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

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.