A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma

J. L. Grem, N. McAtee, R. F. Murphy, F. M. Balis, S. M. Steinberg, J. M. Hamilton, J. M. Sorensen, O. Sartor, B. S. Kramer, L. J. Goldstein, L. M. Gay, K. M. Caubo, B. Goldspiel, C. J. Allegra

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Abstract

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon α-2a (rIFN α-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN α-2a at 5 x 106 or 10 x 106 U/m2/d on days 1 to 7, or with 3 x 106 U/m2/d on days 1 to 14. In 26 matched cycles, rIFN α-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN α-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 106 U/m2/d rIFN α-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 106 and 5 x 106 U/m2/d rIFN α-2a had acceptable toxicity. Administration of rIFN α-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 106 and 10 x 106 U/m2/d rIFN α-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN α-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 106 U/m2/d dose of rIFN α-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

Original languageEnglish (US)
Pages (from-to)1811-1820
Number of pages10
JournalJournal of Clinical Oncology
Volume9
Issue number10
DOIs
StatePublished - Jan 1 1991

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Leucovorin
Fluorouracil
Interferons
Carcinoma
Mucositis
interferon alfa-2a
Diarrhea
Pharmacokinetics
Granulocytes
Area Under Curve
Gastrointestinal Tract
Adenocarcinoma
Blood Platelets

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. / Grem, J. L.; McAtee, N.; Murphy, R. F.; Balis, F. M.; Steinberg, S. M.; Hamilton, J. M.; Sorensen, J. M.; Sartor, O.; Kramer, B. S.; Goldstein, L. J.; Gay, L. M.; Caubo, K. M.; Goldspiel, B.; Allegra, C. J.

In: Journal of Clinical Oncology, Vol. 9, No. 10, 01.01.1991, p. 1811-1820.

Research output: Contribution to journalArticle

Grem, JL, McAtee, N, Murphy, RF, Balis, FM, Steinberg, SM, Hamilton, JM, Sorensen, JM, Sartor, O, Kramer, BS, Goldstein, LJ, Gay, LM, Caubo, KM, Goldspiel, B & Allegra, CJ 1991, 'A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma', Journal of Clinical Oncology, vol. 9, no. 10, pp. 1811-1820. https://doi.org/10.1200/JCO.1991.9.10.1811
Grem, J. L. ; McAtee, N. ; Murphy, R. F. ; Balis, F. M. ; Steinberg, S. M. ; Hamilton, J. M. ; Sorensen, J. M. ; Sartor, O. ; Kramer, B. S. ; Goldstein, L. J. ; Gay, L. M. ; Caubo, K. M. ; Goldspiel, B. ; Allegra, C. J. / A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. In: Journal of Clinical Oncology. 1991 ; Vol. 9, No. 10. pp. 1811-1820.
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abstract = "Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon α-2a (rIFN α-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN α-2a at 5 x 106 or 10 x 106 U/m2/d on days 1 to 7, or with 3 x 106 U/m2/d on days 1 to 14. In 26 matched cycles, rIFN α-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN α-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 106 U/m2/d rIFN α-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 106 and 5 x 106 U/m2/d rIFN α-2a had acceptable toxicity. Administration of rIFN α-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 106 and 10 x 106 U/m2/d rIFN α-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN α-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6{\%}) and seven partial (31.8{\%}) responses were seen, for an overall response rate of 45.4{\%} (95{\%} confidence interval, 24.4{\%} to 67.8{\%}). Since the 5 x 106 U/m2/d dose of rIFN α-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.",
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AU - Grem, J. L.

AU - McAtee, N.

AU - Murphy, R. F.

AU - Balis, F. M.

AU - Steinberg, S. M.

AU - Hamilton, J. M.

AU - Sorensen, J. M.

AU - Sartor, O.

AU - Kramer, B. S.

AU - Goldstein, L. J.

AU - Gay, L. M.

AU - Caubo, K. M.

AU - Goldspiel, B.

AU - Allegra, C. J.

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N2 - Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon α-2a (rIFN α-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN α-2a at 5 x 106 or 10 x 106 U/m2/d on days 1 to 7, or with 3 x 106 U/m2/d on days 1 to 14. In 26 matched cycles, rIFN α-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN α-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 106 U/m2/d rIFN α-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 106 and 5 x 106 U/m2/d rIFN α-2a had acceptable toxicity. Administration of rIFN α-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 106 and 10 x 106 U/m2/d rIFN α-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN α-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 106 U/m2/d dose of rIFN α-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

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