Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations

Hei Cheul Jeung, SunYoung Rha, Kyo Kim Hoon, Young Lim Ho, Samyong Kim, Young Kim Si, Jeong Gong Soo, Hee Park Chan, Bae Ahn Joong, Hoon Noh Sung, Hyuncheol Chung

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)543-554
Number of pages12
JournalOncologist
Volume12
Issue number5
DOIs
Publication statusPublished - 2007 Nov 1

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Pharmacogenetics
Stomach Neoplasms
Hemoglobins
Comparative Genomic Hybridization
Pharmacokinetics
Anemia
Gene Dosage
Feasibility Studies
Oligonucleotide Array Sequence Analysis
Survival Rate
Logistic Models
Regression Analysis
Confidence Intervals
Survival
DNA
Therapeutics
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Jeung, Hei Cheul ; Rha, SunYoung ; Hoon, Kyo Kim ; Ho, Young Lim ; Kim, Samyong ; Si, Young Kim ; Soo, Jeong Gong ; Chan, Hee Park ; Joong, Bae Ahn ; Sung, Hoon Noh ; Chung, Hyuncheol. / Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations. In: Oncologist. 2007 ; Vol. 12, No. 5. pp. 543-554.
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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.",
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Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations. / Jeung, Hei Cheul; Rha, SunYoung; Hoon, Kyo Kim; Ho, Young Lim; Kim, Samyong; Si, Young Kim; Soo, Jeong Gong; Chan, Hee Park; Joong, Bae Ahn; Sung, Hoon Noh; Chung, Hyuncheol.

In: Oncologist, Vol. 12, No. 5, 01.11.2007, p. 543-554.

Research output: Contribution to journalArticle

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AU - Jeung, Hei Cheul

AU - Rha, SunYoung

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AU - Ho, Young Lim

AU - Kim, Samyong

AU - Si, Young Kim

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AU - Chan, Hee Park

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AU - Sung, Hoon Noh

AU - Chung, Hyuncheol

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N2 - 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.

AB - 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.

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