International Journal of Clinical Oncology

, Volume 18, Issue 2, pp 335–342 | Cite as

Multicenter phase II study of modified FOLFOX6 as neoadjuvant chemotherapy for patients with unresectable liver-only metastases from colorectal cancer in Japan: ROOF study

  • Takao TakahashiEmail author
  • Yoshihisa Shibata
  • Yuichiro Tojima
  • Kenji Tsuboi
  • Eiji Sakamoto
  • Katsuyuki Kunieda
  • Hiroshi Matsuoka
  • Kazuyoshi Suzumura
  • Mikinori Sato
  • Tatsushi Naganuma
  • Junichi Sakamoto
  • Satoshi Morita
  • Ken Kondo
Original Article



Neoadjuvant chemotherapy for unresectable colorectal liver metastases can reduce tumor size, which sometimes leads to curative resection. The aim of the present study was to identify and describe patients with initially unresectable liver-only metastases from colorectal cancer who obtained sufficient chemotherapeutic benefit that eventually lead to the removal of the metastatic diseases in the liver.


A phase II multicenter cooperative study was conducted in 38 medical institutions using modified FOLFOX6 (mFOLFOX6) as neoadjuvant chemotherapy from January 2008 to June 2009. Patients with liver-only metastases from colorectal cancer that was deemed not optimally resectable by liver surgeons received mFOLFOX6 as preoperative neoadjuvant chemotherapy for 6-8 cycles. Patients were reassessed for resectability after 6 cycles of mFOLFOX6. Surgery was carried out 3-6 weeks after chemotherapy. The primary endpoint was the rate of macroscopic curative surgery including liver resection.


36 patients (23 male/13 female, ECOG performance status 0-1) were enrolled. The median age of the patients was 62.5 years; 78% (28 patients) had 5 or more metastatic tumors, and 50% (18 patients) had metastatic tumors over 5 cm diameter. The mFOLFOX6 regimen was safety administered resulting in 18 partial responses (50%), 12 stable disease, and 4 progressive disease. There was no grade 3/4 neurotoxicity. Fourteen patients (38.9%) underwent surgery (R0: 13; R1: 1). Of these, thirteen patients (36.1%) underwent R0 surgery.


Our data suggest that mFOLFOX6 has a high response rate in patients with liver-only metastases from colorectal cancer, allowing for R0 resection of liver metastases in a proportion of patients initially not judged to be optimally resectable.


ROOF study mFOLFOX6 Colorectal cancer Unresectable liver-only metastases Liver resection 



We thank Mai Hatta for her great help. This work was supported, in part, by a Non Profit Organization Epidemiological & Clinical Research Information Network (ECRIN).

Conflict of interest

No author has any conflict of interest.


  1. 1.
    Finan PJ, Marshall RJ, Cooper EH et al (1985) Factors affecting survival in patients presenting with synchronous hepatic metastases from colorectal cancer: a clinical and computer analysis. Br J Surg 72:373–377PubMedCrossRefGoogle Scholar
  2. 2.
    Goslin R, Steele G, Zamcheck N et al (1982) Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon or rectum. Dis Colon Rectum 25:749–754PubMedCrossRefGoogle Scholar
  3. 3.
    Bengtsson G, Carlsson G, Hafström L et al (1981) Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 141:586–589PubMedCrossRefGoogle Scholar
  4. 4.
    Fong Y, Fortner J, Sun RL et al (1999) Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230:309–318PubMedCrossRefGoogle Scholar
  5. 5.
    Adam R, Delvart V, Pascal G et al (2004) Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 240:644–657PubMedCrossRefGoogle Scholar
  6. 6.
    Adam R, Wicherts DA, de Haas RJ et al (2009) Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 27:1829–1835PubMedCrossRefGoogle Scholar
  7. 7.
    Simmonds PC, Primrose JN, Colquitt JL et al (2006) Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 94:982–999PubMedCrossRefGoogle Scholar
  8. 8.
    Fong Y (1999) Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 49:231–255PubMedCrossRefGoogle Scholar
  9. 9.
    Bismuth H, Adam R, Lëvi F et al (1996) Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509–520PubMedCrossRefGoogle Scholar
  10. 10.
    Alberts SR, Horvath WL, Sternfeld WC et al (2005) Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group Phase II Study. J Clin Oncol 23:9243–9249PubMedCrossRefGoogle Scholar
  11. 11.
    General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus: 7th Edition, 2009: Japanese Society for Cancer of the Colon and RectumGoogle Scholar
  12. 12.
    Adam R, Avisar E, Ariche A et al (2001) Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 8:347–353PubMedCrossRefGoogle Scholar
  13. 13.
    Delaunoit T, Alberts SR, Sargent DJ et al (2005) Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol 16:425–429PubMedCrossRefGoogle Scholar
  14. 14.
    Tournigand C, André T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 15:229–237Google Scholar
  15. 15.
    Falcon A, Ricci S, Brunetti I et al (2007) Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 25:1670–1676CrossRefGoogle Scholar
  16. 16.
    de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947PubMedGoogle Scholar
  17. 17.
    Okines A, del Puerto O, Cunningham D et al (2009) Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO 16966 trial. Br J Cancer 101:1033–1038PubMedCrossRefGoogle Scholar
  18. 18.
    Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417PubMedCrossRefGoogle Scholar
  19. 19.
    Bokemeyer C, Bondarenko I, Makhson A et al (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671PubMedCrossRefGoogle Scholar
  20. 20.
    Folprecht G, Gruenberger T, Bechstein WO et al (2010) Tumour response and secondary respectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomized phase 2 trial. Lancet Oncol 11:38–47PubMedCrossRefGoogle Scholar
  21. 21.
    Folprecht G, Grothey A, Albert S et al (2005) Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumor response and resection rates. Ann Oncol 16:1311–1319PubMedCrossRefGoogle Scholar
  22. 22.
    Vauthey JN, Pawlik TM, Ribero D et al (2006) Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065–2072PubMedCrossRefGoogle Scholar
  23. 23.
    Ribero D, Wang H, Donadon M et al (2007) Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastasis. Cancer 110:2761–2767PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2012

Authors and Affiliations

  • Takao Takahashi
    • 1
    Email author
  • Yoshihisa Shibata
    • 2
  • Yuichiro Tojima
    • 3
  • Kenji Tsuboi
    • 4
  • Eiji Sakamoto
    • 5
  • Katsuyuki Kunieda
    • 6
  • Hiroshi Matsuoka
    • 7
  • Kazuyoshi Suzumura
    • 8
  • Mikinori Sato
    • 9
  • Tatsushi Naganuma
    • 10
  • Junichi Sakamoto
    • 11
  • Satoshi Morita
    • 12
  • Ken Kondo
    • 13
  1. 1.Department of Surgical OncologyGifu University School of MedicineGifuJapan
  2. 2.Department of SurgeryToyohashi Municipal HospitalToyohashiJapan
  3. 3.Department of SurgeryChukyo HospitalNagoyaJapan
  4. 4.Department of SurgeryTosei General HospitalSetoJapan
  5. 5.Department of SurgeryNagoya Daini Red Cross HospitalNagoyaJapan
  6. 6.Department of SurgeryGifu Prefectural General Medical CenterGifuJapan
  7. 7.Department of SurgeryFujita Health UniversityToyoakeJapan
  8. 8.Department of SurgeryAichi Medical UniversityNagakuteJapan
  9. 9.Department of Gastroenterological SurgeryNagoya City University Graduate School of Medical SciencesNagoyaJapan
  10. 10.Department of SurgerySaiseikai Matsusaka General HospitalMatsusakaJapan
  11. 11.Young Leaders’ Program in Healthcare Administration, Department of Social Life ScienceNagoya University, Graduate School of MedicineNagoyaJapan
  12. 12.Department of Biostatistics and EpidemiologyYokohama City University School of Medicine and University Medical CenterYokohamaJapan
  13. 13.Department of SurgeryNagoya Medical CenterNagoyaJapan

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