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

Jean L. Grem, Nanette McAtee, Robert F. Murphy, Frank M. Balis, Seth M. Steinberg, J. Michael Hamilton, J. Mel Sorensen, Oliver Sartor, Barnett S. Kramer, Lori J. Goldstein, Laura M. Gay, Kathleen M. Caubo, Barry Goldspiel, Carmen J. Allegra

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112 Scopus citations


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 (rlFN 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 × 106 or 10 × 106 U/m2/d on days 1 to 7, or with 3 × 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. Doselimiting 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 × 106 U/m2/d rIFN α-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 × 106 and 5 × 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 × 106 and 10 × 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 × 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
Issue number10
StatePublished - Oct 1991
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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