VEGF has demonstrated an intimate connection with the pathogenesis of corneal NV.15
In animal models of corneal NV, increased expression levels of VEGF and VEGF receptors have been confirmed.14, 28, 29
In humans, pathological studies have confirmed that VEGF and its receptors are present in higher concentrations in corneal buttons with NV than in normal corneas, irrespective of the cause of neovascularisation.15, 30
Furthermore, VEGF blockade, at both the protein and mRNA level, has been shown to reduce corneal NV and improve corneal graft survival in experimental animals.16
Bevacizumab is a full-length, recombinant humanized monoclonal immunoglobulin G1 (IgG1) that binds to and inhibits the activity of VEGF-A, thereby inhibiting angiogenesis.31
It was the first anti-VEGF antibody to be approved by the U.S. Food and Drug Administration specifically for the treatment of metastatic colon cancer, and recently, for non-small cell lung cancer and metastatic breast cancer.32
Off-label intravitreal administration of bevacizumab for treatment of choroidal NV18
has gained wide and rapid acceptance because of its safety, efficacy, and lower cost in comparison to other anti-VEGF drugs.
In the aggregate, the present study shows that topical bevacizumab 1% is effective in the treatment of clinically stable corneal NV as evidenced by a nearly 50% reduction in 2 corneal NV metrics (NA and VC). In the two-dimensional plane of a corneal photograph, if vessel area (NA) is regarded as a function of mean vessel width (VC) and total vessel length, it would appear that the reduction in VC accounted for most of the improvement that was seen in NA. Furthermore, the absence of meaningful change in IA in our study indirectly supports the conclusion that significant narrowing of blood vessels rather than reduction in blood vessel length is the main outcome of anti-VEGF therapy in corneal NV. VEGF acts at several levels on vascular beds: it is a survival factor for endothelial cells, it is a potent vasodilator, and it increases microvascular permeability.33
VEGF, once considered as vascular permeability factor (VPF),34
was later found to promote endothelial cell growth.35
VEGF, therefore, renders the microvasculature hyper-permeable to circulating macromolecules with a potency about 50,000 times greater than histamine.34
Therefore, the vascular stabilization (reduction in vascular permeability) affected by anti- VEGF therapy may diminish the vascular flow rate, causing reduction in the caliber of blood vessels.
The study shows a highly variable efficacy across the cohort treated with bevacizumab (, , ), which is evidenced by the high standard deviations of the computed corneal NV metrics. The level of therapeutic response in case 6 (almost a complete resolution of corneal NV as shown in ) and case 8 (a very modest therapeutic response to the anti-VEGF treatment as shown in ) exemplify the therapeutic spectrum of topical bevacizumab in the treatment of corneal NV. Several hypotheses may explain this variability in response to topical bevacizumab, including heterogeneity in corneal NV etiologies, variable levels of VEGF expression in the pathobiology of diverse cases, and variable levels of drug penetration.
Figure 3 The effect of topical bevacizumab in patient 6, a 65-year-old woman with history of herpes zoster ophthalmicus in the left eye complicated by corneal thinning, scarring, and neovascularization. A, Baseline picture shows a main vessel branch emerging from (more ...)
Figure 4 The effect of topical bevacizumab in patient 7, a 39-year-old woman with history of LASIK surgery and partial limbal stem cell deficiency in the left eye complicated by corneal neovascularization. A, Baseline picture shows superficial and deep corneal (more ...)
Figure 5 The effect of topical bevacizumab in patient 8, a 42-year-old man with failed penetrating keratoplasty in the left eye complicated by corneal neovascularization. A, Baseline picture shows corneal opacity with severe superficial and deep corneal neovascularization. (more ...)
Topical application is the preferred method of administration of a drug to the cornea and ocular surface. However, topical treatment will only be effective if the drug can penetrate through the corneal epithelial barrier to reach the target tissues within a therapeutic level. Topical administration of full-length immunoglobulins, such as bevacizumab with a molecular weight of 149kD, is typically considered ineffective because such molecules are too large to penetrate the intact corneal epithelium. However, epithelium over the neovascularized area can be defective, particularly in patients with ocular surface disease which interferes with normal corneal epithelial function and results in incompetent barrier function.36
Our recent work in a mouse model of corneal NV has clearly demonstrated that bevacizumab can penetrate the neovascularized cornea after topical application (Sadrai, Z, et all. Invest Ophthalmol Vis Sci
2008;49: ARVO E-Abstract 1488). In view of the size of the bevacizumab molecule, however, the degree of inadequacy of the corneal epithelial barrier likely varies to a large extent from one vascularized cornea to another.
Our study did not show any systemic or local adverse effects. Systemic blood pressure remained stable at the baseline level, and no serious life-threatening side effects occurred during the follow-up period. This shows that topical bevacizumab 1%, in both twice daily and four times a day regimens, is safe. This finding, however, may be due in part to the precautions applied to our study, such as the placement of punctal plugs and the exclusion of any patient aged 75 or older or having a history of hypertension, diabetes mellitus, or thromboembolic event. Similarly, from an eye standpoint, topical bevacizumab 1% (with benzalkonium 0.01% as a preservative) was tolerated very well in all patients. No local irritation, allergic reaction, or surface epitheliopathy was observed. This is in contrast with a 60% rate of spontaneous loss of epithelial integrity as recently reported by Kim et al.25
In this report, the investigators used topical bevacizumab at a slightly higher concentration (1.25%) twice daily for a much longer period (3 months), and adverse effects generally appeared during the second month of treatment.25
This suggests that the duration of treatment may well determine the safety of topical bevacizumab.
While anti-VEGF therapy shows efficiency in treating corneal NV, VEGF has desirable effects that may be blocked by bevacizumab therapy. These include the capacity to promote the formation of collateral vessels, to control vascular tone, to affect corneal nerve regeneration,37
and a substantial role in wound healing.38
In this regard it is important to note that the long-term neutralization of VEGF may have unintended local or systemic consequences that our study has not yet determined. Prolonged blockade of VEGF may impair wound healing and the regeneration of corneal nerves, which may cause a loss of epithelial integrity in cornea. Although delivered in a small dose on the surface of the eye, anti-VEGF drugs could also pass into the systemic circulation. Hypertension, proteinuria and various cardiovascular events are potential consequences of the systemic inhibition of VEGF.
In summary, the significant narrowing of corneal blood vessel diameter and diminishing neovascular area in response to topical bevacizumab therapy provides evidence that anti-VEGF therapy could offer an alternative or adjunctive measure to conventional therapies in the treatment of stable corneal neovascularization. However, further research using larger patient cohorts is warranted to determine the exact dosage and indications for use.