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The role of UFT in metastatic colorectal cancer.5-Fluorouracil (5-FU) has been the most widely used chemotherapeutic agent for metastatic colorectal cancer (mCRC) and 5-FU combination therapy improves efficacy compared with monotherapy. The oral fluoropyrimidine UFT (tegafur-uracil) with leucovorin (LV) improves tolerability and has replaced 5-FU in many regimens. The efficacy and tolerability of UFT with LV in the first-line treatment of mCRC has been demonstrated in a number of phase II studies. In two phase III studies, UFT with LV has been shown to have comparable efficacy and improved tolerability versus intravenous bolus 5-FU, with very few cases of hand-foot syndrome (HFS). Indirect comparisons of UFT and capecitabine suggest that they are comparable in terms of survival. In first-line treatment, UFT in combination with oxaliplatin (TEGAFOX) or irinotecan (TEGAFIRI) is effective and well tolerated, with similar efficacy and tolerability to the corresponding 5-FU- and capecitabine-based combinations, but with a lower incidence of HFS. Alternating cycles of TEGAFOX and TEGAFIRI are effective and well tolerated, and the combination of TEGAFIRI and the targeted monoclonal antibody cetuximab has shown promising activity, similar to that of FOLFIRI plus cetuximab. UFT can be considered a rational replacement for intravenous 5-FU in the first- and second-line treatment of patients with mCRC.