Bevacizumab and Recurrent Malignant
Gliomas: A European Perspective
TO THE EDITOR: Bevacizumab, a monoclonal antibody against
vascular endothelial growth factor (VEGF; Avastin, Genentech, South
San Francisco, CA, and Roche, Basel, Switzerland), was approved in
2009 by the US Food and Drug Administration for the treatment of
recurrent glioblastoma. The basis for this accelerated approval was
uncontrolled phase II trials with a total of 215 patients; a single-arm
phase II trial of bevacizumab with irinotecan added at progression and
a randomized phase II trial of the same regimen or first-line treatment
with the combination of bevacizumab and irinotecan.1 Even before
USFood and Drug Administration approval, bevacizumab was widely
used in this indication in the United States and in some European
countries, and is currently given off-label for patients with newly
diagnosed high-grade glioma. The marketing application to the European
Medicines Agency was rejectedNovember2009. EuropeanMedicines
Agency felt that the still existing question about activity in
recurrent glioblastoma prevented registration with the given data.
It is remarkable that over the 3 years since the first report on the
efficacy of bevacizumab in recurrent glioblastoma only a few hundred
patients with recurrent glioblastoma were accrued into reported prospective
clinical trials, while already thousands of patients have been
treated off-label. Despite the rapid US Food and Drug Administration
approval, numerous questions with regard to dosing, timing, and
efficacy remain. Opportunities to adequately test this promising agent
were missed or avoided. This has already led to considerable national
differences with respect to access and reimbursement of bevacizumab
for patients with glioma.
Based on these reports and our own clinical experience, bevacizumab
is without doubt a useful drug in recurrent glioma. However,
the uncontrolled trials that evaluated bevacizumab and irinotecan
versus bevacizumab alone (and the addition of irinotecan at progression)
leave many questions unanswered.
Wasthe right end point used? The primary end point was the rate
of patients alive and free of progression at 6 months, a surrogate end
point that had been considered valuable for cytotoxic agents, but is
inappropriate when studying antiangiogenic agents that will modify
vascular permeability and thus the imaging response assessment based
on contrast enhancement.2,3 VEGF was initially also referred to as
vascular permeability factor4 and it is well recognized that VEGF is a
major mediator of blood-brain barrier disturbance. Inhibiting VEGF
signaling decreases tumor enhancement even without an intrinsic
antitumor effect. Indeed, clinical progression has been observed in the
absence of evident tumor progression on T1-gadolinium–enhanced
magnetic resonance imaging with T2-weighted sequences showing
tumor extension without disruption of the blood-brain barrier.5 The
substantial differences in response rates when independently assessed
by the investigators (39% and46%for bevacizumab and bevacizumab
with irinotecan, respectively), by a sponsor-mandated central radiologic
review (28% and 38%),6 and finally by the US Food and Drug
Administration (20% and 26%),7 illustrate the difficulties and limitations
of objective response as the primary end point for outcome to
treatment with antiangiogenic agents. Of note, an international panel
is currently revisiting the response criteria for brain tumors,8 and has
judged the response rate and progression-free survival inappropriate
end points for anti-VEGF signaling treatments.2
Does treatment with bevacizumab increase survival? The reported
survival times of 8 to 9 months correspond to what had been
reported as median survival after progression for patients treated with
radiotherapy alone,9 or radiotherapy and concomitant temozolomide
before the availability of bevacizumab, and needs to be compared with
6 to 7 months in many bluntly negative trials on recurrent glioblastoma.
10 The disappointing disparity between the high response rates
reported for bevacizumab in recurrent glioblastoma and the modest at
best survival benefit may partly be explained by the limited effect on
the tumor mass itself.11 The obvious question is whether the effects of
bevacizumab byandlarge resemble that of dexamethasoneandshould
therefore be named pseudoresponse.2 The duration of a response, and
ultimately overall survival, are probably more accurate indicators of
the therapeutic activity of a compound. The data reported in Journal of
Clinical Oncology6 remain immature, with a minimum follow-up of
only 6 months and just half of the patients having died at the time
of analysis in September 2007, 2 years before publication. No update
has been made available yet.
Do we know the optimal bevacizumab dose? Stark-Vance’s12
initial experience of high response rates in recurrent glioma with
bevacizumab used a dose of 5 mg/kg every 2 weeks; nevertheless, the
dose of bevacizumab in subsequent trials was doubled without further
investigations or justification. One cannot rule out that the higher
dose of bevacizumab actually increases toxicity and complication rate,
this not even considering the economical impact.
Should bevacizumab be given as a single agent or in combination?
In most indications, anti-VEGF agents had to be combined with
classical cytotoxic drugs to demonstrate activity. Based on overall
survival, this trial shows no added benefit of irinotecan when looking
at overall survival, and a marginal improvement in response rate. Yet,
irinotecan is largely responsible for the toxicity of the regimen.6 Anti-
VEGF signaling drugs may increase the penetration of co-medication
into tumors by reducing the intratumoral pressure and through normalization
of abnormal and nonfunctional capillary networks. As a
severe unwanted effect, drug penetration might be decreased by restoring
the blood-brain barrier.12 Examples of the importance of welldesigned
trials included Randomized Phase III Study of Capecitabine,
Oxaliplatin, and Bevacizumab With or Without Cetuximab in Advanced
Colorectal Cancer (CAIRO 2), where the use of bevacizumab
in the adjuvant setting did not translate into improved outcome, and
the simultaneous administration of both bevacizumab and cetuximab
even seemed to be detrimental.13
Do we know the best timing of bevacizumab? A source of concern
is the rebound edema after discontinuation of bevacizumab.
Because of this, salvage therapy after failure of bevacizumab has been
particularly challenging, and no drug or regimen either alone or in combination with bevacizumab has demonstrated activity.14 Should
other treatments therefore be applied before initiating bevacizumab
while withholding bevacizumab as long as possible? This will also
impact the design of future trials in recurrent glioblastoma.
What is the significance of the gliomatosis cerebri like pattern of
recurrence that has been observed in some of the bevacizumab and
other VEGF signaling pathway interfering agents? Recent experience
suggests induction of a more aggressive and diffusely invasive tumor
phenotype as a mechanism of escape to anti-VEGF therapy.5,14 The
clinical impact of this is yet unclear, but at least some patients show
cognitive deterioration.
Lastly, the accelerated approval of bevacizumab is likely to
influence future drug development. It encourages cheap(er) drug
development strategies based on phase II protocols, promoting preregistration
widespread clinical use rather than conclusive phase III
trials with well-considered end points showing clear clinical benefit.
There is no one generally agreed standard of care in recurrent
glioblastoma but there are an array of treatment options largely based
on level III evidence or expert opinion. Although ideally patients are
enrolled into clinical trials, the numerous ongoing uncontrolled bevacizumab
combination trials are unlikely to answer any of the most
burning questions. From the patient’s perspective, any clinical improvement
leading to improved quality of life and with the least
toxicity is of benefit. Such an effect is observed with bevacizumab in
particular in patients with symptomatic peritumoral edema causing
deficits and requiring steroids. But we lack properly designed trials to
determine how to best and most economically use the agent. The
widespread use of bevacizumab even before the registration impedes
the possibility to conduct the appropriate trials that would answer
these questions. Instead of conducting yet another uncontrolled
study, attempts should be made to develop well-designed protocols
that give answers to pertinent clinical questions outlined above.
Quelle: http://jco.ascopubs.org/cgi/reprint/JCO ... 9027v3.pdf
