Jeung Hei-Cheul, Rha Sun Young, Kim Hoon Kyo, Lim Ho Young, Kim Samyong, Kim Si Young, Gong Soo Jeong, Park Chan Hee, Ahn Joong Bae, Noh Sung Hoon, Chung Hyun Cheol
Yonsei University College of Medicine, Seodaemun-Ku, CPO Box 8044, Seoul, 120-752, Korea.
Oncologist. 2007 May;12(5):543-54. doi: 10.1634/theoncologist.12-5-543.
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.
本研究描述了新型口服氟嘧啶S-1在非日本亚洲晚期胃癌患者中的首个II期研究。S-1每6周每日给药2次，持续28天。在第1和第3周期的第28天进行了药代动力学研究。使用基于cDNA微阵列的比较基因组杂交（CGH）方法分析外周单个核细胞的基因组DNA。31例患者最初接受每日2次、每次35 mg/m²（bid）的剂量（第1组）；随后，由于对S-1耐受性良好，方案进行了修订，另外31例患者将剂量增加至每日2次、每次40 mg/m²（第2组）。总缓解率为19.3%（95%置信区间，9.2%-29.5%）。在中位随访期265天内，中位疾病进展时间和总生存时间分别为126天和264天。1年生存率为34%。无4级毒性，主要不良事件为贫血。药代动力学参数与之前日本报告中的参数相似。微阵列CGH鉴定出18个基因的拷贝数发生变化，这些变化与S-1治疗导致的血红蛋白降低相关。一项逻辑回归分析整合了一个临床参数（初始血红蛋白水平）和三个基因拷贝数变异（HIST1H2BL、C10orf127和XPNPEP2），提供了一个预测严重血红蛋白降低发生的模型。总之，本研究表明在胃癌中使用35 mg/m² bid的S-1是可行的。我们认为本研究中鉴定出的药物基因组学标志物可能是预测S-1治疗后贫血的潜在候选标志物。
