Failure of high-dose leucovorin to improve therapy with the maximally tolerated dose of 5-fluorouracil: a murine study with clinical relevance?
Almost all of the completed and ongoing phase III trials of the leucovorin/5-fluorouracil (LV/5-FU) combination have used either a single-agent 5-FU control arm in which the 5-FU was administered in a different schedule from the LV/5-FU arm or one in which the 5-FU was not at the maximally tolerated dose (MTD). Because both dose intensity and scheduling are known to affect drug activity, the LV/5-FU combination was evaluated in the preclinical CD8F1 murine model of advanced first-passage spontaneous breast tumors using the same dose (at MTD) and schedule for 5-FU alone and in the LV/5-FU combination arm. Overall, therapy with 5-FU at MTD was not improved by LV. Further, although the activity of 5-FU doses lower than the MTD could be increased by LV, the therapeutic result was comparable to that of single-agent 5-FU at MTD. In an evaluation with other modulators of 5-FU (e.g., uridine, PALA, methotrexate), therapy with various modulated 5-FU combinations at their MTD was not improved with LV. In conclusion, although LV can enhance the cytotoxicity of 5-FU in these in vivo preclinical studies, it does not confer enhanced selectivity to 5-FU, a conclusion at odds with many present clinical reports. Whether or not these murine findings have clinical relevance can be determined only by clinical trials designed with the MTD of 5-FU alone in the control arm, the MTD of 5-FU (or as close as tolerated) in the LV/5-FU arm, and identical schedules in both arms.
Martin
D S
DS
Department of Surgery, Catholic Medical Center, New York, NY.
Stolfi
R L
RL
Colofiore
J R
JR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D002955:Leucovorin / Q000008:administration & dosage*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014529:Uridine / Q000008:administration & dosage
D002955:Leucovorin; D005472:Fluorouracil; D014529:Uridine