NOV 2013

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

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52 EW CORNEA November 2013 Cornea editor's corner of the world Anti-VEGFs for corneal neovascularization by Ellen Stodola EyeWorld Staff Writer the cornea/external disease service, Toronto Western Hospital, University Health Network, along with others in Canada have been looking into anterior segment uses of bevacizumab. What is an anti-VEGF C orneal neovascularization, which is associated with complications in corneal diseases, can cause lipid deposition, decreased vision, and increased risk for corneal graft rejection. This problem can be frustrating for the ophthalmologist to manage. Topical steroids are a primary mode of treatment, and argon laser coagulation of large feeder vessels has also been described. With the advent of anti-VEGF drugs used by our retina colleagues for the treatment of wet age-related macular degeneration and a plethora of other posterior segment conditions, the extended use of this modality for the anterior segment has been studied.  Indeed the ability of anti-VEGF agents to halt the development of abnormal blood vessels has been revolutionary. Reports of topical, subconjunctival, and intrastromal use of anti-VEGF agents abound. This month's "Cornea editor's corner of the world" has Sonia Yeung, MD, PhD, Stephen Tuft, MD, and Allan Slomovic, MD, discussing their experience with using anti-VEGF agents for corneal neovascularization. S Clara C. Chan, MD, cornea editor tudies recently have been looking at the use of antiVEGF drugs in the anterior segment, with special attention paid to the effectiveness of these drugs for treating corneal neovascularization. A number of doctors are involved with studies and trials to examine the results of this. Stephen Tuft, MD, Moorfields Eye Hospital, London, was recently involved with a pilot randomized placebo-controlled double-masked trial to look at the use of subconjunctival bevacizumab (Avastin, Genentech, San Francisco) for corneal neovascularization. Sonia Yeung, MD, PhD, Vancouver Hospital Eye Care Centre, St. Paul's Hospital, and assistant professor, Department of Ophthalmology, University of British Columbia, Vancouver, and Allan Slomovic, MD, associate professor of ophthalmology, University of Toronto, and research director of "VEGF-A (vascular endothelial growth factor-A) is the key pro-angiogenic factor in the development of many neovascular disorders, in particular in ocular neovascularization," Dr. Tuft said. "A naturally occurring inhibitor of VEGF, sFlt-1, which is normally present in the cornea, is a key maintainer of the avascular state of a normal cornea, predominantly through its inhibition of VEGF." He said both Avastin and Lucentis (ranibizumab, Genentech) are synthetic monoclonal antibodies toward VEGF. Avastin was mainly developed for a variety of non-ocular cancers, while Lucentis was specifically focused on intraocular use. "The latter is licensed for use in neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion," he said. However, neither drug is licensed for use in corneal neovascularization. "Although open label data exists suggesting efficacy with Lucentis (which would be expected), higher level randomized controlled trial data is available only for Avastin, and which suggests a significant inhibitory effect of Avastin," Dr. Tuft said. Dr. Yeung said that it is hard to compare whether Avastin and Lucentis would be better for treatment of corneal neovascularization because there have not been any "well-powered prospective randomized head-to-head studies" that compare the two for treating this condition. Concentration and dosing When using anti-VEGF agents, concentration and dosing come into play, as do a number of other factors. Dr. Tuft explained that Avastin is significantly less expensive than Lucentis. Therefore, Avastin was the drug of choice used in the trial to look at potential results. The dose used was 2.5 mg of Avastin in 0.1 ml, and this was chosen from past experiments in animal and human studies. Dr. Slomovic uses three separate injections of Avastin, separated by four to six weeks. There are different delivery techniques (topical, subconjunctival, and intrastromal) that can be used, and he has looked at the possibilities in different studies. He has experimented with a subconjunctival injection, as well as a combination of subconjunctival and intrastromal injections. Currently, he gives half of the injection subconjunctivally (equal to 1.25 mg) and the other half with an intrastromal injection (an additional 1.25 mg). This is done three times, and the three injections are about four to six weeks apart. Avastin and Lucentis in everyday practice "Both Avastin and Lucentis are available currently, although neither is licensed for use in targeting [corneal neovascularization]," Dr. Tuft said. To use the drugs for this purpose, it would require prior discussion with the patient, as it is technically an off-label use. "Avastin is widely used globally off-label to treat wet AMD and has a favorable ocular and systemic safety profile comparable to Lucentis," he said. "However, it must be stressed that although our trial is the only higher-level randomized controlled study in humans using any of these agents, it was a pilot study with an anatomical end point." Dr. Slomovic said that he believes the use of Avastin is ready for prime time now, although he does inform his patients that it is an off-label use of the medication. What etiologies of corneal neovascularization are ideal for anti-VEGF? There are a number of diverse etiologies that can result in corneal neovascularization. "Common to all appears to be a central role of VEGF/Flt-1 receptor/sFlt-1 interactions and hypoxia," he said. This conclusion is based on experiments and non-randomized clinical series, and it seems this would only be effective for recent onset new vessels. When looking at the etiologies for corneal neovascularization in his studies, Dr. Slomovic said that the results were diverse. The main etiologies seemed to be herpetic eye disease and failed corneal grafts. Prior lipid deposition It is generally believed anti-VEGFs can still work if there is already lipid deposition. "Our studies have shown that anti-VEGF treatment can result in reduced corneal NV [neovascularization] and subsequent reduction in lipid deposition," Dr. Yeung said. When anti-VEGFs will not work There are some patients in which anti-VEGFs should not be used. "We anticipate that anti-VEGF targeting would be most efficacious for recent onset corneal neovascularization, in which the new vessels are immature," Dr. Tuft said. This means that they have not been unsheathed in pericyte cells, which could cause some resistance to anti-VEGF drugs. Dr. Yeung agreed that there are some patients that anti-VEGF agents would not work for. "Patients who have ongoing VEGF stimulus appear to require repeated treatment, and the treatment may not ultimately work," she said. "Also, patients with long-term established vessels appear to derive less benefit from this drug." Dr. Slomovic did not find that anti-VEGF helped much in treating the recurrence of pterygium. "I reviewed all the literature on Avastin for pterygium recurrence, and besides just a couple of case histories, the overwhelming majority of the articles say that it doesn't prevent pterygium recurrence," he said. However, he thinks the dosages may be too low for treating this condition, and it may need to be increased to at least three or four injections over several months to have an affect. Dr. Slomovic said it is important to know that corneal neovascularization is not a benign condition and can lead to complications over time if not addressed. "They'll often recur down the road, and it's important to monitor these patients so that if they do recur, you can treat them again," he said. Physicians should use both pharmacological and surgical resources to reduce and eliminate corneal neovascularization, he said. EW Editors' note: The physicians have no financial interests related to this article. Contact information Slomovic: allan.slomovic@utoronto.ca Tuft: stephen.tuft@moorfields.nhs.uk Yeung: sonia.y@gmail.com

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