Several trials comparing 5-fluorouracil alone with combinations based on biochemical modulation have indicated better objective tumour response with the combination treatment.

The order of administration of the three agents was chosen to optimally exploit the reported differing mechanisms of biochemical modulation.

Recent attempts to enhance the therapeutic activity of 5-fluorouracil have focused on biochemical modulation: several randomised studies have shown that its effect is greater when used in combination with leucovorin.

Poon MA, O'Connell MJ, Wieand HS, et al.: Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.