Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 6, pp 1281–1289 | Cite as

A phase II and pharmacokinetic study of first line S-1 for advanced gastric cancer in Taiwan

  • Jen-Shi Chen
  • Yee Chao
  • Ruey-Kuen Hsieh
  • Ann-Lii Cheng
  • Po-Min Chen
  • Tzeon-Jye Chiou
  • Tsu-Yi Chao
  • Kun-Huei Yeh
  • Li-Tzong Chen
  • Jacqueline Whang-Peng
Original Article



To evaluate the efficacy, safety and pharmacokinetic profiles of S-1, which composed of tegafur (FT, a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine and potassium oxonate (Oxo), in Taiwanese advanced gastric cancer (AGC) patients.


Patients with chemo-naïve, histologically confirmed AGC were eligible. S-1 was given orally at dose of 40, 50 or 60 mg, twice daily for patients with body surface <1.25, 1.25–1.5 and >1.5 m2, respectively, on day 1–28 every 42 days/cycle.


Thirty-four patients were included. On intent-to-treat analysis, the overall response rate, median progression-free and overall survival were 35.3% [95% confidence interval (CI): 19.2–51.3%], 2.9 (95% CI: 2.4–5.8) months and 9.8 (95% CI: 6.1–NA) months, respectively. The most common grade 3–4 toxicities were anemia 23.5% and neutropenia 11.8%. There were two treatment-related mortality, which occurred in patients with suboptimal renal function underestimated by serum creatinine level at study entry. Single-dose pharmacokinetic study showed trend toward lower AUC5–FU, and higher AUCFT and AUCOxo comparing to most Western reports.


The efficacy, toxicity and pharmacokinetic profiles of S-1 in current study are compatible with those from other Asian populations. Accurate renal function assessment and more closely monitoring is mandatory for S-1 therapy in patients with low body mass. Literature review suggests that, besides AUC5–FU, AUCOxo may also attribute to the difference in the compliance to S-1 between Asian and Caucasian populations.


Gastric cancer S-1 Chemotherapy Pharmacokinetic study Phase II 



The authors wish to thank the centres and physicians participating in the study: National Taiwan University Hospital (Chih-Hung Hsu, M.D., Ph.D.); Veterans General Hospital, Taipei (Chung-Pin Li, M.D. Ph.D.); Chang-Gung Memorial Hospital, Linkou (Tsai-Shen Yang, M.D.); National Institute of Cancer Research, Tainan (Her-Shyong Shiah, M.D., Jang-Yang Chang, M.D.); Mackay Memorial Hospital, Taipei (Tsang-En Wang, M.D.); Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung (Chang-Ming Jan, M.D.). The study was funded by TTY Biopharm Co., Ltd., Taipei, Taiwan, and Taiho Pharmaceutical Co., Ltd., Tokyo, Japan.

Conflict of interest

Jen-Shi Chen, Yee Chao and Li-Tzong Chen received honoraria from TTY Biopharm Co., Ltd, Taipei, Taiwan. Li-Tzong Chen received research funding from TTY Biopharm Co., Ltd and Taiho Pharmaceutical Co., Ltd, Tokyo, Japan.

Supplementary material

280_2010_1416_MOESM1_ESM.doc (34 kb)
Supplementary material 1 (DOC 33 kb)


  1. 1.
    Garcia M, Jemal A, Ward EM et al (2007) Global cancer facts & figures 2007. American Cancer Society, Atlanta, GAGoogle Scholar
  2. 2.
    Hsu PY (2008) Statistics on causes of death. In: Health statistics in Taiwan 2006 Department of Health, Executive Yuan, R.O.C. (Taiwan), Taipei, pp 12–43Google Scholar
  3. 3.
    Hunahl SA, Menck HR, Mansour EG, Winchester DP (1997) The National Cancer Data Base report on gastric carcinoma. Cancer 80:2333–2341CrossRefGoogle Scholar
  4. 4.
    Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE (2006) Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 24:2903–2909PubMedCrossRefGoogle Scholar
  5. 5.
    Ohtsu A (2005) Current status and future prospects of chemotherapy for metastatic gastric cancer: a review. Gastric Cancer 8:95–102PubMedCrossRefGoogle Scholar
  6. 6.
    Shirasaka T (2009) Development history and concept of an oral anticancer agent S-1 (TS-1). Its clinical usefulness and future vistas. Jpn J Clin Oncol 39:2–15PubMedCrossRefGoogle Scholar
  7. 7.
    Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T (1998) Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1M Tegafur-0.4M Gimestat-1M Otastat Potassium) in advanced gastric cancer patients. Eur J Cancer 34:1715–1720PubMedCrossRefGoogle Scholar
  8. 8.
    Koizumi W, Kurihara M, Nakano S, Hasegawa K (2000) The S-1 Cooperative Gastric Cancer Study Group. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology 58:191–197PubMedCrossRefGoogle Scholar
  9. 9.
    Boku N, Yamamoto S, Fukuda H et al (2009) Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol 10:1063–1069PubMedCrossRefGoogle Scholar
  10. 10.
    Jeung HC, Rha SY, Kim HK et al (2007) Multi-Institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations. Oncologist 12:543–554PubMedCrossRefGoogle Scholar
  11. 11.
    Hirata K, Horikoshi N, Aiba K et al (1999) Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer Res 5:2000–2005PubMedGoogle Scholar
  12. 12.
    Van Groeningen CJ, Peters GJ, Schornagel JH et al (2000) Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin Oncol 18:2772–2779PubMedGoogle Scholar
  13. 13.
    Chu QS, Hammond LA, Schwartz G et al (2004) Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies. Clin Cancer Res 10:4913–4921PubMedCrossRefGoogle Scholar
  14. 14.
    Zhu AX, Clark JW, Ryan DP et al (2007) Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer. Cancer Chemother Pharmacol 59:285–293PubMedCrossRefGoogle Scholar
  15. 15.
    Hoff PM, Saad ED, Ajani JA et al (2003) Phase I study with pharmacokinetics of S-1 on an oral daily schedule for 28 days in patients with solid tumors. Clin Cancer Res 9:134–142PubMedGoogle Scholar
  16. 16.
    Chollet P, Schoffski P, Weigang-Kohler K et al (2003) Phase II trial with S-1 in chemotherapy-naïve patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG). Eur J Cancer 39:1264–1270PubMedCrossRefGoogle Scholar
  17. 17.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  18. 18.
    Simon R (1998) Optimal two-stage design for phase II clinical trials. Control Clin Trials 10:1–10CrossRefGoogle Scholar
  19. 19.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  20. 20.
    Ikeda M, Furukawa H, Imamura H et al (2002) Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor agent in animal model and in patients with impaired renal function. Cancer Chemother Pharmacol 50:25–32PubMedCrossRefGoogle Scholar
  21. 21.
    Peters GJ, Noordhuis P, Van Kuilenburg AB et al (2003) Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2, 4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors. Cancer Chemother Pharmacol 52:1–12PubMedCrossRefGoogle Scholar
  22. 22.
    Koizumi W, Narahara H, Hara T et al (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9:215–221PubMedCrossRefGoogle Scholar
  23. 23.
    Lee JL, Kang YK, Kang HJ et al (2008) A randomized multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. Br J Cancer 99:584–590PubMedCrossRefGoogle Scholar
  24. 24.
    Ajani JA, Faust J, Ikeda K et al (2005) Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 23:6957–6965PubMedCrossRefGoogle Scholar
  25. 25.
    Shirasaka T, Shimamoto Y, Fukushima M (1993) Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53:4004–4009PubMedGoogle Scholar
  26. 26.
    Takechi T, Nakano K, Uchida J et al (1997) Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 39:205–211PubMedCrossRefGoogle Scholar
  27. 27.
    Sakuramoto S, Sasako M, Yamaguhi T et al (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820PubMedCrossRefGoogle Scholar
  28. 28.
    Tsuruoka Y, Kamano T, Kitajima M et al (2006) Effect of gastrectomy on the pharmacokinetics of 5-fluorouracil and gimeracil after oral administration of S-1. Anticancer Drug 17:393–399CrossRefGoogle Scholar
  29. 29.
    Kochi M, Fujii M, Kanamori N et al (2007) Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients. Cancer Chemother Pharmacol 60:693–701PubMedCrossRefGoogle Scholar
  30. 30.
    Kim WY, Nakata B, Hirakawa K (2007) Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and α-fluoro-β-alanine after oral administration of S-1 following total gastrectomy. Cancer Sci 98:1604–1608PubMedCrossRefGoogle Scholar
  31. 31.
    Cunningham D, Starling N, Rao S et al (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46PubMedCrossRefGoogle Scholar
  32. 32.
    Kang YK, Kang WK, Shin DB et al (2009) Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 20:666–673PubMedCrossRefGoogle Scholar
  33. 33.
    Seol YM, Song MK, Choi YJ et al (2009) Oral fluoropyrimidines (capecitabine or S-1) and cisplatin as first-line treatment in elderly patients with advanced gastric cancer: a retrospective study. Jpn J Clin Oncol 39:43–48PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jen-Shi Chen
    • 1
  • Yee Chao
    • 2
  • Ruey-Kuen Hsieh
    • 3
  • Ann-Lii Cheng
    • 4
    • 5
  • Po-Min Chen
    • 6
  • Tzeon-Jye Chiou
    • 6
  • Tsu-Yi Chao
    • 7
  • Kun-Huei Yeh
    • 5
    • 8
  • Li-Tzong Chen
    • 9
    • 10
    • 11
  • Jacqueline Whang-Peng
    • 11
    • 12
  1. 1.Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial HospitalChang Gung UniversityTaoyuan CountyTaiwan
  2. 2.Cancer CenterVeterans General HospitalTaipeiTaiwan
  3. 3.Division of Hematology and Oncology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
  4. 4.Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
  5. 5.Department of OncologyNational Taiwan University HospitalTaipeiTaiwan
  6. 6.Division of Medical-Oncology, Department of Internal MedicineVeterans General HospitalTaipeiTaiwan
  7. 7.Division of Hematology-Oncology, Department of Internal MedicineTri-Service General HospitalTaipeiTaiwan
  8. 8.Department of Internal MedicineFar Eastern Memorial HospitalTaipeiTaiwan
  9. 9.Department of Internal MedicineNational Cheng Kung University HospitalTainanTaiwan
  10. 10.Department of Internal Medicine, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  11. 11.National Institute of Cancer Research, National Health Research InstitutesTainanTaiwan
  12. 12.Cancer Center Wan Fang HospitalTaipei Medical UniversityTaipeiTaiwan, ROC

Personalised recommendations