Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 5, pp 1181–1188 | Cite as

Phase I trial of oral S-1 combined with gemcitabine and cisplatin for advanced biliary tract cancer (KHBO1002)

  • Masashi Kanai
  • Etsuro Hatano
  • Syogo Kobayashi
  • Yutaka Fujiwara
  • Daisuke Sakai
  • Yuzo Kodama
  • Tetsuo Ajiki
  • Hiroaki Nagano
  • Tatsuya Ioka
Original Article

Abstract

Purpose

We aimed to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the addition of S-1, an oral fluorouracil derivative, to gemcitabine and cisplatin combination therapy, which is the current standard treatment for advanced biliary tract cancer.

Methods

Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were eligible for inclusion. The planned dosages of gemcitabine (mg/m2)/cisplatin (mg/m2)/S-1 (mg/m2/day) were as follows: level 0, 800/25/60; level 1, 1,000/25/60; and levels 2 and 3, 1,000/25/80. In each cycle, gemcitabine and cisplatin were intravenously administered on day 1 (or days 1 and 8 at level 3), and S-1 was orally administered twice daily on days 1–7 (or days 1–14 at level 3); this was repeated every 14 days (or 21 days at level 3).

Results

Seventeen patients were enrolled, and level 1 was chosen as the starting dose. Two of six patients developed DLTs (grade 4 neutropenia and grade 3 febrile neutropenia) at level 1, and the dose was escalated to level 2. DLTs (grade 3 rashes and grade 3 vasovagal reactions) occurred in two of six assessable patients at level 2; we then proceeded to level 3. The first three assessable patients enrolled at level 3 developed DLTs (two cases of grade 4 neutropenia, one of grade 4 leucopenia, two of grade 3 fatigue, one of grade 3 anorexia, and one of grade 3 febrile neutropenia) during their first cycle, and this dose was determined to be the MTD. Therefore, we selected level 2 as the recommended dose (RD) for a subsequent phase II study.

Conclusions

We determined the RD of gemcitabine/cisplatin/S-1 combination therapy for advanced biliary tract cancer; we are proceeding to a phase II study to investigate the efficacy of this combination therapy for advanced biliary tract cancer.

Keywords

S-1 Gemcitabine Cisplatin Biliary tract cancer 

References

  1. 1.
    Eckel F, Schmid RM (2007) Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 96:896–902PubMedCrossRefGoogle Scholar
  2. 2.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247PubMedCrossRefGoogle Scholar
  3. 3.
    Furuse J, Okusaka T, Boku N, Ohkawa S, Sawaki A, Masumoto T, Funakoshi A (2008) S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study. Cancer Chemother Pharmacol 62:849–855PubMedCrossRefGoogle Scholar
  4. 4.
    Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, Roka R, Freimann-Pircher S, Gruenberger T (2010) Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 11:1142–1148PubMedCrossRefGoogle Scholar
  5. 5.
    Ichinose Y, Yoshimori K, Sakai H, Nakai Y, Sugiura T, Kawahara M, Niitani H (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 10:7860–7864PubMedCrossRefGoogle Scholar
  6. 6.
    Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, Youssef BM, Klimstra D, Blumgart LH (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234:507–517; discussion 517–519Google Scholar
  7. 7.
    Kanai M, Yoshimura K, Tsumura T, Asada M, Suzuki C, Niimi M, Matsumoto S, Nishimura T, Nitta T, Yasuchika K, Taura K, Mori Y, Hamada A, Inoue N, Tada S, Yanagihara K, Yazumi S, Osaki Y, Chiba T, Ikai I, Fukushima M, Uemoto S, Hatano E (2010) A multi-institution phase II study of gemcitabine/S-1 combination chemotherapy for patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 67:1429–1434PubMedCrossRefGoogle Scholar
  8. 8.
    Kawahara M, Furuse K, Segawa Y, Yoshimori K, Matsui K, Kudoh S, Hasegawa K, Niitani H (2001) Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer. Br J Cancer 85:939–943PubMedCrossRefGoogle Scholar
  9. 9.
    Kiba T, Nishimura T, Matsumoto S, Hatano E, Mori A, Yasumi S, Doi R, Ikai I, Kitano T, Yoshikawa K, Ishiguro H, Yanagihara K, Doi E, Teramukai S, Fukushima M (2006) Single-agent gemcitabine for biliary tract cancers. Study outcomes and systematic review of the literature. Oncology 70:358–365Google Scholar
  10. 10.
    Kim YJ, Im SA, Kim HG, Oh SY, Lee KW, Choi IS, Oh DY, Lee SH, Kim JH, Kim DW, Kim TY, Kim SW, Heo DS, Yoon YB, Bang YJ (2008) A phase II trial of S-1 and cisplatin in patients with metastatic or relapsed biliary tract cancer. Ann Oncol 19:99–103PubMedCrossRefGoogle Scholar
  11. 11.
    Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M (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
  12. 12.
    Leonard GD, O’Reilly EM (2005) Biliary tract cancers: current concepts and controversies. Expert Opin Pharmacother 6:211–223PubMedCrossRefGoogle Scholar
  13. 13.
    Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K (2010) Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol 11:853–860PubMedCrossRefGoogle Scholar
  14. 14.
    Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, Taguchi T (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 83:141–145PubMedCrossRefGoogle Scholar
  15. 15.
    Okusaka T, Funakoshi A, Furuse J, Boku N, Yamao K, Ohkawa S, Saito H (2008) A late phase II study of S-1 for metastatic pancreatic cancer. Cancer Chemother Pharmacol 61:615–621PubMedCrossRefGoogle Scholar
  16. 16.
    Okusaka T, Ishii H, Funakoshi A, Yamao K, Ohkawa S, Saito S, Saito H, Tsuyuguchi T (2006) Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 57:647–653PubMedCrossRefGoogle Scholar
  17. 17.
    Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, Nagino M, Kondo S, Nagaoka S, Funai J, Koshiji M, Nambu Y, Furuse J, Miyazaki M, Nimura Y (2010) Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 103:469–474PubMedCrossRefGoogle Scholar
  18. 18.
    Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Lenauer A, Depisch D, Krauss G, Schneeweiss B, Scheithauer W (2001) Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12:183–186PubMedCrossRefGoogle Scholar
  19. 19.
    Saek T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, Morimoto K, Kimura M, Aoyama H, Ota J, Noguchi S, Taguchi T (2004) A phase II study of S-1 in patients with metastatic breast cancer–a Japanese trial by the S-1 cooperative study group, breast cancer working group. Breast Cancer 11:194–202PubMedCrossRefGoogle Scholar
  20. 20.
    Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820PubMedCrossRefGoogle Scholar
  21. 21.
    Sasaki T, Isayama H, Nakai Y, Ito Y, Kogure H, Togawa O, Toda N, Yasuda I, Hasebe O, Maetani I, Sasahira N, Hirano K, Tsujino T, Tada M, Omata M (2010) Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 65:1101–1107Google Scholar
  22. 22.
    Sasaki T, Isayama H, Nakai Y, Mizuno S, Yamamoto K, Yagioka H, Yashima Y, Kawakubo K, Kogure H, Togawa O, Matsubara S, Ito Y, Sasahira N, Hirano K, Tsujino T, Toda N, Tada M, Omata M, Koike K (2010) Multicenter phase II study of S-1 monotherapy as second-line chemotherapy for advanced biliary tract cancer refractory to gemcitabine. Invest New Drugs [Epub ahead of print]Google Scholar
  23. 23.
    Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C (2004) Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 91:1769–1774PubMedCrossRefGoogle Scholar
  24. 24.
    Vaccaro V, Sperduti I, Milella M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 365:768–769; author reply 769Google Scholar
  25. 25.
    Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281PubMedCrossRefGoogle Scholar
  26. 26.
    Yoshizawa J, Takizawa A, Takeuchi O, Hiraku O, Sasaki K, Morimoto Y, Atsuda K, Inoue G, Suzuki Y, Asanuma F, Yamada Y (2009) Experimental study of combination therapy with S-1 against pancreatic cancer. Cancer Chemother Pharmacol 64:1211–1219PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Masashi Kanai
    • 1
  • Etsuro Hatano
    • 2
  • Syogo Kobayashi
    • 3
  • Yutaka Fujiwara
    • 4
  • Daisuke Sakai
    • 5
  • Yuzo Kodama
    • 6
  • Tetsuo Ajiki
    • 7
  • Hiroaki Nagano
    • 3
  • Tatsuya Ioka
    • 8
  1. 1.Outpatient Oncology UnitKyoto University HospitalKyotoJapan
  2. 2.Department of Surgery, Graduate School of MedicineKyoto University HospitalKyotoJapan
  3. 3.Department of Surgery, Graduate School of MedicineOsaka UniversityOsakaJapan
  4. 4.Department of Medical Oncology and HematologyKobe University Graduate School of MedicineKobeJapan
  5. 5.Department of Frontier Science for Cancer and Chemotherapy, Graduate School of MedicineOsaka UniversityOsakaJapan
  6. 6.Department of Gastroenterology and Hepatology, Graduate School of MedicineKyoto University HospitalKyotoJapan
  7. 7.Department of Surgery, Division of Hepato-Biliary-Pancreatic SurgeryKobe University Graduate School of MedicineKobeJapan
  8. 8.Osaka Medical Center for Cancer and Cardiovascular DiseasesOsakaJapan

Personalised recommendations