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Background
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.
In a multi-center, randomized, active-controlled, phase III clinical trial, Dugel et al (2013) the safety and efficacy of epi-macular brachytherapy (EMBT) for the treatment of neovascular ARMD. A total of 494 participants with treatment-naive neovascular ARMD were included in this study. Participants with classic, minimally classic, and occult lesions were randomized in a 2:1 ratio to EMBT or a ranibizumab monotherapy control arm. The EMBT arm received 2 mandated, monthly loading injections of 0.5-mg ranibizumab. The control arm received 3 mandated, monthly loading injections of ranibizumab, then quarterly injections. Both arms also received monthly as needed (pro re nata [PRN]) re-treatment. Main outcome measures were the proportion of participants losing fewer than 15 ETDRS letters from baseline VA and the proportion gaining more than 15 ETDRS letters from baseline VA. At 24 months, 77 % of the EMBT group and 90 % of the control group lost fewer than 15 letters. This difference did not meet the pre-specified 10 % non-inferiority margin. This end-point was non-inferior using a 20 % margin and a 95 % confidence interval (CI) for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. The EMBT did not meet the superiority end-point for the proportion of participants gaining more than 15 letters (16 % for the EMBT group versus 26 % for the control group): this difference was statistically significant (favoring controls) for occult lesions, but not for predominantly classic and minimally classic lesions. Mean VA change was -2.5 letters in the EMBT arm and +4.4 letters in the control arm. Participants in the EMBT arm received a mean of 6.2 ranibizumab injections versus 10.4 in the control arm. At least 1 serious adverse event occurred in 54 % of the EMBT arm, most commonly post-vitrectomy cataract, versus 18 % in the control arm. Mild, non-proliferative radiation retinopathy occurred in 3 % of the EMBT participants, but no case was vision threatening. The authors concluded that the 2-year effectiveness data do not support the routine use of EMBT for treatment-naïve wet ARMD, despite an acceptable safety profile. They stated that further safety review is required.
In a prospective, multi-center, interventional, non-controlled clinical trial, Petrarca et al (2013) reported the optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) results of the Macular Epiretinal Brachytherapy in Treated Age-Related Macular Degeneration study. A total of 53 eyes of 53 participants with chronic, active neovascular ARMD requiring frequent anti-VEGF re-treatment. Participants underwent pars plana vitrectomy with a single 24-gray dose of epi-macular brachytherapy (EMB), delivered with an intra-ocular, hand-held, cannula containing a strontium 90/yttrium 90 source positioned over the active lesion. Participants were retreated with ranibizumab administered monthly as needed, using pre-defined re-treatment criteria. Patients underwent FFA at baseline, month 1, and month 12. Patients underwent OCT at baseline and then monthly for 12 months. The FFA and OCT images were evaluated by independent, central reading facilities. Main outcome measures were change in OCT center-point thickness and angiographic lesion size 12 months after EMB. Mean center-point thickness increased by 50 μm, from 186 to 236 μm (p = 0.292), but 70 % of participants had an increase of less than the mean, with a median increase of only 1.8 μm. The FFA total lesion size increased slightly by 0.79 mm(2), from 14.69 to 15.48 mm(2) (p = 0.710). Total CNV area increased by 1.17 mm(2), from 12.94 to 14.12 mm(2) (p = 0.556). The classic CNV area decreased substantially by 3.70 mm(2), from 3.90 to 0.20 mm(2) (p < 0.01). Predominantly classic lesions showed the greatest response, with mean ETDRS VA improving by 1.5 letters (versus -4.0 for all participants combined); mean center-point thickness decreased by 43 μm (p = 0.875). The angiographic and OCT response did not correlate with lesion size at baseline. The authors concluded that in chronic, active, neovascular ARMD, EMB is associated with non-significant changes in center-point thickness and FFA total lesion size over 12 months.
In a multi-center, active-controlled, randomized clinical trial, Jackson et al (2013) reported the FA and OCT results of a clinical trial of EMBT used for the treatment of neovascular ARMD. A total of 494 participants with treatment-naive, neovascular ARMD were included in this study. Participants with classic, minimally classic, and occult lesions were randomized to receive (i) EMBT and 2 mandated monthly ranibizumab injections followed by PRN ranibizumab, or (ii) 3 mandated monthly ranibizumab injections followed by mandated quarterly plus PRN ranibizumab. Participants underwent FA at screening and at months 1, 6, 12, 18, and 24. Optical coherence tomography scans were undertaken monthly for 24 months. The FA and OCT images were analyzed at respective independent reading centers. Main outcome measures were change at 24 months in mean FA total lesion size and CNV size and change in mean OCT center-point thickness. The mean (standard deviation) changes in FA total lesion size in the EMBT and control arms were +1.9 (8.7) and -3.0 (7.2) mm(2), respectively, with a mean change in total CNV size of +0.4 (8.4) and -4.7 (6.5) mm(2), respectively. Mean (standard deviation) changes in OCT center-point thickness were -144 (246) and -221 (185) μm, respectively. Retrospective subgroup analyses showed no significant difference between treatment arms in mean center-point thickness in some subgroups, including eyes with classic lesions. The control arm showed a significantly larger reduction in mean total lesion size and mean CNV size than the EMBT arm in all subgroups analyzed. Nine eyes in the EMBT arm showed features consistent with mild, non-proliferative radiation retinopathy, but with a mean gain of 5.0 ETDRS letters. The authors concluded that both FA and OCT suggested that EMBT with PRN ranibizumab results in an inferior structural outcome than quarterly plus PRN ranibizumab. Some subgroup analyses suggested that classic lesions may be more responsive than occult lesions, although generally both subgroups are inferior to ranibizumab. A non-vision-threatening radiation retinopathy occurs in 2.9 % of eyes over 24 months, but longer follow-up is needed.
Epiretinal radiation may be a promising treament for wet ARMD, however, randomized prospective studies are needed to demonstrate its effectiveness.
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