A PHASE-I TRIAL OF A MODIFIED, DOSE-INTENSIVE FAMTX REGIMEN (HIGH-DOSE 5-FLUOROURACIL PLUS DOXORUBICIN PLUS HIGH-DOSE METHOTREXATE PLUS LEUCOVORIN) WITH ORAL URIDINE RESCUE
Gk. Schwartz et al., A PHASE-I TRIAL OF A MODIFIED, DOSE-INTENSIVE FAMTX REGIMEN (HIGH-DOSE 5-FLUOROURACIL PLUS DOXORUBICIN PLUS HIGH-DOSE METHOTREXATE PLUS LEUCOVORIN) WITH ORAL URIDINE RESCUE, Cancer, 78(9), 1996, pp. 1988-1995
BACKGROUND. Dose intensification of 5-fluorouracil (5-FU) is complicat
ed by increased toxicity. 5-FU is a fluorine-substituted pyrimidine an
alog of uracil. In preclinical studies, administration of oral uridine
(Ur) has been shown to allow for dose intensification of 5-FU with en
hancement of its antitumor activity. Therefore, a Phase I trial was de
signed aimed at dose intensification of 5-FU as a component of a modif
ied 5-FU-doxorubicin-methotrexate (FAMTX) regimen using oral Ur rescue
. METHODS. Methotrexate (MTX) was administered to all patients at a fi
xed dose of 1.5 g/m(2). MTX was followed 24 hours later by escalating
doses of 5-FU starting at 800 mg/m(2) with leucovorin rescue. Cycles o
f 5-FU and MTX were repeated every 15 days. Every other cycle, patient
s received doxorubicin (''Adria cycles'') at a dose of 30 mg/m(2). Ora
l Ur was administered at a dose of 8 gm/m(2) every 6 hours for 12 dose
s. 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. Witho
ut Ur rescue, the maximum tolerated dose (MTD) of 5-FU was 900 mg/m(2)
on the Adria cycles and 1.1 gm/m(2) on the non-Adria cycles. With Ur,
the MTD of 5-FU increased to 1.2 gm/m(2) on the Adria cycles and to 1
.6 gm/m(2) on the non-Adria cycles. CONCLUSIONS. In this modified FAMT
X 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. (C) 199
6 American Cancer Society.