Clinical Investigation
Antivascular Endothelial Growth Factor Bevacizumab for Radiation Optic Neuropathy: Secondary to Plaque Radiotherapy

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Purpose

To evaluate the intravitreal antivascular endothelial growth factor, bevacizumab, for treatment of radiation optic neuropathy (RON).

Methods and Materials

A prospective interventional clinical case series was performed of 14 patients with RON related to plaque radiotherapy for choroidal melanoma. The RON was characterized by optic disc edema, hemorrhages, microangiopathy, and neovascularization. The entry criteria included a subjective or objective loss of vision, coupled with findings of RON. The study subjects received a minimum of two initial injections of intravitreal bevacizumab (1.25 mg in 0.05 mL) every 6–8 weeks. The primary objectives included safety and tolerability. The secondary objectives included the efficacy as measured using the Early Treatment Diabetic Retinopathy Study chart for visual acuity, fundus photography, angiography, and optical coherence tomography/scanning laser ophthalmoscopy.

Results

Reductions in optic disc hemorrhage and edema were noted in all patients. The visual acuity was stable or improved in 9 (64%) of the 14 patients. Of the 5 patients who had lost vision, 2 had relatively large posterior tumors, 1 had had the vision decrease because of intraocular hemorrhage, and 1 had developed optic atrophy. The fifth patient who lost vision was noncompliant. No treatment-related ocular or systemic side effects were observed.

Conclusions

Intravitreal antivascular endothelial growth factor bevacizumab was tolerated and generally associated with improved vision, reduced papillary hemorrhage, and resolution of optic disc edema. Persistent optic disc neovascularization and fluorescein angiographic leakage were invariably noted. The results of the present study support additional evaluation of antivascular endothelial growth factor medications as treatment of RON.

Introduction

Radiation optic neuropathy (RON) is a devastating complication of exposure to the visual pathways 1, 2, 3, 4, 5. It occurs in patients who have undergone radiotherapy (RT) for tumors in the choroid, retina, orbit, paranasal sinuses, or cranial fossa 1, 6, 7, 8. Although spontaneous resolution has occasionally been reported, RON typically results in severe, irreversible, blindness 5, 9.

Radiation optic neuropathy and radiation maculopathy have been the leading causes of irreversible vision loss associated with ophthalmic plaque RT (7). Although RON and radiation maculopathy differ in their anatomic location, their pathophysiology (characterized by an exudative vasculopathy, edema, and late vascular closure) has been quite similar 1, 10, 11. However, unlike the macular retina, the optic nerve is confined within the scleral canal and dura as it approaches the orbit and brain. Thus, RON-associated exudative vasculopathy and edema occurs within a confined space and appears as a more fulminant process.

Both RON and radiation maculopathy have been reported to be dose dependent 4, 12, 13, 14. For example, as many as 46% of patients (5-year data using 125I plaque brachytherapy) treated for large uveal melanomas developed RON (13). In contrast, in our recent report of 400 cases of uveal melanomas (all sizes and locations) treated with 103Pd, only 6% developed RON (15). However, it is reasonable to assume that the incidence of RON has been increasing owing to the more widespread clinical use of eye-sparing radiation techniques for juxtapapillary, circumpapillary, and large melanomas using specialized plaques, the gamma knife, and charged particle RT 16, 17, 18.

In 1982, Brown et al. (3) reported that RON “manifests acutely as disc swelling with surrounding exudate, hemorrhages and subretinal fluid.” In that series of 14 patients, 8 had received 60Co plaque (mean 125 Gy to the anterior optic nerve) and 6, external beam RT (mean dose, 55 Gy) (3). The visual acuity outcomes varied and were attributed (in part) to the variables of synchronous radiation maculopathy and rare spontaneous improvement in RON (3). Late optic atrophy typically occurred.

The pathophysiology of RON involves the creation of radiation-induced free radicals (primarily hydroxyl) in tissue that affect both optic nerve vascular endothelial cells and neuroglial progenitor cells 19, 20, 21. Consequently, radiation effects on the optic nerve will be both vascular and neuropathic. Radiation vasculopathy progressively includes reductions in endothelial cells, perivascular inflammation, obliterative endarteritis, hyalinization, and fibrosis 22, 23 Although progressive ischemia will lead to neovascularization, the primary clinical findings have been vascular incompetence, leading to closure. Leakage will be seen as swelling of the optic nerve (papilledema) with hemorrhage and trace lipid deposition. With time, the leakage will be replaced by vascular closure, evidenced by nonperfused “ghost” vessels and optic atrophy. Thus, radiation-altered intraneural fluid dynamics affect the course of RON (Fig. 1) 1, 2, 3.

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis 24, 25. It has been implicated in the pathologic angiogenesis associated with tumors and macular degeneration. In ophthalmology, VEGF inhibition (anti-VEGF) strategies have been used to prevent angiogenesis and vascular leakage 26, 27, 28, 29, 30, 31, 32. At present, three types of intravitreal anti-VEGF agents are used in ophthalmology. Pegaptanib (Macugen) was the first available anti-VEGF agent approved for ophthalmic use by the Food and Drug Administration in 2004 for neovascular-exudative age-related macular degeneration (Food and Drug Administration product label, available from: www.fda.gov, 2004). In 2006, the Food and Drug Administration approved ranibizumab (Lucentis) for ophthalmic use for age-related macular degeneration. These agents, along with bevacizumab (Avastin, Genentech, San Francisco, CA), have also been commonly used off-label by ophthalmologists for a multitude of diagnoses. Several centers have also reported using anti-VEGF strategies to treat secondary brain necrosis 33, 34, 35.

The results from laboratory studies have suggested that VEGF increases hydraulic conductivity of the microvessels mediated by calcium influx 24, 36, 37, 38. Therefore, VEGF inhibition offered the potential to reduce vascular permeability and extravasation of intravascular components. This has resulted in clinical evidence of decreased edema, hemorrhage, and exudation 26, 27, 28, 39, 40, 41. Therefore, VEGF inhibition (anti-VEGF medications) offered a method for inhibiting new blood vessel formation (neovascularization) and normal vessel endothelial cell loss and limiting transudation of intravascular components 25, 42.

Because of the pathophysiology of RON and the mechanisms of action of anti-VEGF agents, the present study was initiated to evaluate the safety, tolerability, and initial clinical findings of a series of patients treated with bevacizumab for RON.

Section snippets

Methods and Materials

The present study complied with the Health Insurance Portability and Accountability Act of 1996 and the tenets of the Declaration of Helsinki and was approved by the institutional review board of the New York Eye Cancer Center in 2006. All patients provided verbal and then written informed consent before treatment. The patients were informed that this was a research study, of the number of patients previously treated, and the ongoing results of treatment of this condition. Because the present

Results

Since 2006, 14 patients with RON secondary to ophthalmic plaque RT for choroidal melanoma were treated with intravitreal bevacizumab (Table 1). Their mean age was 67 years (median, 68; range, 34–89). Of the 14 patients, 10 were women, and 6 eyes were right eyes. No patient had non–insulin-dependent diabetes, and 8 had systemic hypertension. No patient had received synchronous chemotherapy during the study period.

The 7th edition, American Joint Committee on Cancer–International Union Against

Discussion

Radiotherapy (brachytherapy and teletherapy) has offered eye- and vision-sparing alternatives to enucleation for patients with choroidal melanoma, retinoblastoma, and metastatic ocular tumors 7, 8, 46. For example, the medium-size tumor trial of the Collaborative Ocular Melanoma Study showed no survival advantage when comparing 125I plaque RT to enucleation (47). In addition, the local control rate for 103Pd plaque brachytherapy has been reported to be as great as 97% (15). RT also offers

Conclusions

The present study is the first clinical case series reporting on the effects of the anti-VEGF agent bevacizumab in the treatment of RON. Intravitreal administration was associated with decreased optic disc edema and vision retention in most cases. Owing to the limited nature of our study, the long-term efficacy and safety of this strategy should be monitored. Larger, more statistically significant studies should be performed to analyze the effect of radiation dose, dose rate, and time of onset

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    Supported by an unrestricted imaging grant from Myrna and John Daniels, Toronto, ON, Canada and from the Eye Cancer Foundation, New York, NY (available from: (www.eyecancerfoundation.net).

    Conflict of interest: Dr. Finger was awarded U.S. Patent 7553486, titled “Anti-VEGF Treatment for Radiation Induced Vasculopathy,” on June 30, 2009.

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