Proton Beam Irradiation for Neovascular Age-Related Macular Degeneration Hadi J. Zambarakji, FRCOphth, MD, 1 Anne Marie Lane, MPH, 1 Eric Ezra, FRCOphth, MD, 1 Danny Gauthier, MD, 1 Michael Goitein, PhD, 2 Judy A. Adams, CMD, RT(T)(R), 2 John E. Munzenrider, MD, 2 Joan W. Miller, MD, 1 Evangelos S. Gragoudas, MD 1 Objective: To evaluate safety and visual outcomes after proton therapy for subfoveal neovascular age- related macular degeneration (AMD). Design: Randomized dose-ranging clinical trial. Participants: One hundred sixty-six patients with angiographic evidence of classic choroidal neovascular- ization resulting from AMD and best-corrected visual acuity of 20/320 or better. Methods: Patients were assigned randomly (1:1) to receive 16-cobalt gray equivalent (CGE) or 24-CGE proton radiation in 2 equal fractions. Visual acuity was measured using standardized protocol refraction. Complete ophthalmological examinations, color fundus photography, and fluorescein angiography were per- formed before and 3, 6, 12, 18, and 24 months after treatment. Main Outcome Measure: Proportion of eyes losing 3 or more lines of vision from baseline. Kaplan–Meier statistics were used to compare cumulative rates of vision loss between the 2 treatment groups. Results: At 12 months after treatment, 36 eyes (42%) and 27 eyes (35%) lost 3 or more lines of vision in the 16-CGE and 24-CGE groups, respectively. Rates increased to 62% in the 16-CGE group and 53% in the 24-CGE group by 24 months after treatment (P = 0.40). Radiation complications developed in 15.7% of patients receiving 16 CGE and 14.8% of patients receiving 24 CGE. Conclusions: No significant differences in rates of visual loss were found between the 2 dose groups. Proton radiation may be useful as an adjuvant therapy or as an alternative for patients who decline or are not appropriate for approved therapies. Ophthalmology 2006;113:2012–2019 © 2006 by the American Academy of Ophthalmol- ogy. Anti–vascular endothelial growth factor therapy with pe- gaptanib (Macugen, Eyetech Pharmaceuticals, New York, NY) and photodynamic therapy (PDT) using verteporfin currently are the preferred treatments for patients with sub- foveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). 1–4 Although pa- tients treated with PDT experience less visual loss than patients who receive no treatment, the beneficial effects of PDT depend on lesion characteristics, 1,3,5 with lesion size being the strongest predictor of treatment benefit. 5 With room for improvement in our therapy for neovascular AMD, alternatives such as radiation are being investigated. Radi- ation may be effective through several mechanisms, includ- ing inhibition of proliferating endothelial cells, angiogenic cytokine-producing inflammatory cells, and cell types in- volved in scar formation, including the retinal pigment epithelium. Radiation has the added benefit of fewer treat- ments, which can present a significant advantage for the elderly. In preclinical studies, these angiogenic inhibitory effects have been demonstrated using radiation doses of 16 Gy or less, 6 and significant radiation retinopathy has not been ob- served in patients treated with low doses of radiation (25 Gy) for orbital, paranasal, and nasopharyngeal tumors. 7 These findings have stimulated interest in evaluating radiation as a treatment method for CNV secondary to AMD. Initial data by Chakravarthy et al 8 reported an inhib- itory effect of radiation therapy on CNV. A number of additional studies have demonstrated possible benefit, 8 –13 whereas data from several other studies suggest no treat- ment effect. 14 –16 Interpretation of these conflicting results is difficult because of one or a combination of the following factors: variable doses and fractionation schemes, small sample sizes, differences in patient risk factors and prog- nostic factors, lack of long-term follow-up, and nonrandom- ized designs. Originally received: July 12, 2005. Accepted: May 26, 2006. Manuscript no. 2005-636. 1 Retina Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. 2 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Presented in part at: Retina Society Annual Meeting, December 1999, Wailea, Hawaii. Supported by the Massachusetts Eye and Ear Infirmary Retina Research and Melanoma Research Funds, Boston, Massachusetts; T. F. C. Frost Trust, London, United Kingdom; and Cripplegate and Dowsett Educational Fund, London, United Kingdom. The authors have no conflicts of interest related to the article. Correspondence to Evangelos S. Gragoudas, MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. E-mail: Evangelos_ Gragoudas@meei.harvard.edu. 2012 © 2006 by the American Academy of Ophthalmology ISSN 0161-6420/06/$–see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2006.05.036