• Glaucoma

    Anti-vascular endothelial growth factor (anti-VEGF) agents have recently been introduced as potential modulators of the post-filtration surgery healing process. Newer anti-VEGF agents have become popular as intravitreal injections for choroidal and retinal neovascular disease, which has lead to their early adoption as wound modulators for glaucoma surgery. This article describes common anti-VEGF agents, reviews preclinical and clinical reports exploring their use for glaucoma surgery and suggests steps for developing a broader knowledge base to better understand their utility for the practicing glaucoma surgeon.

    Introduction

    The ultimate goal of trabeculectomy surgery is to decrease intraocular pressure (IOP) by creating a fistula connecting the anterior chamber with the sub-Tenon's space. Current guarded filtration surgery has remained essentially unchanged from the concept first introduced by JE Cairns in the 1960s.1 A major limitation in achieving postoperative success with this technique is the body's natural tendency to heal after creation of an incision. Fibroblast proliferation often leads to scarring of the created fistula at the level of the scleral flap and surrounding tissue.2

    The introduction of mictomycin C (MMC) and 5-fluorouracil (5-FU) as adjuncts at the time of surgery or in the early postoperative phase represented major steps toward overcoming the natural healing process.3,4 Unfortunately, the improved success at lowering IOP achieved with MMC and 5-FU came at the expense of increased complications, such as ischemic blebs, leaking blebs and higher rates of endophthalmitis.2,5-7 Alternatives to these anti-fibrotic agents have been explored but none have been proven superior or able to supplant these agents in glaucoma procedures.8,9

    Anti-VEGF Agents

    VEGF is a hypoxia-inducible cytokine intimately involved in the formation of vessels throughout the body. It is also involved in inflammation and cellular proliferation.10 Many isoforms exist that vary in size, as well as spatial distribution, from cell-bound to diffusible. Anti-VEGF agents have been available for decades in various forms and have been described as potential adjuncts to glaucoma surgery in the past.11

    Recently, ranibizumab (Lucentis) and bevacizumab (Avastin) have been used for diseases ranging from wet age-related macular degeneration (AMD) to proliferative diabetic retinopathy.12 Ranibizumab, a Fab fragment of a recombinant humanized IgG1 kappa isotype murine monoclonal antibody, is FDA-approved for treating choroidal neovascular membranes related to AMD. Bevacizumab, a humanized monoclonal antibody, is FDA-approved for treating colorectal cancer but has been used extensively as an off-label treatment for ocular neovascular disease. Neither agent is FDA-approved for use in glaucoma surgery, and there are no published randomized clinical trials detailing their utility in this realm. The potential utility of anti-VEGF agents for wound modulation is due to their direct effect on vascular and fibroblast proliferation, as well as their indirect effect of decreasing the influx of pro-inflammatory cytokines into the bleb by way of surrounding vessels.

    Preclinical Reports

    VEGF plays a role in mitogenesis, angiogenesis and endothelial cell survival. While the blockage of VEGF and the subsequent effects on neovascular disease are well known, relatively little is known about the direct effect of anti-VEGF agents on fibroblasts in and around the human eye. The research team lead by Joel S. Schuman, MD, and Robert J. Noecker, MD, at University of Pittsburgh Medical Center (UPMC) has illustrated in vitro effects of bevacizumab on human corneal and conjunctival fibroblast cell lines. The researchers noted that corneal stromal fibroblasts exposed to bevacizumab exhibited significant morphological changes and loss of cell-to-cell adhesions in a dose-dependent manner compared with fibroblasts exposed to bevacizumab vehicle, as well as to vehicle combined with molar equivalents of IgG.13 However, Efdal Yoeruek and colleagues noted no such changes when exposing human corneal fibroblast cells to concentrations as high as 5mg/ml.14

    In a follow-up study by the UPMC group, treated conjunctival stromal fibroblasts also exhibited significant morphological changes compared with control treated fibroblasts.15 Marked loss of cell-cell interaction and adhesions were noted in a dose-dependent fashion at treatment concentrations of 0.6mg/0.05 ml and 1.25mg/0.05 ml. Others have noted dose-dependent alterations in human tenon fibroblast morphology and proliferation/survival when exposed to bevacizumab and ranibizumab in vitro at doses similar to or higher than those used for intravitreal injection.16,17

    A recent report by Farnaz Memarzadeh, MD, and colleagues investigated the effects of subconjunctival injections of bevacizumab on bleb morphology in rabbits following trabeculectomy.18 They noted that bevacizumab prolonged bleb survival and led to more favorable bleb morphology compared to 5-FU and control (balanced salt solution) groups. Bleb survival was 16.0 (± 1.3) days for the bevacizumab group versus 6.9 (± 0.6) and 7.4 (± 0.85) days for the 5-FU and control groups, respectively.

    Clinical Reports

    In 2006, I was the lead author of the first report on bevacizumab use for modulating wound healing after bleb needle revision.8 We noted a significant and lasting decrease in IOP after needling of a failing bleb and injection of 1 mg of bevacizumab adjacent to the bleb at the end of the procedure. Many reports have followed illustrating the utility of both bevacizumab and ranibizumab as post-filtration surgery sub-Tenon's injections or for use during bleb needle revision.19-21

    Frederick Kapetansky, MD, and colleagues studied the utility of subconjunctival bevacizumab injections administered proximal to blebs after trabeculectomy at the earliest sign of vascularization.20 They noted that nearly two-thirds of the blebs had an observable reduction in vascularity when IOP decreased from a mean of 17.8 mmHg (± 6.4) to 14 mmHg (± 4.0) one month after injection. Improved results were noted when the injections were done earlier in the postoperative phase. JM Purcell, MD, and colleagues noted decreased IOP and bleb vascularization after bleb needle revision using ranibizumab.21 However, this effect was short-lasting, with increased vascularization observed after one month.

    DS Grewal, MD, and colleagues recently reported results from their nonrandomized, open-label, prospective, interventional case series of 12 patients who received subconjunctival injections of bevacizumab (1.25 mg/0.05 ml) adjacent to the bleb at the time of trabeculectomy.9 The mean preoperative IOP was 24.4 mmHg (± 7.1) and decreased to a mean of 11.6 mmHg (± 2.2) after six months. They concluded that subconjunctival bevacizumab is a potential adjunctive treatment for reducing the incidence of bleb failure after trabeculectomy. Interestingly, they observed increased bleb vascularity after three months, which they stated might decrease the incidence of thin cystic blebs that frequently develop after MMC-augmented trabeculectomy surgery. They added that further studies are needed to better determine the optimal bevacizumab dose and route of injection, as well as the drug's side effects on the corneal endothelium and trabecular meshwork.

    Conclusions

    Further preclinical and clinical studies should be conducted in order to better understand how anti-VEGF agents might benefit patients undergoing glaucoma filtration surgery. Safety studies are ongoing to determine if these agents have previously unknown side effects and if any side effects vary by administration route. It is important to understand duration of action when injecting into the intra- or sub-Tenon's space and how this might influence efficacy. Use of an intravitreal depot might be more desirable due to its extended release and potential for longer term influence on bleb morphology. It is also important to further study the pharmacokinetics and pharmacodynamics of anti-VEGF agents when they come into contact with the sclera, as applying them directly to the surgical bed, as in the case of MMC, might prolong their retention and lead to improved long-term efficacy.22

    Plans are under way for randomized controlled trials with long-term follow-up, including bleb morphology evaluation, to tease out differences between anti-VEGF agents and the current gold standard, MMC. It is possible that the best option for successful wound modulation might include use of a combination of agents at the time of surgery, as there is no reason to believe that a single agent will offer the best results. Trabeculectomy is likely to remain the gold standard glaucoma surgical procedure for some time, particularly when targeting a low IOP. Anti-VEGF agents might be an attractive option for maintaining or enhancing current expectations of success while decreasing unwanted side effects and providing better patient care.

    References

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    3. Heuer DK, Parrish RK, Gressel MG, et al. 5-fluorouracil and glaucoma filtering surgery. II. A pilot study. Ophthalmology. 1984;91(4):384-394.
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    13. Guerriero E, Yu JY, Kahook MY, SundarRaj N, Schuman JS, Noecker RJ. Morphologic Evaluation Of Bevacizumab (Avastin) Treated Corneal Stromal Fibroblasts. Invest Ophthalmol Vis Sci. 2006;47:Association for Research in Vision and Ophthalmology E-Abstract 1642.
    14. Yoeruek E, Spitzer MS, Tatar O, Aisenbrey S, Bartz-Schmidt KU, Szurman P. Safety profile of bevacizumab on cultured human corneal cells. Cornea. 2007;26(8):977-982.
    15. Yu JY, Kahook MY, Noecker RJ, Schuman JS. The Effect of Avastin on Conjunctival Fibroblasts. Paper presented at: American Glaucoma Society 2007 Annual Meeting; March 2, 2007; San Francisco, CA.
    16. Qin Q, Van Bergen N, Liew D, et al. Anti-VEGF Treatment on Human Tenons' Fibroblasts Scarring Activity in vitro. Invest Ophthalmol Vis Sci. 2008;49:Association for Research in Vision and Ophthalmology E-Abstract 4541.
    17. Vasudevan SK. Anti-VEGF Anti-Fibrosis-A Comparison of Ranibizumab and Bevacizumab in vitro. Invest Ophthalmol Vis Sci. 2009;50:Association for Research in Vision and Ophthalmology E-Abstract 466.
    18. Memarzadeh F, Varma R, Lin LT, et al. Post-operative use of Bevacizumab as an Anti-fibrotic Agent in Glaucoma Filtration Surgery in the Rabbit. Invest Ophthalmol Vis Sci [epublished ahead of print]. January 31, 2009.
    19. Kapetansky FM, Pappa KS, Krasnow MA, Baker ND, Francis CD. Subconjunctival Injection(s) of Bevacizumab for Failing Filtering Blebs. Invest Ophthalmol Vis Sci. 2007;48:Association for Research in Vision and Ophthalmology E-Abstract 837.
    20. Kapetansky FM, Pappa KS, Krasnow MA, Baker ND, Francis CD. Subconjunctival Injection(s) of Bevacizumab for Failing Filtering Blebs. Invest Ophthalmol Vis Sci. 2008;49:Association for Research in Vision and Ophthalmology E-Abstract 4149.
    21. Purcell JM, Teng CC, Tello C, Liebmann JM, Ritch R. Effect of Needle Bleb Revision With Ranibizumab as a Primary Intervention in a Failing Bleb Following Trabeculectomy. Invest Ophthalmol Vis Sci. 2008;49:Association for Research in Vision and Ophthalmology E-Abstract 4165.
    22. Yu JY, Kahook MY, Schuman JS, SundarRaj N, Guerriero E, Noecker RJ. Bevacizumab Binding to Human Sclera Post Topical Application. Invest Ophthalmol Vis Sci. 2007;48:Association for Research in Vision and Ophthalmology E-Abstract 4815.

    Author Disclosure

    The author states that he receives research support from Genentech.