugs given i.v. every 3-4 weeks) that are more amenable to hematopoietic growth factor support may be more suitable to combine with higher doses of IFN-ä that may produce modulation.
|Original language||English (US)|
|Number of pages||4|
|State||Published - Aug 1993|
ASJC Scopus subject areas
- Cancer Research