Skip to main content

Advertisement

SpringerLink
Log in

S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102)

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

A Correction to this article was published on 14 November 2017

This article has been updated

Abstract

Background

Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC.

Methods

Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 80 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m2 and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS).

Results

Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval [CI] 8.7–37.9), and the disease control rate was 76.5 % (95 % CI 58.8–89.3). The median PFS was 5.6 months (95 % CI 3.8–7.0). The median overall survival was 16.4 months (95 % CI 8.1–20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred.

Conclusions

The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.

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
Fig. 2

Similar content being viewed by others

Change history

  • 14 November 2017

    In the original publication, in Abstract, the sentence that reads as, “Oral S-1 at a dose of 80 mg/m2 was…………. drug-free interval” should read as, “Oral S-1 at a dose of 40 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval.

References

  1. 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 53:4004–4009

    CAS  PubMed  Google Scholar 

  2. Shirasaka T, Nakano K, Takechi T et al (1996) Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 56:2602–2606

    CAS  PubMed  Google Scholar 

  3. 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 Drug 7:548–557

    Article  CAS  Google Scholar 

  4. Miyamoto Y, Sakamoto Y, Yoshida N et al (2014) Efficacy of S-1 in colorectal cancer. Expert Opin Pharmacother 15:1761–1770

    Article  CAS  PubMed  Google Scholar 

  5. Goto A, Yamada Y, Yasui H et al (2006) Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer. Ann Oncol 17:968–973

    Article  CAS  PubMed  Google Scholar 

  6. Yoshioka T, Kato S, Gamoh M et al (2009) Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer. Br J Cancer 101:1972–1977

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Komatsu Y, Yuki S, Sogabe S et al (2012) Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer. Acta Oncol 51:867–872

    Article  CAS  PubMed  Google Scholar 

  8. Yamada Y, Yamaguchi T, Matsumoto H et al (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 Drug 30:1690–1696

    Article  CAS  Google Scholar 

  9. Muro K, Boku N, Shimada Y et al (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 11:853–860

    Article  CAS  PubMed  Google Scholar 

  10. Schmoll HJ, Van Cutsem E, Stein A et al (2012) ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol 23:2479–2516

    Article  CAS  PubMed  Google Scholar 

  11. Wagner AD, Arnold D, Grothey AA et al (2009) Anti-angiogenic therapies for metastatic colorectal cancer. Cochrane Database Syst Rev. doi:10.1002/14651858

    PubMed  Google Scholar 

  12. Strickler JH, Hurwitz HI (2014) Palliative treatment of metastatic colorectal cancer: what is the optimal approach? Curr Oncol Rep 16:363

    Article  PubMed  Google Scholar 

  13. Welch S, Spithoff K, Rumble RB et al (2010) Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol 21:1152–1162

    Article  CAS  PubMed  Google Scholar 

  14. Baba H, Watanabe M, Okabe H et al (2012) Upregulation of ERCC1 and DPD expressions after oxaliplatin-based first-line chemotherapy for metastatic colorectal cancer. Br J Cancer 107:1950–1955

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Komatsu Y, Yuki S, Sogabe S et al (2011) Phase II study of combined treatment with irinotecan and S-1 (IRIS) in patients with inoperable or recurrent advanced colorectal cancer (HGCSG0302). Oncology 80:70–75

    Article  CAS  PubMed  Google Scholar 

  16. Shiozawa M, Akaike M, Sugano N et al (2010) A phase II study of combination therapy with irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer. Cancer Chemother Pharmacol 66:987–992

    Article  CAS  PubMed  Google Scholar 

  17. Oh SY, Ju YT, Choi SK et al (2011) Phase II study of irinotecan/S-1 combination chemotherapy for patients with oxaliplatin-refractory colorectal cancer. Invest New Drug 29:1050–1056

    Article  CAS  Google Scholar 

  18. Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914

    Article  CAS  PubMed  Google Scholar 

  19. Fuchs CS, Marshall J, Mitchell E et al (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25:4779–4786

    Article  CAS  PubMed  Google Scholar 

  20. Bennouna J, Sastre J, Arnold D et al (2013) Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 14:29–37

    Article  CAS  PubMed  Google Scholar 

  21. Suenaga M, Nishina T, Mizunuma N et al (2015) Multicenter phase II study of FOLFIRI plus bevacizumab after discontinuation of oxaliplatin-based regimen for advanced or recurrent colorectal cancer (CR0802). BMC Cancer 15:176

    Article  PubMed Central  PubMed  Google Scholar 

  22. Tsutsumi S, Ishibashi K, Uchida N et al (2012) Phase II trial of chemotherapy plus bevacizumab as second-line therapy for patients with metastatic colorectal cancer that progressed on bevacizumab with chemotherapy: the Gunma Clinical Oncology Group (GCOG) trial 001 SILK study. Oncology 83:151–157

    Article  CAS  PubMed  Google Scholar 

  23. Bendell JC, Tournigand C, Swieboda-Sadlej A et al (2013) Axitinib or bevacizumab plus FOLFIRI or modified FOLFOX-6 after failure of first-line therapy for metastatic colorectal cancer: a randomized phase II study. Clin Colorectal Cancer 12:239–247

    Article  CAS  PubMed  Google Scholar 

  24. Nakayama G, Uehara K, Ishigure K et al (2012) The efficacy and safety of bevacizumab beyond first progression in patients treated with first-line mFOLFOX6 followed by second-line FOLFIRI in advanced colorectal cancer: a multicenter, single-arm, phase II trial (CCOG-0801). Cancer Chemother Pharmacol 70:575–581

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Iwamoto S, Takahashi T, Tamagawa H et al (2015) FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study. Ann Oncol 26:1427–1433

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Suenaga M, Mizunuma N, Matsusaka S et al (2015) A phase I/II study of biweekly capecitabine and irinotecan plus bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer. Drug Des Devel Ther 9:1653–1662

    Article  PubMed Central  PubMed  Google Scholar 

  27. Kubicka S, Greil R, André T et al (2014) Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first disease progression (PD) in patients with metastatic colorectal cancer (mCRC) previously treated with BEV-based therapy: outcomes according to KRAS status and first-line CT backbone in the ML18147 study. J Clin Oncol 32(suppl 3):S520

    Article  Google Scholar 

  28. Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499–508

    Article  CAS  PubMed  Google Scholar 

  29. Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499–3506

    Article  PubMed  Google Scholar 

  30. Peeters M, Price TJ, Cervantes A et al (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:4706–4713

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all the patients and families who participated in this trial, and we are indebted to the physicians and all of the clinical study teams at the participating institutions. We also thank Ms. Sanae Sakamoto for her excellent secretarial assistance at the data center of Clinical Research Support Center Kyushu.

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Yuji Miyamoto & Hideo Baba

  2. Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Akihito Tsuji

  3. Department of Medical Oncology, Okayama Rousai Hospital, Okayama, Japan

    Hiroaki Tanioka

  4. Department of Surgery, Munakata Medical Association Hospital, Fukuoka, Japan

    Soichiro Maekawa

  5. National Hospital Organization, Beppu Medical Center, Beppu, Japan

    Hirofumi Kawanaka

  6. Clinical Research Institute and Department of Surgery, Oita, Japan

    Hirofumi Kawanaka

  7. Gastroenterological Surgery, Nanpuh Hospital, Kagoshima, Japan

    Masaki Kitazono & Hiroshi Saeki

  8. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Eiji Oki & Yoshihiko Maehara

  9. Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan

    Yasunori Emi

  10. Department of Surgery, Kurume University School of Medicine, Kurume, Japan

    Hidetsugu Murakami & Yoshito Akagi

  11. Department of Surgery, Kurume University Medical Center, Kurume, Japan

    Yutaka Ogata

  12. Department of Cancer Information Research, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Mototsugu Shimokawa

  13. Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Shoji Natsugoe

Authors
  1. Yuji Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akihito Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroaki Tanioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Soichiro Maekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hirofumi Kawanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masaki Kitazono
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eiji Oki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasunori Emi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hidetsugu Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yutaka Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Saeki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mototsugu Shimokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shoji Natsugoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yoshito Akagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hideo Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yoshihiko Maehara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideo Baba.

Ethics declarations

Conflict of interest

Y Miyamoto, H Tanioka, S Maekawa, H Kawanaka, M Kitazono, H Murakami, Y Ogata, H Saeki, M Shimokawa, S Natsugoe and Y Akagi have no conflict of interest. A Tsuji has received honoraria from Taiho Pharmaceutical. E Oki has received fees for promotional materials from Taiho Pharmaceutical, Yakult Honsha, Chugai Pharmaceutical and Merck Serono. Y Emi has received honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical and Yakult Honsha. H Baba has received research funding and honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo. Y Maehara has received research funding and honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha and Daiichi Sankyo.

Additional information

A correction to this article is available online at https://doi.org/10.1007/s10147-017-1212-0.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10147_2015_943_MOESM1_ESM.ppt

Supplementary Fig. 1 Kaplan–Meier survival curve for progression-free survival (A) and overall survival (B) among patients receiving prior chemotherapy with or without bevacizumab. Bmab: bevacizumab (ppt 115 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyamoto, Y., Tsuji, A., Tanioka, H. et al. S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102). Int J Clin Oncol 21, 705–712 (2016). https://doi.org/10.1007/s10147-015-0943-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-015-0943-z

Keywords

Search

Navigation