title: Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations.
abstract: 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/m(2) twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m(2) 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/m(2) 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.
authors.affiliation: Yonsei University College of Medicine, Seodaemun-Ku, CPO Box 8044, Seoul, 120-752, Korea.
authors.forename: Hei-Cheul
authors.initials: HC
authors.lastname: Jeung
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Hoon Kyo
authors.initials: HK
authors.lastname: Kim
authors.forename: Ho Young
authors.initials: HY
authors.lastname: Lim
authors.forename: Samyong
authors.initials: S
authors.lastname: Kim
authors.forename: Si Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Gong
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Park
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Noh
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D001830:Body Surface Area; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D004338:Drug Combinations; D004341:Drug Evaluation; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010094:Oxonic Acid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010597:Pharmacogenetics; D011237:Predictive Value of Tests; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016019:Survival Analysis; D005641:Tegafur / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004338:Drug Combinations; D006454:Hemoglobins; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid