Abstract
BACKGROUND
Dose intensification of 5‐fluorouracil (5‐FU) is complicated by increased toxicity. 5‐FU is a fluorine‐substituted pyrimidine analog of uracil. In preclinical studies, administration of oral uridine (Ur) has been shown to allow for dose intensification of 5‐FU with enhancement of its antitumor activity. Therefore, a Phase I trial was designed aimed at dose intensification of 5‐FU as a component of a modified 5‐FU‐doxorubicin‐methotrexate (FAMTX) regimen using oral Ur rescue.
METHODS
Methotrexate (MTX) was administered to all patients at a fixed dose of 1.5 g/m2. MTX was followed 24 hours later by escalating doses of 5‐FU starting at 800 mg/m2 with leucovorin rescue. Cycles of 5‐FU and MTX were repeated every 15 days. Every other cycle, patients received doxorubicin (“Adria cycles”) at a dose of 30 mg/m2. Oral Ur was administered at a dose of 8 gm/m2 every 6 hours for 12 doses. In the first phase of the study, patients received Ur only if they developed Grade 3 or 4 hematologic toxicity. In the second phase, all patients received Ur 24 hours after 5‐FU on all cycles.
RESULTS
Without Ur rescue, the maximum tolerated dose (MTD) of 5‐FU was 900 mg/m2 on the Adria cycles and 1.1 gm/m2 on the non‐Adria cycles. With Ur, the MTD of 5‐FU increased to 1.2 gm/m2 on the Adria cycles and to 1.6 gm/m2 on the non‐Adria cycles.
CONCLUSIONS
In this modified FAMTX regimen, oral Ur administration allowed for dose‐intensification of 5‐FU, with a 33% increase in the MTD of 5‐FU on the Adria cycles and a 45% increase in the MTD of 5‐FU dose on the non‐Adria cycles. Cancer 1997=6;78:1988‐95.