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

Jean 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, Jean 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, Jean 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, Jean 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.

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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.

AB - 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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