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| Editor’s Note |
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| Leaps of faith |
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National Cancer Institute News Release
November 29, 2004
“Preliminary results from a large, randomized
clinical trial for patients with advanced colorectal
cancer who had previously received treatment show that
those who received bevacizumab (Avastin™) in
combination with an oxaliplatin (Eloxatin™) regimen
known as FOLFOX4 lived longer than patients who received
FOLFOX4 alone.
“The Data Monitoring Committee overseeing the
trial (known as E3200) recommended that the results
of a recent interim analysis be made public because
the study had met its primary endpoint of demonstrating
improved overall survival. Researchers found that the
patients in the trial who received bevacizumab in combination
with FOLFOX4 (a regimen of oxaliplatin, 5-fluorouracil
and leucovorin) had a median overall survival of 12.5
months compared to patients treated with FOLFOX4 alone,
who had a median overall survival of 10.7 months. This
difference is statistically significant and corresponds
to a 17 percent improvement in median overall survival.
There was a 26 percent reduction in the risk of death
(hazard ratio of 0.74) for patients in this study who
received bevacizumab plus FOLFOX4 compared to those
who received FOLFOX4 alone.
“The clinical trial was sponsored by the National
Cancer Institute (NCI)...
“A total of 829 patients were enrolled in the
study between October 2001 and April 2003. Patients
previously had received a fluorouracil-based therapy
and irinotecan (Camptosar®), either alone or at
the same time, for advanced disease or if their disease
had relapsed within six months of concluding adjuvant
(postsurgical) treatment with these chemotherapy agents.
Patients were randomized to one of three treatment
groups. One patient group received the standard FOLFOX4
treatment plus bevacizumab. The second group received
the standard FOLFOX4 treatment only, and the third
group received bevacizumab alone. ...
“Treatment toxicities observed in this study
were consistent with those side effects observed in
other clinical trials in which bevacizumab was combined
with chemotherapy. Side effects included neuropathy
(problems with nerve function) for FOLFOX4 and high
blood pressure and bleeding for bevacizumab. ... “ ‘These
results are simply more good news for people with colorectal
cancer,’ said Study Chair Bruce J Giantonio,
MD, of the University of Pennsylvania’s Abramson
Cancer Center in Philadelphia. ‘We now know that
bevacizumab added to second-line chemotherapy with
FOLFOX4 improves survival. With these findings, we
can now more confidently expect survival for people
with advanced disease to be more than double what it
was just a few years ago. ...’
“ ‘The results of this study are very
important for all those living with advanced colorectal
cancer,’ said NCI Director Andrew C von Eschenbach,
MD. ‘They provide further confirmation that a
biologic agent that targets a tumor’s blood supply
can prolong survival when combined with chemotherapy,
even for patients who have previously received therapy
for advanced disease.’ ” |
When Herb Hurwitz first electrified a 2003 ASCO audience
with results from a trial evaluating IFL with or without
bevacizumab, my first thought was, “Now what are people
going to use for first-line metastatic disease?” The
obvious dilemma that had instantly been dropped on the table
was that since the initial launch of the IFL-bev study, oxaliplatin-containing
regimens had taken over as the preferred first-line therapy
for people with metastases. Would docs make a leap of faith
and assume that bevacizumab results in similar synergy with
FOLFOX, and use that combination up front? What would the
FDA do?
At the same time, researchers like Lee Ellis were gaining
support for their postulations of novel and somewhat counterintuitive
hypothetical mechanisms of action of bevacizumab. Lee and
others have speculated that rather than the Folkman-like
concept of cutting off tumor blood supply, bevacizumab actually
normalizes intratumoral blood vessel architecture, allowing
greater permeability for chemotherapy.
However, it was not known whether all chemo agents would
be associated with a similar synergy. A key related factor
was the convincing data that bevacizumab also added benefit
to 5-FU/leucovorin without oxaliplatin.
The FDA took the lead by approving bevacizumab for use
with any 5-FU combination, and many or most clinicians and
researchers seemed to quickly conclude that FOLFOX plus bevacizumab
was optimal first-line therapy. In this issue of Colorectal
Cancer Update, John Marshall notes that this involved
two leaps of faith — going from bolus 5-FU in the IFL
regimen to infusional 5-FU in FOLFOX, and going from irinotecan
to oxaliplatin. After more than a year of waiting, E3200
seemed to justify this practice pattern.
Other “leaps of faith” in systemic therapy for
colorectal cancer are being considered more conservatively.
Many of these involve the use of capecitabine instead of
5-FU. All three research leaders interviewed for this issue
comment on the common clinical scenarios in which this substitution
is considered: preoperative chemoradiation for rectal cancer,
adjuvant therapy alone or with oxaliplatin, and first-line
metastatic disease for which the potential synergy of capecitabine
with bevacizumab is not clearly defined.
In our recent special edition “Think Tank” for
this series, Herb Hurwitz made an interesting comment about
the use of therapies without clear-cut supportive research
data, specifically referring to the use of FOLFOX/bevacizumab
at that time. He noted that the existence of a clinical trial
containing such a therapy in a randomization arm might justify
the use of that regimen in a nonprotocol setting until the
definitive results of the study became available.
For more than a year, many clinicians and patients have
essentially followed that path by selecting FOLFOX/bevacizumab
as first-line therapy for metastatic disease. These actions
have now been justified by yet another trial that has moved
the field forward.
— Neil Love, MD
NLove@ResearchToPractice.net
Select publications
Fernando NH et al. A phase II study of oxaliplatin,
capecitabine and bevacizumab in the treatment of metastatic
colorectal cancer. Proc ASCO GI Cancer Symposium 2005;Abstract
289.
Fernando NH, Hurwitz HI. Targeted therapy of colorectal
cancer: Clinical experience with bevacizumab. Oncologist 2004;9(Suppl
1):11-8. Abstract
Giantonio B et al. High-dose bevacizumab in combination
with FOLFOX4 improves survival in patients with previously
treated advanced colorectal cancer: Results from the Eastern
Cooperative Oncology Group (ECOG) study E3200. Proc
ASCO GI Cancer Symposium 2005;Abstract 169a.
Hochster HS et al. Bevacizumab (B) with oxaliplatin
(O)-based chemotherapy in the firstline therapy of metastatic
colorectal cancer (mCRC): Preliminary results of the randomized “TREE-2” trial. Proc
ASCO GI Cancer Symposium 2005;Abstract
241.
Hurwitz H et al. Bevacizumab (a monoclonal antibody
to vascular endothelial growth factor) prolongs survival
in first-line colorectal cancer (CRC): Results of a phase
III trial of bevacizumab in combination with bolus IFL
(irinotecan, 5-fluorouracil, leucovorin) as first-line
therapy in subjects with metastatic CRC. Proc
ASCO 2003;Abstract
3646.
Hurwitz H et al. Bevacizumab plus irinotecan, fluorouracil,
and leucovorin for metastatic colorectal cancer. N
Engl J Med 2004;350(23):2335-42. Abstract
Kabbinavar F et al. Phase II, randomized trial
comparing bevacizumab plus fluorouracil (FU)/ leucovorin
(LV) with FU/LV alone in patients with metastatic colorectal
cancer. J Clin Oncol 2003;21(1):60-5.
Abstract
Saltz LB et al. Interim report of randomized phase
II trial of cetuximab/bevacizumab/ irinotecan (CBI) versus
cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal
cancer. Proc ASCO GI Cancer Symposium 2005;Abstract
169b.
Willett CG et al. Direct evidence that the VEGF-specific
antibody bevacizumab has antivascular effects in human
rectal cancer. Nat Med 2004;10(2):145-7.
Abstract
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