A phase I trial of a modified, dose intensive FAMTX regimen (high dose 5-fluorouracil+doxorubicin+high dose methotrexate+leucovorin) with oral uridine rescue.
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.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
G K
GK
Schwartz
K
K
Christman
L
L
Saltz
E
E
Casper
V
V
Quan
J
J
Bertino
D S
DS
Martin
J
J
Colofiore
D
D
Kelsen
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D014529:Uridine / Q000008:administration & dosage
D000931:Antidotes; D004317:Doxorubicin; D002955:Leucovorin; D005472:Fluorouracil; D014529:Uridine; D008727:Methotrexate