5-Fluorouracil (5FU) with or without folinic acid (LV) in human colorectal cancer? Multivariate meta-analysis of the literature.

This meta-analysis is based on 106 evaluations of response from 77 clinical studies about 5-fluorouracil (5FU) treatment with or without leucovorin (LV) in metastatic colorectal carcinoma. Overall, in naive patients, LV is associated with a median response rate of 31% as compared with a 12% figure with 5FU alone. Using a forward stepwise multilinear regression analysis, it is shown that as much as 44% of the variance in the reported response rates in naive patients can be accounted for by treatment-related variables (P less than 0.001). The significant parameters are LV adjunction (partial R = 0.636), cumulative total 5FU dose (R = 0.344), and 5FU weekly schedule (R = 0.246). In pretreated patients, the latter parameter is the only significant one (R = 0.443). Unexpectedly, LV administration behaves like an all-or-nothing governor, without any obvious dose-effect relationship. Protracted 5FU infusion over weeks allows a mean cumulative drug delivery, 3 times higher than bolus regimens (21.3 vs 7.02 g m-2, P less than 0.001) and may represent the best clinical approach to influence the 5FU-related variables. Accordingly, it is suggested that 5FU protracted infusion, titrated to the highest tolerable doses and potentiated with low doses of leucovorin, could represent the most efficacious way for using 5FU in colorectal disseminated cancer. This hypothesis and its eventual impact on survival should be tested in randomized trials.