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Sequential Biochemical Modulation of Fluorouracil With Folinic Acid, N-Phosphonacetyl-L-Aspartic Acid, and Interferon Alfa-2a in Advanced Colorectal Cancer

From the Division of Medicine and Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Wichita Community Cancer Oncology Program, Wichita, and Kansas City Community Cancer Oncology Program, Kansas City, KS; The Helen and Harry Gray Cancer Institute at Good Samaritan Medical Center, West Palm Beach, FL; Ozarks Regional Community Cancer Oncology Program, Springfield, MO; and Atlanta Regional Community Cancer Oncology Program, Atlanta, GA.

Address reprint requests to Richard Pazdur, MD, Box 92, Section of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email rpazdur{at}mdanderson.org

PURPOSE: Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFN-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma.

PATIENTS AND METHODS: Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m² followed by 5-FU 425 mg/m² on days 1 to 5; (cycle 2) PALA 250 mg/m² on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m² as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFN-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m² on days 57 to 61, and then weekly bolus of 5-FU 750mg/m²/wk on days 71, 78, and 85. Response was determined after cycle 3.

RESULTS: All patients had a Zubrod performance status 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue.

CONCLUSION: This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA.

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