The combination of IFN-α-2a (IFN-α) and IFN-γ-1b (IFN-γ) 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-γ with IFN-α, 5-FU, and leucovorin (LV) in a clinical trial. Fifty-three patients received an initial cycle of 5 million units (MU)/m2 IFN-α s.c. on days 1-7 with 500 mg/m2 LV and 370 mg/m2 5- FU i.v. on days 2-6. IFN-γ was then added once tolerable doses of 5-FU and IFN-α were established for each patient. IFN-γ 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-α in the absence and presence of IFN-γ. In 43 matched patient cycles, the addition of IFN-γ did not seem to worsen gastrointestinal toxicity, and skin toxicity tended to be milder. 5-FU clearance was higher in 14 cycles with IFN-γ compared to the patient's prior cycle with the same doses of 5-FU/LV/IFN-α: 798 ± 309 versus 601 ± 2511 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 bad grade 3-4 diarrhea and mucositis. Dose reductions of IFN-γ 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-γ 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-α, IFN-γ and IFN-α appeared to have opposite effects on 5-FU clearance. These results suggest that any potential benefit of adding IFN-α to 5-FU/LV on this schedule may not depend solely on alterations in 5-FU clearance.
|Original language||English (US)|
|Number of pages||10|
|Journal||Clinical Cancer Research|
|State||Published - Jul 1997|
ASJC Scopus subject areas
- Cancer Research