The prevalent thinking by retina specialists with regard to age-related macular degeneration (AMD) is that combination therapy may reduce the current treatment burden of monthly injections and that it may also have the ability to improve visual outcomes. The combination of radiation therapy and anti-vascular endothelial growth factor (anti- VEGF) injections appears to be adequate based on data from the phase 1 NVI-111 study.1

NVI-111 DESIGN
NVI-111 was designed to test safety and to see whether there was a biological signal for radiation therapy. In this ongoing nonrandomized multicenter feasibility study that enrolled 34 patients, subjects with predominantly classic, minimally classic or occult (with no classic) choroidal neovascularization received a single treatment with 24 Gy beta radiation using the Vidion ANV (NeoVista, Inc., Newark, CA) and two injections of bevacizumab (Avastin, Genentech).

Bevacizumab 1.25 mg was delivered in group 1 at 10 days (±4 days) prior to surgery and in group 2 at the time of surgery (after radiation delivery). Groups 1 and 2 received a second injection at 1 month after surgery. After the second injection, bevacizumab 1.25 mg was delivered as needed per investigator discretion based upon evidence of lesion activity.

A total of 34 subjects were enrolled at three sites in Mexico and Brazil from June 2006 through April 2007. One patient was enrolled in Guadalajara, Mexico and has been followed for 2 years; 14 patients were enrolled in Sao Paulo, Brazil, and have been followed for 2 years; and 19 patients were enrolled in Goiana, Brazil, and were followed for 3 years. I will focus on the results from these 19 patients.

The mean age of patients was 71.7 years and age ranged from 51 to 91 years in this study cohort, consistent with the natural occurrence of the disease in the general population. There were more women (65%) than men (35%) enrolled into the study, consistent with the natural predominance of the disease in women. Angiographic lesion classification was not equally distributed.

The lesion size was approximately 4.5 overall disc areas, and angiographic lesion classification was not equally distributed, with 50% of subjects presenting with the occult subtype. The average central retinal thickness was 321.5 μm, and the mean visual acuity was 40 EDTRS letters (20/160 Snellen). Approximately 70% of patients were phakic at baseline.

ADVERSE EVENTS
At year 2, three patients had cataract surgery with IOL implantation, and at year 3, four patients had cataract surgery with IOL implantation. The device-related ocular adverse events included one retinal tear, one subretinal hemorrhage, one subretinal fibrosis, and one nonproliferative case of radiation retinopathy. There were other complications that were thought to be associated with the surgical procedure—cataract formation in 12 out of 13 patients, one case of epiretinal membrane, and two cases of retinal fibrosis.

RADIATION RETINOPATHY
It is likely that radiation retinopathy is a complication that will not be seen until late follow-up. In the one case that we saw in the NVI-111 trial, early changes could be seen at 36 months in the small area where the isotopes were delivered. Interestingly the patient's vision improved from 20/50 to 20/32 and was stable, requiring no retreatment with bevacizumab. We are fortunate to have data on this patient as far as 43 months out and the vision remained at 20/40. The patient shows small microvascular abnormalities and capillary dropout associated with a small area of nonperfusion, which is consistent with known effects of radiation.

VISUAL ACUITY
The visual acuity data showed that at 12 months, 100% of patients lost 15 letters or fewer and at 24 months, 68% of patients lost 15 letters or fewer. Four patients underwent cataract surgery at 24 months and at 36 months, 90% of patients lost 15 letters or fewer.

At 12 months, 84% of patients gained one letter, with a marked decrease of 37% at 24 months that increased again to 53% at month 36. The percentage of patients gaining greater than three lines of vision was 47% at month 12, 60% at month 24, and 21% at month 36. At 3 years, there was a mean change in visual acuity of 3.5 letters and overall, the mean visual acuity gain at 3 years and after cataract surgery was 12 letters. Ninety-one percent of patients remained retreatment-free at 1 year, 79% at 2 years, and 58% at 3 years.

SAFETY AND EFFICACY CONCLUSIONS
In NVI-111, there were minimal complications with accelerated cataract formation due to the surgical procedure of vitrectomy. One patient developed nonproliferative radiation retinopathy but had good clinical outcomes out to 4 years and required no additional treatments with anti-VEGF.

In terms of efficacy, the results of the NVI-111 suggest long-term durability with minimal retreatment with anti- VEGF.

We are currently awaiting the results of the 500-patient CABERNET trial, which may be released early in 2011. These data will shed important light on the effects of combination therapy with epimacular brachytherapy. We will continue to seek longer-term results on the effects of radiation therapy, both in terms of positive effects and adverse events.

David S. Boyer, MD, is a Clinical Professor of Ophthalmology at the University of Southern California Keck School of Medicine, Department of Ophthalmology, in Los Angeles. He states that he is a consultant for Genentech, Alcon Laboratories, Inc., Allergan, Inc., Pfizer, Inc., and Novartis. He has no financial ties with Neovista. Dr. Boyer is a Retina Today Editorial Board member and may be reached at +1 310 854 6201; or via e-mail at vitdoc@aol.com.

Boyer DS. Long term VA outcomes from a pilot study of epimacular brachytherapy and bevacizumab for the treatment of CNV secondary to AMD - year 3 results. Presented at: the American Society of Retina Specialists 28th Annual Meeting; August 28-September 1, 2010; Vancouver, Canada.