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)
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.
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."