Skip to main content
SpringerLink
Log in

A Multicenter Phase 2 Trial to Evaluate the Efficacy of mFOLFOX6 + Cetuximab as Induction Chemotherapy to Achieve R0 Surgical Resection for Advanced Colorectal Liver Metastases (NEXTO Trial)

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs.

Methods

In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923).

Results

Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28–not reached). The 3-year OS rate was 59%.

Conclusion

For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.

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
Fig. 3

Similar content being viewed by others

References

  1. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg. 1990;77:1241–6.

    CAS  PubMed  Google Scholar 

  2. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–83.

    PubMed  PubMed Central  Google Scholar 

  3. Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–35.

    PubMed  Google Scholar 

  4. Ashwin K. 360A. Assessment of tumour response and resection rates in unresectable metastatic colorectal liver metastases following cetuximab with neoadjuvant chemotherapy. Eur J Surg Oncol. 2014;40:S139.

  5. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.

    CAS  PubMed  Google Scholar 

  6. Cai S, Zhang W, Li W, et al. 598P cetuximab plus mFOLFOX-6 as first-line therapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases: an open, non-randomized, multicenter phase 2 clinical trial (CLIME study). Ann Oncol. 2014;25(Suppl 4):iv204–iv204.

  7. Folprecht G, Gruenberger T, Bechstein W, et al. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol. 2014;25:1018–25.

    CAS  PubMed  Google Scholar 

  8. Hatano E, Okuno M, Nakamura K, et al. Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-ras status for unresectable colorectal liver metastasis (BECK study). J Hepatobil Pancreat Sci. 2015;22:634–45.

    Google Scholar 

  9. Kohne C, Bokemeyer C, Heeger S, Sartorius U, Rougier P, Cutsem EV. Efficacy of chemotherapy plus cetuximab according to metastatic site in KRAS wild-type metastatic colorectal cancer (mCRC): analysis of CRYSTAL and OPUS studies. J Clin Oncol. 2011;29(15 Suppl):3576–3576.

  10. Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31:1931–8.

    CAS  PubMed  Google Scholar 

  11. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065–75.

    CAS  PubMed  Google Scholar 

  12. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:2240–7.

    CAS  PubMed  Google Scholar 

  13. Lenz H, Niedzwiecki D, Innocenti F, et al. 501 OCALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (MFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with expanded RAS analyses untreated metastatic adenocarcinoma of the colon or rectum (MCRC). Ann Oncol. 2014;25(Suppl 4):mdu438.413-mdu438.413.

  14. Poston G, Adam R, Xu J, et al. The role of cetuximab in converting initially unresectable colorectal cancer liver metastases for resection. Eur J Surg Oncol. 2017;43:2001–11.

    CAS  PubMed  Google Scholar 

  15. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist. 2012;17:1225–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

  17. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13.

    PubMed  PubMed Central  Google Scholar 

  18. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11:38–47.

    CAS  PubMed  Google Scholar 

  19. Jones RP, Vauthey JN, Adam R, et al. Effect of specialist decision-making on treatment strategies for colorectal liver metastases. Br J Surg. 2012;99:1263–9.

    CAS  PubMed  Google Scholar 

  20. Vallance AE, vanderMeulen J, Kuryba A, et al. Impact of hepatobiliary service centralization on treatment and outcomes in patients with colorectal cancer and liver metastases. Br J Surg. 2017;104:918–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Weledji EP. Centralization of liver cancer surgery and impact on multidisciplinary teams working on stage IV colorectal cancer. Oncol Rev. 2017;11:331.

    PubMed  PubMed Central  Google Scholar 

  22. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–9.

    PubMed  Google Scholar 

  23. Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2010;17:2870–6.

    PubMed  Google Scholar 

  24. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006;24:4983–90.

    CAS  PubMed  Google Scholar 

  25. Memeo R, de Blasi V, Adam R, et al. Parenchymal-sparing hepatectomies (PSH) for bilobar colorectal liver metastases are associated with a lower morbidity and similar oncological results: a propensity score-matching analysis. HPB Oxford. 2016;18:781–90.

    PubMed  PubMed Central  Google Scholar 

  26. Gold JS, Are C, Kornprat P, et al. Increased use of parenchymal-sparing surgery for bilateral liver metastases from colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over time in 440 patients. Ann Surg. 2008;247:109–17.

    PubMed  Google Scholar 

  27. Mise Y, Aloia TA, Brudvik KW, Schwarz L, Vauthey JN, Conrad C. Parenchymal-sparing hepatectomy in colorectal liver metastasis improves salvageability and survival. Ann Surg. 2016;263:146–52.

    PubMed  Google Scholar 

  28. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012;307:1383–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014;15:601–11.

    CAS  PubMed  Google Scholar 

  30. Nordlinger B, Poston GJ, Goldberg RM. Should the results of the new EPOC trial change practice in the management of patients with resectable metastatic colorectal cancer confined to the liver? J Clin Oncol. 2015;33:241–3.

    CAS  PubMed  Google Scholar 

  31. Oba M, Hasegawa K, Matsuyama Y, et al. Discrepancy between recurrence-free survival and overall survival in patients with resectable colorectal liver metastases: a potential surrogate endpoint for time to surgical failure. Ann Surg Oncol. 2014;21(6):1817–24.

    PubMed  Google Scholar 

  32. Ji JH, Park SH, Lee J, et al. Prospective phase II study of neoadjuvant FOLFOX6 plus cetuximab in patients with colorectal cancer and unresectable liver-only metastasis. Cancer Chemother Pharmacol. 2013;72(1):223–30.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hepatobiliary Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto City, Japan

    Yoshihiro Mise MD, Akio Saiura MD & Eiji Shinozaki MD

  2. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Kiyoshi Hasegawa MD, Masaru Oba MD, Shuntaro Yoshida MD & Norihiro Kokudo MD

  3. National Defense Medical College, Tokorozawa, Japan

    Junji Yamamoto MD

  4. Asahi General Hospital, Asahi, Japan

    Yukihiro Nomura MD

  5. Nihon University School of Medicine, Itabashi City, Japan

    Tadatoshi Takayama MD

  6. Teikyo University School of Medicine, Itabashi City, Japan

    Yojiro Hashiguchi MD

  7. JCHO Tokyo Yamate Medical Center, Shinjuku City, Japan

    Masayuki Shibasaki MD

  8. Saitama Cancer Center Hospital, Ina, Japan

    Hirohiko Sakamoto MD

  9. JCHO Tokyo Shinjuku Medical Center, Shinjuku City, Japan

    Seiichi Yamagata MD

  10. Kohnodai Hospital, National Center for Global-Health and Medicine, Shinjuku City, Japan

    Nobuyoshi Aoyanagi MD

  11. Toho University Faculty of Medicine, Ota City, Japan

    Hironori Kaneko MD

  12. JCHO Tokyo Takanawa Hospital, Minato City, Japan

    Hiroto Koyama MD

  13. Shinshu University School of Medicine, Nagano, Japan

    Shinichi Miyagawa MD

  14. Colon and Rectal Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Japan

    Hiroaki Nozawa MD

Authors
  1. Yoshihiro Mise MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiyoshi Hasegawa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akio Saiura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaru Oba MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junji Yamamoto MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yukihiro Nomura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tadatoshi Takayama MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yojiro Hashiguchi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masayuki Shibasaki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hirohiko Sakamoto MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seiichi Yamagata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nobuyoshi Aoyanagi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hironori Kaneko MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroto Koyama MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shinichi Miyagawa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eiji Shinozaki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Shuntaro Yoshida MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hiroaki Nozawa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Norihiro Kokudo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kiyoshi Hasegawa MD.

Ethics declarations

Disclosure

Eiji Shinozaki received honoraria from Merck Biopharm for lecture. All other authors declared no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mise, Y., Hasegawa, K., Saiura, A. et al. A Multicenter Phase 2 Trial to Evaluate the Efficacy of mFOLFOX6 + Cetuximab as Induction Chemotherapy to Achieve R0 Surgical Resection for Advanced Colorectal Liver Metastases (NEXTO Trial). Ann Surg Oncol 27, 4188–4195 (2020). https://doi.org/10.1245/s10434-020-08627-y

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-020-08627-y

Search

Navigation