Why Not Use Oral S-1 in Colon Cancer?

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


November 03, 2014

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Hi. I am David Kerr, professor of cancer medicine at the University of Oxford. I would like to discuss a paper that appeared in Annals of Oncology,[1] by Dr Yoshida and colleagues from Japan.

This is a large, well-designed randomized trial looking at oral adjuvant chemotherapy for stage III colon cancer. They compared S-1 vs tegafur-uracil plus leucovorin (UFT-leucovorin). S-1 is a fluoropyrimidine combination treatment that has been used widely in Japan to treat several gastrointestinal malignancies. In comparison with the West, where it's more common to use intravenous chemotherapy in an adjuvant setting, in Japan oral chemotherapy is more widely used. There is no doubt that oral chemotherapy offers a relative ease of administration and convenience for patients.

S-1 is a fascinating drug. It's a combination of three active agents: tegafur (which is a prodrug of 5-fluorouracil [5-FU]), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, the key enzyme involved in the degradation of 5-FU), and oteracil, a compound that inhibits the activation of 5-FU in the gastrointestinal tract and has been shown to significantly reduce gastrointestinal toxicity that commonly accompanies 5-FU. It's a thoughtful combination of drugs, and the molar combination is just about right.

UFT-leucovorin has been used in trials in the United States[2,3] and is not inferior to conventional intravenous 5-FU leucovorin.[4] These collaborators randomly assigned 1588 patients with stage III colon cancer to receive S-1 or UFT-leucovorin. S-1 was given in a dose of 80-120 mg daily for 1 month and repeated every 6 weeks for four cycles. UFT-leucovorin was given in conventional doses. The endpoint of the study was 3-year disease-free survival, and they showed no inferiority. The disease-free survival rates were 72.5% for S-1 and 71.2% for UFT-leucovorin (no difference whatsoever). The hazard ratio was 0.89, and the confidence intervals were straddling zero. These findings met the noninferiority rules in the design of the study. These are relatively well-tolerated drugs. The incidence of grade 3/4 toxicity was less than 5% in both arms, apart from diarrhea in 5.5% of the UFT-leucovorin group.

This is an interesting trial. It was well designed, well conducted, and reported very succinctly in Annals of Oncology. It suggests that the interesting drug S-1 could be a new treatment option for adjuvant therapy in colon cancer. It is something to think through. We are struggling a little in the West with moderately toxic chemotherapy, often given in combination. This fluoropyrimidine has now been shown in a large, well-designed randomized study to be as good as UFT-leucovorin, and therefore by extrapolation, as good as conventional western 5-FU/leucovorin regimens.


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