Uridine allows dose escalation of 5-fluorouracil when given with N-phosphonacetyl-L-aspartate, methotrexate, and leucovorin

Abstract

Background: In a previous trial in which methotrexate and N-phosphonacetyl-L-aspartate (PALA) were used to modulate 5-fluorouracil (5-FU), four of six patients could not tolerate treatment at the 600 mg/m2 5-FU dose level because of mucositis, diarrhea, and a decrease in performance status. The current study examines the ability of uridine rescue to prevent such toxic effects in the same regimen and, thereby, allow additional dose escalation of 5-FU.

Methods: Twenty-nine patients with advanced malignant neoplasms received PALA and MTX, each at 250 mg/m2, followed 24 hours later by increasing bolus doses of 5-FU (600-750 mg/m2) with a leucovorin rescue (10 mg orally every 6 hours for eight doses) and uridine rescue (3 g/m2/hour, for a 72-hour infusion, 3 hours on, 3 hours off). Treatment was repeated weekly with either 2 weeks on, 2 weeks off, or 3 weeks on, 1 week off.

Results: Mucositis, which occurred in 4 of 12 patients treated at the 750 mg/m2 5-FU dose level, was the only significant chemotherapy-induced toxic effect. However, uridine-related central venous catheter complications (cellulitis in six patients and superior vena cava syndrome in one patient) precluded additional treatment on this protocol.

Conclusions: In the current regimen, uridine allowed dose escalation of 5-FU to 750 mg/m2, which some patients tolerated on a 3-week on, 1-week off schedule. Because of the vascular toxic effects associated with intravenous uridine, the authors recommend additional studies with oral uridine to determine whether the increase in 5-FU dose that uridine allows is associated with improved response rates.