Fluoropyrimidines form the mainstay in treatment of gastrointestinal 
malignancies. For decades 5-fluorouracil (5FU), was the major fluoropyrimidine. 
Currently it is usually given in a combination with leucovorin and oxaliplatin, 
i.e. FOLFOX, or irinotecan, i.e. FOLFIRI, or all three, i.e. FOLFIRINOX, but 
gradually it has been replaced by oral fluoropyrimidine prodrug formulations, 
such as tegafur-uracil and S-1 (both contain ftorafur), and capecitabine 
(Xeloda®). Novel drugs such as the antivascular endothelial growth factor 
antibody, bevacizumab, and the anti-epidermal growth factor receptor antibody, 
cetuximab, are often combined with one of these treatment options. However, when 
resistance emerged, no alternatives were available. TAS-102, a combination of 
trifluorothymidine and the thymidine phosphorylase inhibitor TPI in a 1:0.5 
ratio, is a novel oral formulation, which is active in 5FU-resistant models, 
both in vitro and in xenograft models. In addition to inhibition of thymidylate 
synthase, the major mechanism of action of classical fluoropyrimidines, 
TAS-102's major mechanism of action is incorporation into DNA, thereby causing 
DNA damage. TAS-102 also follows an alternative activation pathway via thymidine 
kinase, and is not a substrate for dihydropyrimidine dehydrogenase. All together 
this explains the efficacy in 5FU-resistant models. In early clinical studies, 
the twice-daily schedule (5 days on, 2 days rest) for 2 weeks every 4 weeks, led 
to a significant disease control rate in various malignancies. This schedule 
showed consistent activity in two randomized trials on fluoropyrimidine 
refractory colorectal cancer patients, reflected by an increase of 2-3 months in 
overall survival in the TAS-102 group compared with placebo. Considering the 
impressive preclinical potential of various combinations TAS-102 has the promise 
to become an alternative for 5FU-resistant cancer.