Radiation maculopathy is the most common cause of irreversible radiation-related vision loss in patients treated for choroidal melanoma.1 In our series, radiation maculopathy affects up to 52% of patients with posteriorly located tumors following plaque brachytherapy and appeared at a mean of 26 months after plaque brachytherapy.1,2
Radiation maculopathy has been treated with nonsteroidal anti-inflammatory agents, laser photocoagulation, and steroids (topical, intravitreous, and peribulbar) with limited success.2 Anti–vascular endothelial growth factor (anti-VEGF) bevacizumab was recently found to be effective in controlling radiation-induced maculopathy and optic neuropathy.3- 5
This study investigates intravitreous ranibizumab (Lucentis) to treat radiation vasculopathy in the macula. The primary objective was to test the safety and tolerability of anti-VEGF intravitreous ranibizumab in the treatment of radiation retinopathy. The secondary objectives were to observe for changes in visual acuity, regression of retinopathy, and changes in tumor size.
US Food and Drug Administration, Investigational New Drug, and The New York Eye Cancer Center Institutional Review Board approvals were obtained. We describe the first 5 consecutive patients enrolled in a phase 1, open-label, Genentech-sponsored (Genentech, Inc, South San Francisco, California), single-center clinical trial.
In this study, all patients had been treated with palladium 103 for 7 consecutive days. Patients received a mean tumor apex dose of 75.3 Gy (range, 58.8-82.3 Gy) and a mean foveal dose of 61.9 Gy (range, 17.4-138.5 Gy) (to convert gray to rad, multiply by 100) (Table 1). Our methods of radiation dosimetry, plaque placement, and follow-up have been described.1
Inclusion criteria were as follows: (1) radiation treatment must have been given at least 6 months prior to enrollment; (2) initial visual acuity of 20/400 or better; (3) a subjective or objective loss of vision; and (4) no intraocular surgery within 60 days. In this series, no subjects had previously received intravitreous anti-VEGF or triamcinolone.
Radiation maculopathy was defined by intraretinal hemorrhage, intraretinal microangiopathy, neovascularization, cotton-wool spots, vascular sheathing, and/or cystoid macular edema.2
Intravitreous injections of 0.5 mg of ranibizumab were required each month for 4 cycles, then modulated depending on the presence and persistence of radiation maculopathy. Treatments were deferred when examination revealed no radiation maculopathy and optical coherence tomography/scanning laser ophthalmoscopy (OPKO-OTI, Toronto, Ontario, Canada) showed no persistent macular edema.
Eyes were prepared with topical proparacaine hydrochloride and then povidone-iodine, followed by subconjunctival injection of lidocaine hydrochloride, 2%. While the anesthetic took effect, ranibizumab was drawn from the bottle into a 1-mL syringe, and a 30-gauge needle was then placed for injection. After a second application of anesthetic and antibiotic eyedrops, an eyelid speculum was placed; this was followed by transscleral injection through the pars plana. Optic nerve perfusion was checked by indirect ophthalmoscopy. After 30 minutes (±10 minutes), intraocular pressures were checked by Goldmann tonometry. Patients were prescribed antibiotic steroid eyedrops to be used 4 times a day for 7 days.
Outcome measures recorded at baseline and then monthly were best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study charts in Collaborative Ocular Melanoma Study–certified rooms), fundus photography, and central foveal thickness on optical coherence tomography. Fluorescein angiography and images were examined at baseline and at months 3, 6, 9, and 12. Blood pressure was recorded at each visit.
A mean of 8.2 intravitreous injections (range, 8-9 injections) were given over a mean follow-up of 8 months (range, 7-9 months). Safety and tolerability were assessed at 7 days (±3 days) and monthly thereafter. There were no cases of endophthalmitis, uveitis, lens damage, retinal tear, or rhegmatogenous retinal detachment.4 There were no cases of secondary arterial thromboembolic events, myocardial infarction, or cerebrovascular accident. There were no changes in blood pressure.
The most common reported findings were subconjunctival hemorrhage at the injection site and transient (postinjection) increases in intraocular pressure. One patient noted transient facial swelling that resolved within a week of injection.
Intravitreous ranibizumab was found to reduce intraretinal hemorrhages, exudation, and macular edema (Figure 1). The most common and reproducible finding was decreased edema, with secondary improvement in the normal anatomy of the macula (Table 2). Best-corrected visual acuity in all 5 patients increased by an average of 6 letters, with 4 patients improving by a mean of 9.5 letters (range, 3-15 letters) and 1 patient losing 7 letters (Table 2). Our 8-month analysis showed a mean 35% reduction in central foveal thickness (range, 32%-39%) on optical coherence tomography/scanning laser ophthalmoscopy (Figure 2). The mean initial central foveal thickness was 416 μm, the mean final foveal thickness was 270 μm, and there was a mean 146-μm decrease in the central foveal thickness over the study interval.
Clinical response to intravitreous ranibizumab. A, Pretreatment fundus photograph demonstrates macular hemorrhage and edema as well as exudates in the posterior pole. The posterior edge of the uveal melanoma can be seen at the 9-o’clock position. B, Pretreatment fluorescein angiogram at the arteriovenous phase demonstrates radiation maculopathy. C, Following 6 treatments with ranibizumab, there is resolution of retinal hemorrhage, marked regression of cotton-wool spots, and disappearance of inferior and inferotemporal exudates. D, Fluorescein angiogram (at a similar phase) after 6 months of treatment shows decreased retinal hemorrhage and macular edema. Note the normalization of retinal arteries and arterioles.
Optical coherence tomographic imaging before (A) and after (B) treatment. A, Pretreatment optical coherence tomographic image demonstrates macular edema. The initial foveal thickness was 496 μm. B, After 7 injections of ranibizumab, there is marked improvement of macular edema with a 39% reduction in foveal thickness. D indicates diopters.
Based on our early experience, intravitreous ranibizumab was found to be a safe and promising treatment for radiation maculopathy. No new or significant adverse effects were observed. Visual acuities improved in 4 of 5 patients (80%) and the central foveal thickness was reduced in all 5 cases (100%). These findings stand in stark contrast to the natural course of radiation maculopathy. Although our sample size is small, our results on central foveal thickness with optical coherence tomography/scanning laser ophthalmoscopy were comparable to those reported by the larger studies for age-related macular degeneration and consistent with our findings using bevacizumab (Avastin).3- 5
Not only has the advent of anti-VEGF treatment offered vision-sparing treatment for patients with radiation vasculopathy, these findings should also affect treatment decisions for patients with small choroidal melanomas. Consider that no cutaneous or other nonocular melanomas are followed up for evidence of growth prior to treatment. However, due to the potential risk of radiation-related vision loss, eye cancer specialists commonly use documented tumor growth to tip the scales toward treatment. Therefore, effective treatments for ophthalmic radiation vasculopathy should change the risk-benefit conversations for the treatment of patients with choroidal melanoma. Current methods of anti-VEGF therapies do vary in cost (in the United States, Lucentis costs $1950 per injection) and should also be addressed during patient education.
This study shows that Lucentis-based anti-VEGF therapy can be used to decrease radiation-induced vascular permeability, suppress retinal neovascularization, and preserve vision.3- 5 Larger, confirmatory studies with longer follow-up, differing dose regimens, and novel, longer-lasting methods of administration are needed.
Correspondence: Dr Finger, The New York Eye Cancer Center, 115 E 61st St, Ste 5B, New York, NY 10065 (email@example.com).
Author Contributions: Dr Finger had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: Drs Finger and Chin have no commercial or financial interest in the product or companies mentioned and did not receive payment as a consultant, reviewer, or evaluator. On June 30, 2009, the US Patent Office awarded Dr Finger patent 7,553,486, “Anti-VEGF Treatment for Radiation Induced Vasculopathy.”
Funding/Support: This study was supported by an investigator-sponsored trial grant from Genentech, Inc and by The EyeCare Foundation, Inc.
Role of the Sponsors: Genentech, Inc had a limited role in the review and approval of the manuscript and had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. The EyeCare Foundation, Inc had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Trial Registration: clinicaltrials.gov Identifier: NCT00750399
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