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Mariela A Blum, Akihiro Suzuki, Takashi Taketa, Jaffer AjaniThe University of Texas, MD Anderson Cancer Center, Division of Gastrointestinal Oncology, Houston, TX, USAAbstract: Gastric cancer is a lethal disease and continues to be the second leading cause of cancer death worldwide. Surgical resection remains the main treatment for early stages with complete resection having the potential for a cure. Recent data suggest that surgery alone is inferior to surgery plus some form of adjunctive therapy. Unfortunately, most patients with gastric cancer are diagnosed in advanced stages, rendering palliative systemic therapy as the only choice of treatment. The most common chemotherapy combination as a first-line treatment in advanced gastric cancer (AGC) includes a platinum compound, a fluoroporyrimidine and a taxane (in the United States) or an antracycline (in Europe). Fluoropyrimidines have been the backbone in the chemotherapy regimens for the treatment of gastric cancer. There has been considerable interest in oral fluoropyrimidines. S-1 is a fourth-generation oral fluoropyrimidine that combines tegafur, which is a prodrug of 5-fluorouracil (5-FU), and two biochemical modulators: (1) 5-chloro-2,4-dihydroxypyridine, a powerful but reversible inhibitor of dihydropyrimidine dehydrogenase that prevents 5-FU degradation, and (2) potassium oxonate, which reduces gastrointestinal (GI) toxicity by inhibition of 5-FU phosphorylation in the GI mucosa. S-1 has produced an advantage in the postoperative setting in a large Phase III trial and has also been evaluated as a preoperative chemotherapy in gastric cancer, but in the preoperative setting, there are no completed Phase III clinical trials. Nonetheless, S-1 is considered, as a single agent, as the standard of care in Japan for the adjuvant treatment of resected gastric cancer and in combination with cisplatin in the advanced setting based on level 1 evidence in Phase III trials. S-1 is now widely available and has been appro