Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa: evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation
| Autor: | Avi I. Einzig, E. L. Schwartz, Peter H. Wiernik, Scott Wadler, Zhihang Lu, R. B. Diasio, Ruiwen Zhang, Joseph A. Sparano |
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| Rok vydání: | 1993 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty medicine.medical_treatment Urology Alpha interferon Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols Mucositis Humans Medicine Drug Interactions Infusions Intravenous Interferon alfa Aged Chemotherapy business.industry Interferon-alpha Middle Aged medicine.disease Treatment Outcome Oncology Fluorouracil Toxicity Conventional PCI Female business Nuclear medicine medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 11:1609-1617 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | PURPOSE To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-alpha) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-alpha on 5-FU pharmacokinetics. PATIENTS AND METHODS Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-alpha, 5 x 10(6) IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-alpha administration using the paired t test. RESULTS The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-alpha 2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-alpha was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-alpha on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-alpha administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1). CONCLUSION IFN-alpha substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-alpha-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-alpha to enhance the toxic effects of 5-FU. |
| Databáze: | OpenAIRE |
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