Chemotherapy for metastatic gastric cancer: past, present, and future.

Despite the numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Two triplet regimens have already demonstrated significant survival prolongation in Western studies. However, the benefit seems to be marginal, and these regimens may be replaced by recently published newer generation regimens for which favorable survival is reported. At present, the combination of 5-fluorouracil (5-FU) and platinum analog is still the most widely accepted standard regimen worldwide: 5-FU can be replaced by S-1 or capecitabine, and cisplatin by oxaliplatin. In Japan, S-1 plus cisplatin is the most reasonable first-line standard, based on recent randomized studies. Some early clinical studies using molecular targeting agents have shown promising activity, particularly in combination with cytotoxic agents for gastric cancer. Several targeting agents such as trastuzumab, bevacizumab, and lapatinib are now under investigation in international randomized studies, including in Japan. These agents have shown a survival benefit in other tumor types. The next-generation targeting agents, including mammalian target of rapamycin inhibitor and a c-Met tyrosine kinase inhibitor, are also being evaluated in early clinical studies in association with biology research. Such agents can be advantageously used in gastric cancer studies, which, because of the ease with which tumor tissues can be obtained by endoscopy and the high incidence of gastric cancer in Japan, might advance the frontiers of biologic therapy. These efforts should result not only in further clinical advances but also in tailored medicine.