Age-related macular degeneration (ARMD) is the leading cause of irreversible visual loss in the United States. There are 2 types of macular degeneration: (i) dry and (ii) wet. The dry, or non-exudative form, involves both atrophic and hypertrophic changes in the retinal pigment epithelium (RPE) underlying the central macula, as well as drusen deposition beneath the RPE. Patients with non-exudative ARMD can progress to the wet, or exudative, form of ARMD, in which pathologic choroidal neovascular (CNV) membranes develop under the retina, leak fluid and blood, and ultimately cause a blinding disciform scar in a relatively short time. Approximately 10 to 20 % of patients with non-exudative ARMD eventually progress to the exudative form, which is responsible for most of the cases of advanced ARMD in the United States (AAO, 2006; Comer, 2006).
Although some subtypes of wet ARMD are treatable, treatment efficacy is low. At present, the only widely accepted intervention for ARMD is the use of high-dose antioxidants. However, this treatment only slows progression in some patients and does not reverse damage already present. After ARMD becomes exudative, laser photocoagulation, photodynamic therapy (PDT) with verteporfin, and therapy with intra-vitreal pegaptanib sodium are the standard treatments to control CNV. Because of the limitations in current treatment, researchers are presently developing alternative therapies for wet ARMD including alternative types of PDT, transpupillary thermotherapy, treatment with a variety of growth-factor modulators, irradiation, and surgical therapy. Effective treatment is limited by a lack of understanding of the underlying cause of the disease (AAO, 2006; Comer, 2006). External beam radiation has been used as a treatment for neovascular ARMD with poor results (NICE, 2004; Sivagnanavel et al, 2004).
The Epi-Rad90 Ophthalmic SystemTM (NeoVista, Inc., Fremont, CA) is an epiretinal radiation delivery device developed to treat wet ARMD. After a vitrectomy is performed, the Epi-Rad90 Ophthalmic System delivers beta radiation (strontium 90) directly to the area of the retina affected by wet ARMD. Patients receive a single treatment of strontium 90 in combination with an injection of an anti-vascular endothelial growth factor (anti-VEGF).
NeoVista, Inc. is conducting a randomized, prospective phase III clinical trial, the CABERNET (CNV Secondary to AMD Treated with BEta RadiatioN Epiretinal Therapy), to evaluate the safety and efficacy of focal delivery of radiation for the treatment of wet AMD compared to the results obtained with anti-VEGF therapy alone. Data from the manufacturer's website describe the results from an unpublished 1-year feasibility study of CNV patients (n = 34) who received a single treatment of epiretinal therapy in combination with 2 injections of Avastin (1 dose at the time of radiation delivery and another 1 month later). The study reported a mean improvement of visual acuity of 13.1 letters using the Early Treatment Diabetic Retinopathy Study (ETDRS) test after 12 months follow-up (15 % required additional injections of Avastin throughout the year). The following adverse events were reported by 12 % of the patients: retinal tear, retinal detachment, subretinal hemorrhage, and vitreous hemorrhage.
In a prospective, non-randomized, multi-center study, Avila et al (2009) evaluated the short-term safety and feasibility of epiretinal strontium-90 brachytherapy delivered concomitantly with intra-vitreal bevacizumab for the treatment of subfoveal CNV due to AMD for 12 months. A 3-year follow-up is planned. A total of 34 treatment-naive patients with predominantly classic, minimally classic and occult subfoveal CNV lesions received a single treatment with 24 Gy beta radiation (strontium-90) and 2 injections of bevacizumab. Adverse events were observed. Best corrected visual acuity (BCVA) was measured using standard ETDRS vision charts. Twelve months after treatment, no radiation-associated adverse events were observed. In the intent-to-treat population, 91 % of patients lost less than 3 lines (15 ETDRS letters) of vision at 12 months, 68 % improved or maintained their BCVA at 12 months, and 38 % gained greater than or equal to 3 lines. The mean change in BCVA observed at month 12 was a gain of 8.9 letters. The authors concluded that the safety and efficacy of intra-ocular, epiretinal brachytherapy delivered concomitantly with bevacizumab for the treatment of subfoveal CNV secondary to AMD were promising in this small study population. They stated that long-term safety will be assessed for 3 years; and this regimen is being evaluated in a large, multi-center, phase III study.
A Cochrane systematic evidence review found no convincing evidence that radiotherapy is an effective treatment for neovascular AMD. The review stated that, if further trials are to be considered to evaluate radiotherapy in AMD, then adequate masking of the control group must be considered. Thirteen trials (n = 1,154) investigated external beam radiotherapy with dosages ranging from 7.5 to 24 Gy; 1 additional trial (n = 88) used plaque brachytherapy (15Gy at 1.75mm for 54 mins/12.6 Gy at 4 mm for 11 mins). The review stated that most studies found effects (not always significant) that favored treatment. The review found that there was overall a small statistically significant reduction in risk of visual acuity loss in the treatment group. The review found considerable inconsistency between trials and the trials were considered to be at risk of bias, in particular because of the lack of masking of treatment group. Subgroup analyses did not reveal any significant interactions; however, there were small numbers of trials in each subgroup (range of 3 to 5). There was some indication that trials with no sham irradiation in the control group reported a greater effect of treatment. The incidence of adverse events was low in all trials; there were no reported cases of radiation retinopathy, optic neuropathy or malignancy. Three trials found non-significant higher rates of cataract progression in the treatment group.
Epiretinal radiation may be a promising treament for wet ARMD, however, randomized prospective studies are needed to demonstrate its effectiveness.