"Yippee!" was the
reaction Bob Kerbel, PhD had to the news that the angiogenesis
inhibitor bevacizumab (Avastin) was proven to extend life
for patients with metastatic colorectal cancer. Professor
Kerbel, who works at Sunnybrook and Women's College Health
Sciences Centre and is a professor at the University of
Toronto, is one of Canada's foremost tumour biologists.
"This is very encouraging,"
he said. "It's the first positive result using
an antiangiogenic drug in phase-III trials." Professor
Kerbel did temper his enthusiasm after his initial outburst.
"It's early days," he said. "This is
just a first step."
The news about the trial was released in the June 3
issue of the New England Journal of Medicine (NEJM).
The trial involved 813 patients who had received no
previous therapy for their colorectal cancer. These
subjects were randomly assigned to receive irinotecan,
bolus fluorouracil, and leucovorin (IFL) chemotherapy
with either bevacizumab or a placebo.
The median duration of survival was 20.3 months in the
group given IFL plus bevacizumab while this number for
the group given placebo was 15.6 months. The difference
might seem small, but it's statistically significant.
"Four and a half months isn't a lot in the larger
scheme, but it's a lot in advanced disease," points
out Professor Kerbel. "Another important factor
is that side effects of the conventional drugs weren't
exacerbated by bevacizumab." The most common side
effect of bevacizumab was hypertension (in 11% of subjects),
which was easily managed. The median duration of progression-free
survival was 10.6 months in the bevacizumab group, as
compared with 6.2 months in the control group -- another
statistically significant result.
Despite the promising results, Professor Kerbel stresses
the need for more investigation: "This was a test
with the most advanced disease and the sickest patients.
Definitive trials can take five to 10 years. The drug
seems safe, but this study lasted only six months whereas
most adjuvant therapies go on for two to three years."
As an accompanying editorial in the NEJM noted,
whether the effect of bevacizumab is attributable to
a direct antiangiogenic mechanism is unclear. Trials
have shown limited benefit of bevacizumab added to fluorouracil
for the initial treatment of colon cancer and a lack
of benefit when added to an oral form of fluorouracil
as second-line therapy for breast cancer. The editorial
points out that the study authors "acknowledge
that bevacizumab may have altered tumour vasculature
and decreased elevated interstitial pressures in tumours,
thereby enhancing the intracellular delivery of chemotherapy
in general and -- possibly -- irinotecan in particular.
Patients need to be informed that bevacizumab does not
cure metastatic colorectal cancer and that there's no
evidence as yet that the antibody has antitumour activity
when administered as a single agent for this disease."
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