A pilot study of γ-1b-interferon in combination with fluorouracil, leucovorin, and α-2a-interferon

Jean L. Grem, Nanette McAtee, Robert F. Murphy, Frank M. Balis, Ellen Cullen, Alice P. Chen, J. Michael Hamilton, Seth M. Steinberg, Mary Quinn, J. Mel Sorensen, Susan G. Arbuck, David Lawrence, Janet Pang, Carmen J. Allegra

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 languageEnglish (US)
Pages (from-to)1125-1134
Number of pages10
JournalClinical Cancer Research
Volume3
Issue number7
StatePublished - Jul 1 1997
Externally publishedYes

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Leucovorin
Fluorouracil
Interferons
Diarrhea
Mucositis
Maximum Tolerated Dose
Anorexia
Colonic Neoplasms
Fatigue
Colorectal Neoplasms
Appointments and Schedules

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Grem, J. L., McAtee, N., Murphy, R. F., Balis, F. M., Cullen, E., Chen, A. P., ... Allegra, C. J. (1997). A pilot study of γ-1b-interferon in combination with fluorouracil, leucovorin, and α-2a-interferon. Clinical Cancer Research, 3(7), 1125-1134.

A pilot study of γ-1b-interferon in combination with fluorouracil, leucovorin, and α-2a-interferon. / Grem, Jean L.; McAtee, Nanette; Murphy, Robert F.; Balis, Frank M.; Cullen, Ellen; Chen, Alice P.; Hamilton, J. Michael; Steinberg, Seth M.; Quinn, Mary; Sorensen, J. Mel; Arbuck, Susan G.; Lawrence, David; Pang, Janet; Allegra, Carmen J.

In: Clinical Cancer Research, Vol. 3, No. 7, 01.07.1997, p. 1125-1134.

Research output: Contribution to journalArticle

Grem, JL, McAtee, N, Murphy, RF, Balis, FM, Cullen, E, Chen, AP, Hamilton, JM, Steinberg, SM, Quinn, M, Sorensen, JM, Arbuck, SG, Lawrence, D, Pang, J & Allegra, CJ 1997, 'A pilot study of γ-1b-interferon in combination with fluorouracil, leucovorin, and α-2a-interferon', Clinical Cancer Research, vol. 3, no. 7, pp. 1125-1134.
Grem JL, McAtee N, Murphy RF, Balis FM, Cullen E, Chen AP et al. A pilot study of γ-1b-interferon in combination with fluorouracil, leucovorin, and α-2a-interferon. Clinical Cancer Research. 1997 Jul 1;3(7):1125-1134.
Grem, Jean L. ; McAtee, Nanette ; Murphy, Robert F. ; Balis, Frank M. ; Cullen, Ellen ; Chen, Alice P. ; Hamilton, J. Michael ; Steinberg, Seth M. ; Quinn, Mary ; Sorensen, J. Mel ; Arbuck, Susan G. ; Lawrence, David ; Pang, Janet ; Allegra, Carmen J. / A pilot study of γ-1b-interferon in combination with fluorouracil, leucovorin, and α-2a-interferon. In: Clinical Cancer Research. 1997 ; Vol. 3, No. 7. pp. 1125-1134.
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N2 - 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.

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