Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 3, pp 605–614 | Cite as

S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies

  • Satoru Iwasa
  • Kengo Nagashima
  • Tatsuro Yamaguchi
  • Hiroshi Matsumoto
  • Yasushi Ichikawa
  • Ayumu Goto
  • Hisateru Yasui
  • Ken Kato
  • Natsuko Tsuda Okita
  • Yasuhiro Shimada
  • Yasuhide Yamada
Original Article



S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens.


We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX.


Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65 % in SIR/SIRB vs. 52 % in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX.


S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.


Colorectal cancer Irinotecan Phase II Pooled analysis S-1 


Compliance with ethical standards

Ethical standard

This work was supported in part by Taiho Pharmaceutical Co., Ltd. Tatsuro Yamaguchi has received speakers’ bureau from Taiho and Yakult. Yasushi Ichikawa has received research funding from Taiho and Yakult. Ayumu Goto has received honoraria from Taiho. Hisateru Yasui has received honoraria from Taiho and owns stock in Yakult. Yasuhiro Shimada has received honoraria from Taiho and Yakult, and research funding from Taiho and Yakult and has consulting fees from Taiho. Yasuhide Yamada has received honoraria from Taiho and Yakult, and research funding from Taiho and Daiichi-Sankyo. All other authors declare that they have no conflict of interest relevant to this study. All procedures performed in phase II studies were in accordance with the ethical standards of the institutional review board at each participating center and with the 1964 Declaration of Helsinki and Japanese Good Clinical Practice Guidelines.

Informed consent

Written informed consent was obtained from all individual participants included in each phase II study.


  1. 1.
    Punt CJA (2004) New options and old dilemmas in the treatment of patients with advanced colorectal cancer. Ann Oncol 15:1453–1459CrossRefPubMedGoogle Scholar
  2. 2.
    Fuchs CS, Marshall J, Barrueco J (2008) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol 26:689–690CrossRefPubMedGoogle Scholar
  3. 3.
    Borner MM, Schoffski P, de Wit R, Caponigro F, Comella G, Sulkes A, Greim G, Peters GJ, van der Born K, Wanders J, de Boer RF, Martin C, Fumoleau P (2002) Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 38:349–358CrossRefPubMedGoogle Scholar
  4. 4.
    Yamada Y, Hamaguchi T, Goto M, Muro K, Matsumura Y, Shimada Y, Shirao K, Nagayama S (2003) Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil. Br J Cancer 89:816–820PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    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 83:141–145PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Shirao K, Ohtsu A, Takada H, Mitachi Y, Hirakawa K, Horikoshi N, Okamura T, Hirata K, Saitoh S, Isomoto H, Satoh A (2004) Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer 100:2355–2361CrossRefPubMedGoogle Scholar
  7. 7.
    Van den Brande J, Schöffski P, Schellens JH, Roth AD, Duffaud F, Weigang-Köhler K, Reinke F, Wanders J, de Boer RF, Vermorken JB, Fumoleau P (2003) EORTC early clinical studies group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer. Br J Cancer 88:648–653PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    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 11:853–860CrossRefPubMedGoogle Scholar
  9. 9.
    Yamada Y, Yamaguchi T, Matsumoto H, Ichikawa Y, Goto A, Kato K, Hamaguchi T, Shimada Y (2012) Phase II study of oral S-1 with irinotecan and bevacizumab (SIRB) as first-line therapy for patients with metastatic colorectal cancer. Invest New Drugs 30:1690–1696CrossRefPubMedGoogle Scholar
  10. 10.
    Goto A, Yamada Y, Yasui H, Kato K, Hamaguchi T, Muro K, Shimada Y, Shirao K (2006) Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer. Ann Oncol 17:968–973CrossRefPubMedGoogle Scholar
  11. 11.
    Iwasa S, Yamada Y, Kato K, Goto A, Honma Y, Hamaguchi T, Shimada Y (2012) Long-term results of a phase II study of S-1 plus irinotecan in metastatic colorectal cancer. Anticancer Res 32:4157–4161PubMedGoogle Scholar
  12. 12.
    Okita NT, Esaki T, Baba E, Sakai D, Tokunaga S, Takiuchi H, Mizunuma N, Nagashima K, Kato K (2012) A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer. Invest New Drugs 30:2026–2031CrossRefPubMedGoogle Scholar
  13. 13.
    Iwasa S, Shimada Y, Inaba Y, Mera K, Yasui H, Ogata Y, Sugihara K, Arai T, Katsumata K, Ikeda S, Akaike M, Kato T, Hamaguchi T, Kato T (2014) Multicenter phase II study of FOLFOX6 for previously untreated unresectable metastatic colorectal cancer. J Integr Oncol 3:120. doi: 10.4172/2329-6771.1000120 CrossRefGoogle Scholar
  14. 14.
    Schemper M, Smith TL (1996) A note on quantifying follow-up in studies of failure time. Control Clin Trials 17:343–346CrossRefPubMedGoogle Scholar
  15. 15.
    Brookmeyer R, Crowley JJ (1982) A confidence interval for the median survival time. Biometrics 38:29–41CrossRefGoogle Scholar
  16. 16.
    Hosmer DW, Lemeshow S, May S (2008) Applied survival analysis: regression modeling of time to event data. Wiley, HobokenCrossRefGoogle Scholar
  17. 17.
    Grambsch PM, Therneau TM (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 82:515–526CrossRefGoogle Scholar
  18. 18.
    Cain KC, Lange NT (1984) Approximate case influence for the proportional hazards regression model with censored data. Biometrics 40:493–499CrossRefPubMedGoogle Scholar
  19. 19.
    Cook RD (1986) Assessment of local influence. J R Stat Soc Ser B 48:133–169Google Scholar
  20. 20.
    van Buuren S, Boshuizen HC, Knook DL (1999) Multiple imputation of missing blood pressure covariates in survival analysis. Stat Med 18:681–694CrossRefPubMedGoogle Scholar
  21. 21.
    Rubin DB (1987) Multiple imputation for nonresponse in surveys. Wiley, New YorkCrossRefGoogle Scholar
  22. 22.
    Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, Yoshida M, Iwamoto S, Shimada K, Komatsu Y, Sasaki Y, Satoh T, Takahashi K, Mishima H, Muro K, Watanabe M, Sakata Y, Morita S, Shimada Y, Sugihara K (2013) Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 14:1278–1286CrossRefPubMedGoogle Scholar
  23. 23.
    Sloan JA, Goldberg RM, Sargent DJ, Vargas-Chanes D, Nair S, Cha SS, Novotny PJ, Poon MA, O’Connell MJ, Loprinzi CL (2002) Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 20:1491–1498CrossRefPubMedGoogle Scholar
  24. 24.
    Chansky K, Benedetti J, Macdonald JS (2005) Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer 103:1165–1171CrossRefPubMedGoogle Scholar
  25. 25.
    Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, German 5-FU Toxicity Study Group (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26:2131–2138CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Satoru Iwasa
    • 1
  • Kengo Nagashima
    • 2
  • Tatsuro Yamaguchi
    • 3
  • Hiroshi Matsumoto
    • 3
  • Yasushi Ichikawa
    • 4
  • Ayumu Goto
    • 4
  • Hisateru Yasui
    • 5
  • Ken Kato
    • 1
  • Natsuko Tsuda Okita
    • 1
  • Yasuhiro Shimada
    • 1
  • Yasuhide Yamada
    • 1
  1. 1.Gastrointestinal Medical Oncology DivisionNational Cancer Center HospitalTokyoJapan
  2. 2.Clinical Research CenterChiba University HospitalChibaJapan
  3. 3.Department of SurgeryTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  4. 4.Department of Clinical OncologyYokohama City University Graduate School of MedicineYokohamaJapan
  5. 5.Medical Oncology DivisionKyoto Medical CenterKyotoJapan

Personalised recommendations