Rapid development of S-1 in the west for therapy of advanced gastric carcinoma.

Therapy for patients with advanced gastric cancer is not satisfactory. The median survival of patients with advanced gastric cancer is approximately 6-9 months and less than 10% of patients survive one year. Despite identification of new classes of agents, such as camptothecins, taxanes, and new platinum analogs, the improvement has been limited and therapy intensive resulting in considerable morbidity. More intensive therapies are challenging not only for the patients and their relatives but also for the health care providers. Oral fluropyrimidines like capecitabine and S-1 have generated considerable interest because of convenience and their activity against gastric carcinoma. S-1 is of significant interest because of many studies in Japan in gastric cancer patients demonstrating its substantial activity as a single agent and in combination with other agents. Furthermore, S-1 represents a fourth generation "designer" drug. It has a component that enhances the cytotoxic activity of tegafur by inhibiting dihydropyrimidine dehydrogenase (DPD) and also has a component that reduces phosphorylation of 5-fluorouracil in the gastrointestinal tract to potentially reduce toxicity. This unique combination is rarely found in an oral agent. In addition, considerable ethnic differences in the tolerated doses of S-1 have been considered related to varying efficiency rates of conversion of tegafur to 5-fluorouracil by the CYP450 enzyme system. The varying efficiency is thought to be due to the presence of certain polymorphisms in the CYP2A6 gene responsible for metabolizing tegafur to 5-fluorouracil. S-1 is under rapid development in the West for gastric carcinoma. Phase I/II studies of the combination of S-1 plus cisplatin have been completed and a global phase III study, accruing rapidly, is comparing S-1 plus cisplatin to 5-fluorouracil plus cisplatin (a reference regimen).