FOLFOX4 + Avastin Ups Survival in Colorectal Ca

ORLANDO-Adding high-dose bevacizumab (Avastin) to FOLFOX4 improves overall survival, progression-free survival (PFS), and response in previously treated patients who have advanced colorectal cancer, Bruce J. Giantonio, MD, reported at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 2). Dr. Giantonio, of the University of Pennsylvania, presented results of the Eastern Cooperative Oncology Group (ECOG) E3200 study.

At a median follow-up of 28 months, the median overall survival for patients treated with FOLFOX4 plus bevacizumab was 12.9 months vs 10.8 months for FOLFOX4 alone (P = .0018; hazard ratio [HR] for death, 0.76). The median overall survival for patients treated with bevacizumab alone was 10.2 months, Dr. Giantonio said. FOLFOX4 plus bevacizumab also significantly increased PFS (7.2 months vs 4.8 months; P < .0001; HR for disease progression, 0.64). The median PFS with bevacizumab alone was 2.7 months. RECIST criteria showed 21.8% complete responses with the combination vs 9.2% with FOLFOX4 alone and 3% with bevacizumab alone.

E3200 was a randomized, phase III trial of high-dose bevacizumab 10 mg/kg IV biweekly, either alone or in combination with FOLFOX4. This FOLFOX regimen includes biweekly oxaliplatin (Eloxatin) 85 mg/m² on day 1; leucovorin 200 mg/m² IV for 2 hours; and fluorouracil 400 mg/m² IV bolus followed by 600 mg/m² by continuous IV infusion for 22 hours on days 1 and 2. The combination was compared with FOLFOX4 alone and initially also with bevacizumab alone in 829 patients randomized among the three arms.

The rationale for testing bevacizumab in this combination is that the humanized monoclonal antibody inhibits angiogenesis by binding vascular endothelial growth factor (VEGF) and has improved survival when combined with chemotherapy for advanced colorectal cancer in previous studies.

Prior treatment with a fluoropyrimidine and an irinotecan (Camptosar)-based regimen used either alone or in combination was required for eligibility in the trial. Prior oxaliplatin or bevacizumab use was not allowed.

Interestingly, bevacizumab appears to be relatively inactive as a single agent in this previously treated population. In February 2003, the ECOG Data Monitoring Committee recommended closing the bevacizumab-alone arm because survival in that arm was nearing a predetermined boundary suggesting inferiority when compared with the chemotherapy-containing arms.

Adverse Events

The adverse effects of most concern were hypertension, peripheral neuropathy, and hemorrhage (see Table on page 2). Dr. Giantonio suggested that the increased rates of grade 3-4 sensory neuropathy seen in the bevacizumab arms might be a function of increased time on treatment for these patients. "Sensory neuropathy is a known adverse effect of oxaliplatin, the incidence and severity of which increase with the drug's use," he said. Patients receiving FOLFOX4 plus bevacizumab had a median duration of therapy of 10 cycles vs 7 cycles for those on the FOLFOX4 arm and 4 cycles for those on the bevacizumab arm. Hypertension has been previously associated with bevacizumab use, and Dr. Giantonio noted that this association also was demonstrated in E3200.

Although bleeding was infrequent, a statistically significant difference in bleeding events was also noted for patients who received FOLFOX4 plus bevacizumab. There were 10 bleeding events in patients on that arm of the study, 9 of which were grade 3. These events included eight cases of gastrointestinal bleeding, one case of bleeding from a biliary tube where there was noted to be tumor with erosion into a portal vein, and one case of bleeding following surgery that required a transfusion.

Dr. Giantonio concluded, "Bevacizumab at 10 mg/kg in combination with FOLFOX4 improved overall survival, progression-free survival, and response for previously treated patients with advanced colorectal cancer. Bevacizumab and FOLFOX4 were well tolerated."