This multicentre open label randomised phase clinical trial

Leucovorin enhances the efficacy of fluorouracil by stabilising the ternary complex formed between fluorodeoxyuridine monophosphate (FdUMP) and thymidylate synthase. Findings of a meta-analysis7 including more than 3000 patients with colorectal cancer showed that leucovorin significantly increased the proportion of patients with a response and overall survival when combined with infusional fluorouracil. In clinical trials of oral fluoropyrimidines combined with leucovorin, uracil and tegafur plus leucovorin was shown to be non-inferior to Hexanoylcarnitine fluorouracil plus leucovorin in patients with metastatic colorectal cancer,8 and 9 whereas adding leucovorin to capecitabine provided little additional benefit despite more adverse events.10 In view of the fact that the anti-tumour effects and toxic effects of fluoropyrimidines plus leucovorin are time dependent, various treatment schedules of S-1 plus leucovorin have been investigated in several phase 1 and 2 studies.11, 12, 13 and 14 The addition of leucovorin to S-1 in a 2-week schedule (1-week on followed by 1-week off) increases the anti-tumour activity of S-1, while toxic effects remained within a manageable range.12 and 13 Therefore, bronchi schedule was regarded as the optimum platform for the development of further combination regimens.