title: A pilot study of gamma-1b-interferon in combination with fluorouracil, leucovorin, and alpha-2a-interferon.
abstract: The combination of IFN-alpha-2a (IFN-alpha) and IFN-gamma-1b (IFN-gamma) has been found to produce more than additive cytotoxicity with fluorouracil (5-FU) in HT 29 colon cancer cells due to enhanced DNA-directed effects. We therefore studied the combination of IFN-gamma with IFN-alpha, 5-FU, and leucovorin (LV) in a clinical trial. Fifty-three patients received an initial cycle of 5 million units (MU)/m2 IFN-alpha s.c. on days 1-7 with 500 mg/m2 LV and 370 mg/m2 5-FU i.v. on days 2-6. IFN-gamma was then added once tolerable doses of 5-FU and IFN-alpha were established for each patient. IFN-gamma was administered at one of six dose levels between 0.3-4.8 MU/m2 s.c. on days 1-7. This design permitted comparison of the clinical toxicity and pharmacokinetics of 5-FU in two consecutive cycles in an individual treated with the same doses of 5-FU/LV/IFN-alpha in the absence and presence of IFN-gamma. In 43 matched patient cycles, the addition of IFN-gamma did not seem to worsen gastrointestinal toxicity, and skin toxicity tended to be milder. 5-FU clearance was higher in 14 cycles with IFN-gamma compared to the patient's prior cycle with the same doses of 5-FU/LV/IFN-alpha: 798 +/- 309 versus 601 +/- 250 ml/min/m2 (mean +/- SD; P = 0.04). In these 28 cycles, the median 5-FU clearance was significantly lower in 11 cycles that were complicated by more severe diarrhea: 524 versus 798 ml/min/m2 (grade 2 versus 0-1; P = 0. 0032). Overall, 38% and 26% of patients had grade 3-4 diarrhea and mucositis. Dose reductions of IFN-gamma for chronic fatigue, malaise, or anorexia were ultimately required more frequently with >/=2.4 MU/m2 (P = 0.018), and the maximum tolerated dose of IFN-gamma was considered to be 1.2 MU/m2/ day. Objective responses were seen in 41% of 29 measurable colorectal cancer patients. Compared to our previous experience with 5-FU/LV/IFN-alpha, IFN-gamma and IFN-alpha appeared to have opposite effects on 5-FU clearance. These results suggest that any potential benefit of adding IFN-alpha to 5-FU/LV on this schedule may not depend solely on alterations in 5-FU clearance.
authors.affiliation: Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland 20889, USA. jgremj@helix.nih.gov
authors.forename: J L
authors.initials: JL
authors.lastname: Grem
authors.forename: N
authors.initials: N
authors.lastname: McAtee
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: E
authors.initials: E
authors.lastname: Cullen
authors.forename: A P
authors.initials: AP
authors.lastname: Chen
authors.forename: J M
authors.initials: JM
authors.lastname: Hamilton
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: M
authors.initials: M
authors.lastname: Quinn
authors.forename: J M
authors.initials: JM
authors.lastname: Sorensen
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: D
authors.initials: D
authors.lastname: Lawrence
authors.forename: J
authors.initials: J
authors.lastname: Pang
authors.forename: C J
authors.initials: CJ
authors.lastname: Allegra
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002985:Clinical Protocols; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000009:adverse effects / Q000627:therapeutic use*; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D010865:Pilot Projects; D011994:Recombinant Proteins
chemical_list: D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D007371:Interferon-gamma; D002955:Leucovorin; D005472:Fluorouracil