Stereotactic Radiotherapy for Neovascular Age-Related Macular Degeneration Year 2 Results of the INTREPID Study Timothy L. Jackson, PhD, FRCOphth, 1 Usha Chakravarthy, MD, PhD, 2 Jason S. Slakter, MD, 3 Alyson Muldrew, PhD, 4 E. Mark Shusterman, MD, 5 Denis O’Shaughnessy, PhD, 5 Mark Arnoldussen, PhD, 5 Michael E. Gertner, MD, 6 Linda Danielson, MSc, 7 Darius M. Moshfeghi, MD, 8 on behalf of the INTREPID Study Group* Purpose: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). Design: Randomized, double-masked, sham-controlled, multicenter, clinical trial. Participants: A total of 230 participants with neovascular AMD who received 3 ranibizumab or bev- acizumab injections within the preceding year and requiring treatment at enrollment. Methods: Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) rani- bizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. Main Outcome Measures: Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. Results: At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P ¼ 0.008; mean 5.4, P ¼ 0.09; and mean 6.6, respectively). Change in mean BCVA was 10.0, 7.5, and 6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 mm, 55.4 mm, and 33.3 mm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm 2 , respectively. Mean CNV area decreased by 0.1 mm 2 in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm 3 ) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P ¼ 0.001) and mean BCVA 4.4 letters superior to sham (P ¼ 0.24). Conclusions: A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking. Ophthalmology 2015;122:138-145 ª 2015 by the American Academy of Ophthalmology. *Supplemental material is available at www.aaojournal.org. Neovascular age-related macular degeneration (AMD) is a leading cause of blindness in the developed world, with some studies finding that dry and neovascular AMD together account for more blind registrations than all other eye diseases combined. 1e4 The standard of care for neo- vascular AMD involves intravitreal injections of drugs tar- geting vascular endothelial growth factor (VEGF), but for most patients this necessitates ongoing hospital review and repeated intravitreal injections. 5,6 Radiation has been investigated as an alternative treat- ment option, 7 but recent studies present apparently con- flicting results. 8e13 The Choroidal Neovascularization Secondary to AMD Treated with Beta Radiation Epiretinal Therapy (CABERNET) trial was a pivotal randomized controlled trial (RCT) of epimacular brachytherapy (EMB) used for treatment-naïve neovascular AMD. 9,12 Those in the radiation arm received 24 Gray of EMB delivered via a pars plana vitrectomy using an endoscopic probe held over the macula for approximately 3 to 4 minutes. The trial failed to meet either of its co-primary 2-year end points. 12 By contrast, the IRay in Conjunction with Anti-VEGF Treatment for Patients with Wet AMD (INTREPID) RCT met its primary end point, showing a statistically signifi- cant, one-third reduction in anti-VEGF injections at 1 year 138 Ó 2015 by the American Academy of Ophthalmology Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2014.07.043 ISSN 0161-6420/14