A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers

Fifty-two patients with advanced gastrointestinal (GI) malignancies who had not received previous chemotherapy or radiation therapy were randomized to be treated either with 24-hour infusion of weekly fluorouracil (5-FU) or the same plus N-(phosphonacetyl)-L-aspartic acid (PALA). Forty-seven patients were evaluable for the assessment of toxicity and antitumor activity. PALA was administered as an intravenous (IV) bolus over 15 minutes at a fixed dose, 250 mg/m². The latter agent was administered 24 hours before the start of 5-FU infusion. 5-FU was initially administered at 750 mg/m² and was incrementally increased to 3,400 mg/m². In both arms of the randomized study, the courses were repeated every week. In both arms of the study, ataxia and myelosuppression were the dose-limiting toxic effects. At 5-FU dose of 3,400 mg/m², one patient in each arm developed grade 3 hematologic toxicity. Other reversible side effects included grade 2 skin changes, nausea, and vomiting. During the administration of 2,600 mg/m² of 5-FU over 24 hours, the steady state plasma 5-FU concentration was approximately 20 μmol/L. The maximum tolerated dose (MTD) for 5-FU for protracted treatment is 2,600 mg/m² in either arm of the study. Therapeutic response was predominantly seen in the combination arm: there were two patients with complete response (CR) and 11 patients with partial response (PR) of 28 patients in the study. In the 5-FU alone arm there were four PR and 19 patients in the study.