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Gastrointestinal Cancer

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

^aCancer Metastasis Research Center, ^bBrain Korea 21 Project for Medical Science, and ^cDepartment of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; ^dDepartment of Internal Medicine, St. Vincent's Hospital, The Catholic University, Suwon, Korea; ^eDepartment of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea; ^fDepartment of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea; ^gDepartment of Internal Medicine, Kyunghee University College of Medicine, Seoul, Korea; ^hDepartment of Internal Medicine, Eulji University School of Medicine, Seoul, Korea

Key Words. S-1 • Advanced gastric cancer • Predictive marker • Pharmacokinetics • Pharmacogenomics

Correspondence: Hyun Cheol Chung, M.D., Ph.D., Yonsei Cancer Center, Yonsei University College of Medicine, 134, Shinchon-Dong, Seodaemun-Ku, CPO Box 8044, Seoul, 120-752, Korea. Telephone: 82-2-2228-8041; Fax: 82-2-362-5592; e-mail: unchung8{at}yumc.yonsei.ac.kr

This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarray-based comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m² twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m² bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%–29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m² bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment.

Disclosure of potential conflicts of interest is found at the end of this article.

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