High-dose bevacizumab improved survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200

Reviewer: Walter Sall, MD
Last Modified: May 15, 2005

Presenter: Bruce Giantonio
Presenter's Affiliation: University of Pennsylvania
Type of Session: Plenary


  • Bevacizumab (BEV) is a recombinant humanized monoclonal antibody which binds VEGF A.  Half life is 17-21 days. 
  • 40-60% of rectal cancers express VEGF and such expression is associated with recurrence and poorer prognosis.
  • A 4.7 month survival benefit has previously been shown by the addition of BEV to IFL chemotherapy in the first line treatment of advanced colorectal cancer.
  • This trial tested the utility of BEV as second line treatment.


Materials and Methods

  • 3 arm, randomized phase III trial of high dose BEV (10mg/kg, biweekly) alone or in combination with standard FOLFOX4 chemotherapy compared to FOLFOX4 alone.
  • Patients must have previously received both a fluoropyrimidine and irinotecan based regimen, either alone or in combination and have ECOG performance status of 0-2.  Prior BEV use was not allowed.
  • Primary endpoint was overall survival (OS).  Secondary endpoints were recurrence rate (RR), progression free survival (PFS), and toxicity.



  • 829 patients accrued from November 2001 April 2003.  Median follow-up is 28 months.  The BEV alone arm was closed in February 2003 because of inferior survival.
  • OS, PFS and RR (response rate) for the BEV + FOLFOX4 arm vs. FOLFOX4 alone were: 12.9 vs. 10.8months (p=0.0018), 7.2 vs 4.8 months (p<0.001) and 21.8% vs. 9.2%, respectively.  In contrast, for the BEV alone arm, OS, PFS and RR were 10.2 months, 2.7 months and 3.0%, respectively.
  • Toxicity:  Slightly increased rates of hypertension, bleeding, and bowel perforation were seen in the BEV containing arms.  10 bleeding events and 3 bowel perforations occurred in the BEV + FOLFOX4 arm vs. 1 and 0 in the FOLFOX4 alone arm, respectively.  FOLFOX4 led to increased rates of neuropathy as well as nausea and vomiting.  There was no statistically significant difference among the arms in terms of thrombotic events.

Author's Conclusions

  • High dose BEV + FOLFOX4 improves OS, PFS and RR compared to FOLFOX4 alone in the second line treatment  of metastatic colorectal cancer after failing irinotecan and fluoropyrimidine based therapies.
  • BEV + FOLFOX4 is well tolerated with slightly increased rates of bleeding events and bowel perforation.
  • BEV alone is not effective in this disease.

Clinical/Scientific Implications

This study demonstrates a new, and more effective strategy for treating advanced colorectal cancer after the failure of standard first line therapies.  This provides another effective treatment choice capable of extending the life of the thousands of people diagnosed with this disease every year.  Further research will help to better define the best means of combining BEV with standard cytotoxic chemotherapy in the treatment of colorectal cancer.

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