Investigational New Drugs

, Volume 30, Issue 2, pp 758–764 | Cite as

Bevacizumab plus FOLFIRI-3 in chemotherapy-refractory patients with metastatic colorectal cancer in the era of biotherapies



Background: The optimal chemotherapeutic regimen suitable for metastatic colorectal cancer (mCRC) patients previously treated with 5-fluorouracil (5FU), oxaliplatin, irinotecan and biotherapies remains an unresolved issue. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI-3 in mCRC after failure of prior chemotherapy including fluoropyrimidine, irinotecan and oxaliplatin. Methods: Patients were treated with bevacizumab in combination with FOLFIRI-3 every 14 days. The association between treatment efficacy and visceral fat area as measured by CT scan or Carcinoembryonic Antigen (CEA) change after 2 months was also studied. Results: Forty-nine consecutive patients were treated. Four hundred and twenty four cycles of chemotherapy were delivered. Median follow-up was 11 months. Eleven patients (22.4%) had an objective partial response and 26 (53.1%) were stabilized. Median progression-free survival (PFS) and overall survival (OS) were 7 and 13 months respectively. Four grade 4 adverse events occurred (1 digestive perforation, 1 rectal ulcer, 1 pulmonary embolism, and 1 febrile aplasia) but no toxic death was observed. Grade 3 adverse events occurred in 18 patients (38%) including asthenia in 15 patients (30%), nausea and vomiting in 4 patients (8%), diarrhea in 11 patients (22%), anemia in 4 patients (8%), neutropenia in 10 patients (20%) and thrombopenia in 4 patients (8%). Visceral Fat area was significantly lower in responder patients. CEA change at 2 months predicted improved overall survival. Conclusion: This study suggests that bevacizumab combined with FOLFIRI3 may be active in mCRC patients after failure of all classical lines of chemotherapy.


Colorectal cancer Chemotherapy Chemorefractory Metastatic 


  1. 1.
    Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Nordlinger B, Sorbye H, Glimelius B et al (2008) Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 371:1007–1016PubMedCrossRefGoogle Scholar
  3. 3.
    Van den Eynde M, Hendlisz A (2009) Treatment of colorectal liver metastases: a review. Rev Recent Clin Trials 4:56–62PubMedCrossRefGoogle Scholar
  4. 4.
    Douillard JY, Cunningham D, Roth AD et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047PubMedCrossRefGoogle Scholar
  5. 5.
    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 343:905–914PubMedCrossRefGoogle Scholar
  6. 6.
    Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30PubMedCrossRefGoogle Scholar
  7. 7.
    Van Cutsem E, Geboes K (2007) The multidisciplinary management of gastrointestinal cancer. The integration of cytotoxics and biologicals in the treatment of metastatic colorectal cancer. Best Pract Res Clin Gastroenterol 21:1089–1108PubMedCrossRefGoogle Scholar
  8. 8.
    Lenz HJ, Van Cutsem E, Khambata-Ford S et al (2006) Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914–4921PubMedCrossRefGoogle Scholar
  9. 9.
    Folprecht G, Lutz MP, Schoffski P et al (2006) Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 17:450–456PubMedCrossRefGoogle Scholar
  10. 10.
    Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedCrossRefGoogle Scholar
  11. 11.
    Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634PubMedCrossRefGoogle Scholar
  12. 12.
    Grothey A, Sugrue MM, Purdie DM et al (2008) Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 26:5326–5334PubMedCrossRefGoogle Scholar
  13. 13.
    Viel E, Demarchi MF, Chaigneau L et al (2008) A retrospective study of bifractionated CPT-11 with LF5FU infusion (FOLFIRI-3) in colorectal cancer patients pretreated with oxaliplatin and CPT-11 containing chemotherapies. Am J Clin Oncol 31:89–94PubMedCrossRefGoogle Scholar
  14. 14.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–47PubMedCrossRefGoogle Scholar
  15. 15.
    Yoshizumi T, Nakamura T, Yamane M et al (1999) Abdominal fat: standardized technique for measurement at CT. Radiology 211:283–286PubMedGoogle Scholar
  16. 16.
    Guiu B, Petit JM, Bonnetain F et al (2010) Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer. Gut 59:341–347PubMedCrossRefGoogle Scholar
  17. 17.
    Iwanicki-Caron I, Di Fiore F, Roque I et al (2008) Usefulness of the serum carcinoembryonic antigen kinetic for chemotherapy monitoring in patients with unresectable metastasis of colorectal cancer. J Clin Oncol 26:3681–3686PubMedCrossRefGoogle Scholar
  18. 18.
    Kohne CH, Lenz HJ (2009) Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. Oncologist 14:478–488PubMedCrossRefGoogle Scholar
  19. 19.
    Bouche O, Beretta GD, Alfonso PG et al (2010) The role of anti-epidermal growth factor receptor monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer. Cancer Treat Rev 36(Suppl 1):S1–S10Google Scholar
  20. 20.
    Chong G, Dickson JL, Cunningham D et al (2005) Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. Br J Cancer 93:510–514PubMedCrossRefGoogle Scholar
  21. 21.
    Kemeny N, Garay CA, Gurtler J et al (2004) Randomized multicenter phase II trial of bolus plus infusional fluorouracil/leucovorin compared with fluorouracil/leucovorin plus oxaliplatin as third-line treatment of patients with advanced colorectal cancer. J Clin Oncol 22:4753–4761PubMedCrossRefGoogle Scholar
  22. 22.
    Lievre A, Samalin E, Mitry E et al (2009) Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study. BMC Cancer 9:347PubMedCrossRefGoogle Scholar
  23. 23.
    Kang BW, Kim TW, Lee JL et al (2009) Bevacizumab plus FOLFIRI or FOLFOX as third-line or later treatment in patients with metastatic colorectal cancer after failure of 5-fluorouracil, irinotecan, and oxaliplatin: a retrospective analysis. Med Oncol 26:32–37PubMedCrossRefGoogle Scholar
  24. 24.
    Rowland KM, Pitot HC, Sargent DJ, Philip PA, Mitchell EP, Mailliard JA, Goldberg RM, Alberts SR (2005) Results of third line therapy on N9841: a randomized phase III trial of oxaliplatin/5-fluorouracil/leucovorin (FOLFOX4) vs. irinotecan (CPT-11) in patients with advanced colorectal cancer previously treated with prior 5FU chemotherapy. Proc Am Soc Clin Oncol 24:3519, AbstractGoogle Scholar
  25. 25.
    Tournigand C, Andre 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 22:229–237PubMedCrossRefGoogle Scholar
  26. 26.
    Mabro M, Artru P, André T et al (2006) A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. Br J Cancer 94:1287–92PubMedCrossRefGoogle Scholar
  27. 27.
    Bidard FC, Tournigand C, André T et al (2009) Efficacy of FOLFIRI-3 (irinotecan D1, D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study. Ann Oncol 20:1042–7PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Medical OncologyGeorges Francois Leclerc Cancer CenterDijonFrance
  2. 2.Department of GastroenterologyUniversity Hospital DijonDijonFrance
  3. 3.Department of RadiologyUniversity Hospital DijonDijonFrance
  4. 4.Department of Medical OncologyUniversity Hospital AmiensAmiensFrance

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