Reduction in Gastrointestinal Toxicity by Gastric Secretion Inhibitors during S-1 Monotherapy for Patients with Gastric Cancer

Abstract

The purpose of this study was to retrospectively examine the effect of concomitant administration of gastric secretion inhibitors or gastrectomy on the frequency of gastrointestinal toxicity caused by 5-fluorouracil (5-FU) in gastric cancer patients receiving chemotherapy with S-1. In 62 gastric cancer patients treated with S-1 alone, data relating to the occurrence of gastrointestinal toxicity (diarrhea, vomiting, and nausea) and possible contributing factors were retrospectively collected, and logistic regression analysis was performed. Time-to-event data relating to the occurrence of gastrointestinal toxicity were also collected, and the effect of gastric secretion inhibitors on the time-to-event profiles was examined using a log-rank test. Key words oteracil potassium (Oxo); S-1; gastric secretion inhibitor; gastrectomy; 5-fluorouracil S-1 is an oral anti-cancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium (Oxo).1,2) Five-year follow-up data of a recent phase III study, the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC), confirmed that using S-1 as adjuvant chemotherapy for gastric cancer improves overall survival (OS) and relapse-free survival.3) In the ACTS-GC study, patients who received fewer than the planned number of doses of S-1 because of the development of adverse events had worse outcomes than the patients who did not experience adverse events, 3,4) suggesting that the frequency of adverse events is an important factor in evaluating the efficacy of the drug.S-1 includes Oxo to reduce the gastrointestinal (GI) toxicity associated with 5-fluorouracil (5-FU), which develops as a result of its phosphorylation by orotate phosphoribosyltransferase (OPRT).5) Oxo reduces this cytotoxicity by inhibiting OPRT activity in the stomach and intestine, 6,7) as is demonstrated by the usefulness of Oxo in suppressing vomiting and diarrhea in dogs. 8,9) In human studies, the frequency of GI toxicity was also reduced after treatment with S-1 compared to treatment with 5-FU alone. 10,11)Preclinical and clinical data have also indicated that Oxo is degraded by gastric acid, 6,12) and the area under the serum concentration curve (AUC) of Oxo tended to increase with concomitant administration of proton pump inhibitors.12) The AUC and the maximum serum concentration of Oxo also tend to increase after total gastrectomy. 13) These findings suggest that the serum concentration of Oxo increases with the use of gastric secretion inhibitors or after gastrectomy. However, changes in such efficacy in patients have not been thoroughly examined. The purpose of the present study was to retrospectively examine the effect of concomitant administration of gastric secretion inhibitors or gastrectomy on the frequency of GI toxicity caused by 5-FU in gastric cancer patients receiving S-1 chemotherapy. MATERIALS AND METHODS Collection of Patient DataThis was a retrospective study and data were collected from patients who were treated for gastric cancer with S-1 chemotherapy...