BY ABDHISH R. BHAVSAR, MD
to Face Off, a column that explores controversial topics in the diagnosis and
management of retinal diseases. Our typical pattern has involved covering
several topics in each issue with one retina specialist voicing one line of
thought in favor of the treatment or surgery and another retina specialist
voicing an opposing line of thought. In this issue, we will explore the
controversial subject of using Avastin (bevacizumab, Genentech/Novartis) for
intravitreal injection in treating a number of different diseases. Intravitreal
treatment with Avastin is of course an off-label treatment, with a medicine that
has not yet been studied in ophthalmic clinical trials. We do not advocate the
use or lack of use of Avastin. However, the column will be a nice exercise in
exploring pro- and con- aspects of treatment decisions that we face on a daily
basis. This column should be interpreted in the spirit of a debate society. We
hope that you will find the column interesting, entertaining and educational.
will be exploring 3 topics in this issue: Avastin for exudative age-related
macular degeneration (AMD), Avastin for diabetic macular edema (DME), and
Avastin for cystoid macular edema (CME) due to retinal vein occlusions (RVO).
AVASTIN FOR AMD
Robert L. Avery, MD: After
the release of Marina and Anchor data demonstrating a mean improvement in visual
acuity (VA) following ranibizumab treatment for subfoveal neovascular AMD,
physician and patient expectations are much higher. Bevacizumab, the full length
antibody derived from the same murine antibody as ranibizumab, is available in
an unpreserved formulation and is inexpensive in the small doses used
intravitreally. I presented data at the American Academy of Ophthalmology (AAO)
demonstrating statistically significant improvement in VA and optical coherence
tomography (OCT) retinal thickness in a short-term study of the first 81 eyes we
treated for AMD. We found no evidence of ocular or systemic side effects, and I
showed animal studies demonstrating full thickness retinal penetration of 2.5 mg
of intravitreal bevacizumab and the lack of toxicity by electroretinogram (ERG)
and visual evoked potential (VEP) testing. Until ranibizumab is FDA approved,
many patients are willing to undergo treatment with an off-label drug if it
seems to have a better chance of improving their vision. Thousands of patients
have now received this injection, and in the absence of evidence of toxicity, I
have a hard time not offering it to them as long as they understand the risks.
Thomas M. Aaberg, Jr., MD:
An intravitreal injection of Avastin qualifies as an off-label use of a compound
not held to the same processing standards as those used for intraocular use.
Because Avastin is a full-length immunoglobulin, it remains in systemic
circulation significantly longer than its Fab offspring, Lucentis (Genentech/Novartis)
or itsaptamer competitor Macugen (OSI Pharmaceuticals/Pfizer), thereby
potentiating systemic side effects clearly stated in the drug insert.
Medical-legally, a poor outcome or complication (ocular or systemic) may be
difficult to defend. Consequently, if its use is contemplated, all other
currently approved treatment options should be exhausted.
AVASTIN FOR DME
David S. Boyer, MD:
Laser photocoagulation has been the gold standard for the treatment of DME.
Despite this treatment, there are patients who do not respond, continue to lose
vision, or do not have visual improvement. Steroids have been used to treat
unresponsive cases but are associated with side effects including a rise in
intraocular pressure (IOP), cataract, and in some cases, sterile endophthalmitis.
The early Macugen and Ranibizumab (Genentech/Novartis) DME trials have shown an
OCT, and in some cases, a VA improvement. Avastin is similar to Ranibizumab.
Being a larger molecule it may have a longer half-life allowing less frequent
injections and appears to offer a decrease in diabetic leakage by its
antipermeability and anti-VEGF (vascular endothelial growth factor) effect
without the side affects of steroids, such as an IOP rise, cataract, or
inflammation. It clearly has a potent effect on neovascular tissue on the
retinal surface or iris. It appears to be a safe, economical, effective
treatment for patients with DME. I am looking forward to clinical trials to
prove the best treatment paradigm.
Thomas A. Ciulla, MD: Although the use of
anti-VEGF agents for DME merits strong consideration, especially since these
agents might avoid some of the ocular hypertension risk of intravitreal kenalog,
Avastin should not be used for primary treatment of DME at this time. Most
importantly, this agent has not undergone randomized clinical trial in DME, and
its efficacy compared to standard-of-care laser treatment, or other agents, is
unknown. In addition, the proper dose and treatment intervals are completely
unknown. Safety is also a concern, since this colorectal cancer agent would be
used in an off-label fashion in the eye, for which it was not developed. There
are issues of potential immunogenicity, since this larger protein may more
readily elicit an inflammatory response in diabetic retinopathy, in which the
blood-retinal barrier is compromised. However, the use of Avastin in those
patients with severe DME, refractory to multiple sessions of laser treatment,
might be reasonable once the issues of dose and treatment interval have been
more fully assessed in a randomized clinical trial.
AVASTIN FOR CME DUE TO RVO
Dante J. Pieramici,
MD: Elevated levels of VEGF have been documented following retinal venous
occlusive disease and can lead to the development of neovascularization and CME.
It makes sense that anti-VEGF therapy would, amongst other effects, reduce
vascular leakage and CME. Like ranibizumab, intravitreal bevacizumab can have a
rapid, durable effect on vascular permeability and concomitant retinal edema. We
have seen consistent and prompt reduction of CME in patients with central
retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), treated
with intravitreal bevacizumab, however, visual improvement has been less
consistent and follow-up limited. Similar to ranibizumab, bevacizumab appears to
have limited adverse ocular and systemic side effects, but further evaluation is
Sharon Fekrat, MD: Intravitreal Avastin
may be yet another treatment option to add to the expanding potpourri of choices
for eyes with CME due to a CRVO. Because the CME from the CRVO is not likely to
be a self-limited finding, chronic treatment with intravitreal Avastin would
likely be necessary to maintain any resolution of the edema, once achieved. The
National Eye Institute has sponsored the SCORE study for eyes with RVO to
determine a desperately needed answer to whether intravitreal triamcinolone is
safe and effective over the long term. Adding intravitreal Avastin to the
treatment armamentarium without sufficient study will further distract the
vitreoretinal specialist from patient recruitment into SCORE for unproven and
uncertain long-term outcomes. Other ongoing trials for CME due to CRVO are also
recruiting eligible patients to determine the role of anti-VEGF agents and other
steroid preparations and drug delivery devices.
Instead of treating the edema that results in
these eyes; however, we need to focus our limited resources and energy on
finding a way to restore venous outflow in these eyes and only then, will we
likely get marked and persistent VA improvement that patients are seeking.
Abdhish R. Bhavsar, MD, is an attending retina
surgeon at the Phillips Eye Institute, director of clinical research at the
Retina Center, P.A., in Minneapolis, MN., and adjunct assistant professor at the
University of Minnesota. He also serves as state chair of the Minnesota Diabetes
Eye Exam Initiative.
E-mail him about Face Off at
Retinal Physician, Issue: January 2006