FACE OFF
BY ABDHISH R. BHAVSAR, MD

Welcome 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.

 We 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

IN FAVOR OF

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.

OPPOSED

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

IN FAVOR OF

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.

OPPOSED

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

IN FAVOR OF

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 certainly warranted.

OPPOSED

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 bhavs001@umn.edu.