Skip to main content

Advertisement

SpringerLink
Log in

A phase I study of S-1 treatment with a 3 week schedule in advanced biliary cancer patients with or without hepatic dysfunction

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose A 3 week treatment schedule consisting of 2 weeks of S-1 therapy and 1 week of no therapy was introduced to reduce the toxicity and increase the convenience of combination chemotherapy. Hepatic dysfunction (HD) is common in patients with biliary tract cancer. A phase I study was conducted to assess the effects of a 3 week treatment schedule in Asian patients with or without HD. Methods Forty-six patients were stratified into four groups, according to the HD criteria of the National Cancer Institute Organ Dysfunction Working Group. A three dose escalation schema was used. Results In the normal hepatic function group, two dose-limiting toxicity (DLT) events occurred among 12 patients at the prespecified maximal dose of 100 mg/m2/day. This dose was thereby established as the maximal tolerable dose (MTD). No DLT events were observed at the predefined maximal dose of 80 mg/m2/day in the mild HD group. In the moderate HD group, two DLT events occurred among five patients treated with 80 mg/m2/day, and the MTD was defined as 70 mg/m2/day. Two of six subjects in the severe HD group experienced DLT events at doses of 60 mg/m2/day and none developed DLT events at 50 mg/m2/day. Conclusions The MTDs for a 3 week schedule of S-1 treatment were defined in patients with or without hepatic dysfunction. A 3 week treatment regimen of S-1 might be a platform for combination with newer cytotoxic agents or biologics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Shirasaka T, Shimamato Y, Ohshimo H et al (1996) Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 7:548–557

    Article  CAS  PubMed  Google Scholar 

  2. 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 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 34:1715–1720

    Article  CAS  PubMed  Google Scholar 

  3. Koizumi W, Kurihara M, Nakano S, Hasegawa K (2000) Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology 58:191–197

    Article  CAS  PubMed  Google Scholar 

  4. Inuyama Y, Kida A, Tsukuda M, Kohno N, Satake B (2001) Late phase II study of S-1 in patients with advanced head and neck cancer. Gan To Kagaku Ryoho 28:1381–1390

    CAS  PubMed  Google Scholar 

  5. Ohtsu A, Baba H, Sakata Y et al (2000) Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 83:141–145. doi:10.1054/bjoc.2000.1236

    Article  CAS  PubMed  Google Scholar 

  6. Ichinose Y, Yoshimori K, Sakai H et al (2004) S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: a multi-institutional phase II trial. Clin Cancer Res 10:7860–7864

    Article  CAS  PubMed  Google Scholar 

  7. Okusaka T, Funakoshi A, Furuse J et al (2008) A late phase II study of S-1 for metastatic pancreatic cancer. Cancer Chemother Pharmacol 61:615–621. doi:10.1007/s00280-007-0514-8

    Article  CAS  PubMed  Google Scholar 

  8. Park I, Lee JL, Ryu MH et al (2009) Efficacy and safety of S-1 monotherapy in patients with advanced biliary tract adenocarcinoma: retrospective analysis of 162 patients. Oncology 76:126–132

    Article  CAS  PubMed  Google Scholar 

  9. Furuse J, Okusaka T, Boku N et al (2008) S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study. Cancer Chemother Pharmacol 62:849–855. doi:10.1007/s00280-007-0673-7

    Article  CAS  PubMed  Google Scholar 

  10. Taguchi T, Inuyama Y, Kanamaru R et al (1997) Phase I study of S-1. S-1 Study Group. Gan To Kagaku Ryoho 24:2253–2264

    CAS  PubMed  Google Scholar 

  11. MY HN, Sakata Y (1996) S-1, new oral fluoropyrimidine, is very active in patients with advanced gastric cancer (early phase II study). Proc Am Soc Clin Oncol 15:466

    Google Scholar 

  12. Kimura Y, Kikkawa N, Iijima S et al (2003) A new regimen for S-1 therapy aiming at adverse reaction mitigation and prolonged medication by introducing a 1-week drug-free interval after each 2-week dosing session: efficacy and feasibility in clinical practice. Gastric Cancer 6(Suppl 1):34–39

    Article  PubMed  Google Scholar 

  13. Tsukuda M, Kida A, Fujii M et al (2005) Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer. Br J Cancer 93:884–889. doi:10.1038/sj.bjc.6602804

    Article  CAS  PubMed  Google Scholar 

  14. Ishigami H, Kitayama J, Otani K et al (2009) Phase I pharmacokinetic study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer. Oncology 76:311–314

    Article  CAS  PubMed  Google Scholar 

  15. Lee JL, Kang HJ, Kang YK et al (2008) Phase I/II study of 3-week combination of S-1 and cisplatin chemotherapy for metastatic or recurrent gastric cancer. Cancer Chemother Pharmacol 61:837–845. doi:10.1007/s00280-007-0541-5

    Article  CAS  PubMed  Google Scholar 

  16. 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 59:285–293. doi:10.1007/s00280-006-0265-y

    Article  CAS  PubMed  Google Scholar 

  17. 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 23:6957–6965

    Article  CAS  PubMed  Google Scholar 

  18. 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 9:134–142

    CAS  PubMed  Google Scholar 

  19. Lenz HJ, Lee FC, Haller DG et al (2007) Extended safety and efficacy data on S-1 plus cisplatin in patients with untreated, advanced gastric carcinoma in a multicenter phase II study. Cancer 109:33–40. doi:10.1002/cncr.22329

    Article  CAS  PubMed  Google Scholar 

  20. 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 18:2772–2779

    PubMed  Google Scholar 

  21. Ikeda K, Yoshisue K, Matsushima E et al (2000) Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro. Clin Cancer Res 6:4409–4415

    CAS  PubMed  Google Scholar 

  22. Kajita J, Fuse E, Kuwabara T, Kobayashi H (2003) The contribution of cytochrome P450 to the metabolism of tegafur in human liver. Drug Metab Pharmacokinet 18:303–309

    Article  CAS  PubMed  Google Scholar 

  23. Fleming GF, Schilsky RL, Schumm LP et al (2003) Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction. Ann Oncol 14:1142–1147

    Article  CAS  PubMed  Google Scholar 

  24. Twelves C, Glynne-Jones R, Cassidy J et al (1999) Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 5:1696–1702

    CAS  PubMed  Google Scholar 

  25. Patel H, Egorin MJ, Remick SC et al (2004) Comparison of Child-Pugh (CP) criteria and NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction (HD): implications for chemotherapy dosing. J Clin Oncol (Meeting Abstracts) 22:6051

    Google Scholar 

  26. Ducreux M, Rougier P, Fandi A et al (1998) Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol 9:653–656

    Article  CAS  PubMed  Google Scholar 

  27. Glimelius B, Hoffman K, Sjoden PO et al (1996) Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593–600

    CAS  PubMed  Google Scholar 

  28. Choi CW, Choi IK, Seo JH et al (2000) Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol 23:425–428

    Article  CAS  PubMed  Google Scholar 

  29. Valle JW, Wasan HS, Palmer DD et al (2009) Gemcitabine with or without cisplatin in patients (pts) with advanced or metastatic biliary tract cancer (ABC): results of a multicenter, randomized phase III trial (the UK ABC-02 trial). J Clin Oncol (Meeting Abstracts) 27:4503

    Google Scholar 

  30. Nakeeb A, Pitt HA, Sohn TA et al (1996) Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224:463–473, discussion 473–465

    Article  CAS  PubMed  Google Scholar 

  31. Cohen SJ, Leichman CG, Yeslow G et al (2002) Phase I and pharmacokinetic study of once daily oral administration of S-1 in patients with advanced cancer. Clin Cancer Res 8:2116–2122

    CAS  PubMed  Google Scholar 

  32. Fujita K, Yamamoto W, Endo S et al (2008) CYP2A6 and the plasma level of 5-chloro-2, 4-dihydroxypyridine are determinants of the pharmacokinetic variability of tegafur and 5-fluorouracil, respectively, in Japanese patients with cancer given S-1. Cancer Sci 99:1049–1054

    Article  CAS  PubMed  Google Scholar 

  33. Kim K, Jang GD, Lim HS et al (2009) Pharmacokinetic and pharmacogenetic study of S-1 in Korean patients with metastatic biliary cancer. J Clin Oncol (Meeting Abstracts) 27:2505

    Google Scholar 

  34. Ansfield FJ, Schroeder JM, Curreri AR (1962) Five years clinical experience with 5-fluorouracil. JAMA 181:295–299

    CAS  PubMed  Google Scholar 

  35. Floyd RA, Hornbeck CL, Byfield JE, Griffiths JC, Frankel SS (1982) Clearance of continuously infused 5-fluorouracil in adults having lung or gastrointestinal carcinoma with or without hepatic metastases. Drug Intell Clin Pharm 16:665–667

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This manuscript was presented in part at the 15th Congress of the European Cancer Organisation (ECCO) and the 34th Multidisciplinary Congress of the European Society for Medical Oncology (ESMO) in Berlin, Germany, from September 20 to 24, 2009. This work was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare and Family Affairs, R.O.K. (A030001, A062254) and the Asan Institute for Life Sciences (Seoul, Republic of Korea, 2006–231).

Author information

Authors and Affiliations

  1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Korea

    Dok Hyun Yoon, Yong Sang Hong, Kyu-pyo Kim, Sung Sook Lee, Jae-Lyun Lee, Heung Moon Chang, Min-Hee Ryu, Yoon-Koo Kang, Jung Shin Lee & Tae Won Kim

  2. Department of Pharmacy, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Hyo Jung Lee

Authors
  1. Dok Hyun Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyo Jung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Sang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyu-pyo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sung Sook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jae-Lyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heung Moon Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Min-Hee Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoon-Koo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jung Shin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tae Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae Won Kim.

Additional information

Dok Hyun Yoon and Hyo Jung Lee contributed equally to the work as the first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoon, D.H., Lee, H.J., Hong, Y.S. et al. A phase I study of S-1 treatment with a 3 week schedule in advanced biliary cancer patients with or without hepatic dysfunction. Invest New Drugs 29, 332–339 (2011). https://doi.org/10.1007/s10637-009-9378-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-009-9378-6

Keywords

Search

Navigation