Radiation Therapy for Neovascular Age-related Macular Degeneration
Approximately 1 of every 3 people over the age of 70 years in the United States is affected by dry or wet age-related macular degeneration (AMD). Affected patients typically initially have non-neovascular or dry AMD. AMD can be mild, intermediate, or advanced. Mild and intermediate AMD are characterized by a spectrum of signs typified by soft drusen, focal atrophy of the retinal pigment epithelium (RPE), or RPE hyperplasia. Advanced AMD is characterized by dry AMD with fovea-involving geographic atrophy (8-10%) or by transformation of dry AMD into wet AMD with choroidal neovascularization (10-15%).
Although we have no demonstrated treatments for advanced dry AMD with center-involving geographic atrophy, numerous treatments have proven to be beneficial for wet AMD. Historically, thermal laser photocoagulation and verteporfin photodynamic therapy (PDT) were helpful for slowing the rate of vision loss in wet AMD patients but did not result in improved vision after the initiation of treatment in the average patient. In addition, these treatments were not curative, with most patients requiring additional laser or additional PDT treatments to maintain CNV control.
Contemporary Wet AMD Treatment Burden
Since 2005, we have had the benefit of anti-VEGF agents. Delivered intravitreally, anti-VEGF therapy not only mitigates visual loss in wet AMD patients, but 30% to 40% of wet AMD patients will have moderate vision improvement with continued anti-VEGF therapy.1,2 Approximately 40% of patients undergoing anti-VEGF therapy maintain visual acuity at 20/40 or better after 1 year.1 Similar to laser photocoagulation and PDT, however, anti-VEGF therapy with the most commonly used agents (bevacizumab [Avastin, Genentech], ranibizumab [Lucentis, Genentech], and aflibercept [Eylea, Regeneron]) requires treatment as frequently as monthly and on an ad infinitum basis.
Clinical trials with ranibizumab evaluated monthly dosing, with quarterly dosing proving less effective.1,3 Clinical trials with aflibercept demonstrated statistically equivalent efficacy at a monthly or bimonthly dosing frequency. Trials of bevacizumab and ranibizumab employing as-needed (prn) treatment regimens demonstrated results that were not as robust as those observed with monthly dosing. Combination therapy with anti-VEGF and PDT and/or intraocular corticosteroids has been tried in an attempt to diminish the number of necessary anti-VEGF agents, but significant visual, anatomic, or dosing benefits have not been realized with these combined approaches. Investigators have long sought additional combination therapies with anti-VEGF agents in order to extend the anti-VEGF dosing interval.
Informal surveys of retina physicians in the United States have shown that the treat-and-extend dosing regimen is the most commonly employed nonmonthly treatment protocol employed, with the typical wet AMD patient receiving approximately 5 to 7 injections per year on average. Clearly, there is a motivation for the development of a safe treatment protocol that can result in fewer overall treatments and maintain similar or superior visual acuity outcomes.
Is There a Basis for Using Radiation in AMD?
There is a strong biologic rationale for combining radiation with anti-VEGF therapy for the management of choroidal neovascularization (CNV) secondary to neovascular AMD. Radiation has been explored previously for its obvious downstream effect of vasotoxicity. However, its upstream characteristics also make it a desirable choice for combination with anti-VEGF agents. Specifically, radiation has been shown to be antiangiogenic, antiinflammatory, and antifibrotic.4 It is these 3 characteristics that make it appealing not only for CNV modulation and control, but also possibly to mitigate the irreversible damaging effects of subretinal fibrosis. Two different radiation approaches for the management of wet AMD have been evaluated over the years: external beam and brachytherapy with a radioactive plaque.4
External Beam Radiation Therapy (EBRT): Historical Approaches
An extensive review of the historical approaches of external beam radiation therapy (EBRT) using radioactive isotope sources or proton-beam irradiation for the treatment of neovascular AMD is beyond the scope of this piece. It is sufficient to point out that no statistically significant dosedependent treatment effect was evident in pooled trial data, nor was a statistically significant difference in the rate of common intraocular complications observed.4 Importantly, no cases of radiation retinopathy, radiation-induced optic neuropathy, or secondary malignancies were reported. A shortcoming of these analyses was that a limited period of follow-up might have been too short to observe these effects, which are known to typically occur several years after radiation exposure. These early radiation trials were also not double-masked.4
Early studies with radioactive plaque brachytherapy for wet AMD were performed, but were limited by the need for 2 surgeries (plaque placement, plaque removal) and the anteriorly directed radiation beam resulting in a high rate of secondary cataracts.4 For such a common disease, the invasiveness of traditional plaque brachytherapy is not a pragmatic solution. However, these early studies did help later investigators calculate appropriate dosimetry for contemporary studies.
Contemporary Radiation Approaches to Wet AMD
In the past decade, several novel treatment approaches have emerged. The first, from NeoVista Inc, is a twist on traditional plaque brachytherapy. Instead of applying a radioactive isotope on the outside of the eye, NeoVista’s Vidion technology applies radiation through a transvitreal epiretinal approach in conjunction with vitrectomy surgery. After pars plana vitrectomy is complete, the surgeon advances a proprietary strontium-90 radiation probe directly over the area of CNV, holding it manually in place for approximately 3 to 5 minutes to deliver a dose of approximately 24 Gy to the target tissue.5-7 This selective application avoids undue radiation exposure to the lens, surrounding retinal and orbital tissue, and presumably the optic nerve as well. This epimacular brachytherapy treatment (EMBT) is a 1-time treatment that is supplemented with prn delivery of intravitreal anti-VEGF agents. Phase 1 trials with this approach demonstrated no dose-limiting toxicity with the 24 Gy dose and promising visual acuity results.5-7
Two pivotal registration trials followed on the heels of this early work. The CABERNET study evaluated treatmentnaïve patients, and the MERLOT study examined previously treated wet AMD patients. CABERNET enrolled 457 treatment-naïve wet AMD patients in a 2:1 randomization (EMBT: quarterly ranibizumab in a modified PIER protocol).8 Patients in the EMBT group were to receive 24 Gy of EMBT with 2 injections of ranibizumab followed by ranibizumab prn. Patients in the no-radiation group received a modified PIER protocol ranibizumab dosing regimen. The main outcome measure in this prospective noninferiority study was the proportion of patients losing less than 15 ETDRS letters. At year 2, the control group received 11 ranibizumab injections and, visual acuity was, on average, 1 line better than in the radiation group, which received 6 ranibizumab injections. Unfortunately, the prespecified efficacy endpoint was not achieved. Although nonproliferative retinopathy complications in the EMBT group were observed in 10 patients in the CABERNET study, no cases of proliferative radiation retinopathy were observed.8
The MERITAGE study was a prospective, nonrandomized study of 53 previously treated patients in the United Kingdom. Patients received EMBT or prn ranibizumab with a 12-month coprimary endpoint of visual acuity preservation and change in anti-VEGF dosing frequency. Before enrollment, participants had received an average of 12.5 anti-VEGF injections. After a single treatment with EMBT, 81% maintained stable vision, with a mean of 3.49 anti-VEGF retreatments in 12 months. Mean ± standard deviation change in visual acuity was -4.0 ±15.1 ETDRS letters.9
As NeoVista’s Vidion EBMT was a twist on traditional brachytherapy, Oraya’s IRay device is a twist on traditional EBRT. The IRay is a stereotactic, robotic, radiotherapy platform designed to deliver focused, low-energy radiation to the central macula through the pars plana, thereby avoiding the crystalline lens.10 The device is powered using a standard electrical 110-V socket and does not utilize a radioactive isotope source. The eye is stabilized with a suction apparatus and tracked with the IGuide, which uses infrared cameras and fiducials to actively track eye movements and appropriately direct radiation. Excess movement in the X, Y, or Z planes immediately interrupts the delivery of radiation with additional safety measures utilizing an automated gate for releasing the eye from the IGuide, opening of a leaded patient head shield, release of handgrips, and activation of an emergency shutoff button. Following axial length determination with a standard A-scan ultrasound, the dose of radiation is delivered via 3 separate locations through the inferior pars plana that overlap on the macula to deliver the total dose of approximately 16 to 24 Gy in various studies.10-13 The radiation spot size is fixed, so lesions greater than 4 mm are not suitable for this treatment.
Early clinical trials with the device in Mexico employed 16 Gy and 24 Gy doses along with adjunctive ranibizumab in 3 different protocols: (1) 16 Gy plus 2 ranibizumab injections followed by prn ranibizumab; (2) 16 Gy plus prn ranibizumab; and (3) 24 Gy plus 2 ranibizumab injections followed by prn ranibizumab. These studies determined that patients had preserved or improved vision along with a diminished need for ranibizumab using an optical coherence tomography (OCT)-guided retreatment protocol. Moreover, the 16 Gy plus prn ranibizumab group (ie, no mandated ranibizumab injections were given primarily) demonstrated a possible independent biologic effect on the CNV lesion of 16 Gy radiation alone.10-13
These early studies with the Oraya device formed the basis for the larger INTREPID study in previously treated wet AMD patients. This randomized, prospective, double-masked, multicenter, controlled clinical trial was based in Europe with more than 225 patients enrolled. The study had 4 arms in a 2:1:2:1 randomization scheme, with allotment favoring the radiation groups over the sham control groups. All groups received a baseline injection of ranibizumab followed by randomization to 4 treatment groups: (1) 16 Gy followed by prn ranibizumab; (2) sham 16 Gy radiation followed by prn ranibizumab; (3) 24 Gy radiation followed by prn ranibizumab; and (4) sham 24 Gy radiation followed by prn ranibizumab.
In this previously treated patient population, visual acuity was essentially unchanged after 12 months of treatment among the radiation treatment groups, and progressive ability to dehydrate the macula on OCT was demonstrated. The study met its primary efficacy endpoint by demonstrating an ability to reduce the number of prn ranibizumab injections in the active radiation treatment groups by 32% compared with the sham radiation plus prn ranibizumab groups (unpublished data). Also, post-hoc analysis looked at the best responders to stereotactic radiotherapy and identified a group of patients that experienced a 54% reduction in the number of injections and a mean visual superiority of 6.8 ETDRS letters compared with equivalent patients in the control group.
Putting the Clinical Trial Results in Perspective
Let’s put this in perspective. Consider that at the beginning of year 2 in the CATT study, the patients could be thought of as now being “previously treated” patients. In this previously treated patient population, patients received 5 to 11 injections to result in a net loss of vision in each of the 6 subgroups by the end of year 2.14 Similarly, in year 2 of the CATT study, only those patients receiving monthly injections did not gain any fluid on OCT, while those in the prn treatment groups all gained fluid in the second year. The CATT study used retreatment criteria that were representative of what average retina physicians employ in everyday practice for their patients with wet AMD. Namely, these criteria entail treating until there is absence of any intraretinal fluid and subretinal fluid. The INTREPID trial retreatment criteria, created prior to the revelation of the results of the CATT study, employed less-strict retreatment criteria than those of the CATT study, namely an increase in central retinal thickness of 100 μm or more compared with the last visit. Despite having a higher tolerance of fluid before initiating retreatment with ranibizumab, the INTREPID study demonstrated visual acuity stability with continuing dehydration of the macula on OCT with far fewer injections than was seen in the second year of the CATT study. In the INTREPID study, the radiation treatment groups received half as many injections as were performed in the prn treatment groups in the CATT study.
A common misconception when interpreting the results of the INTREPID study is to view them through the lens of treatment-naïve study results. In this study evaluating previously treated wet AMD, patients received 5.5 prior anti-VEGF treatments on average before study enrollment, with three quarters of those patients having received ranibizumab specifically.
By contrast, NeoVista’s CABERNET study, evaluated only treatment-naïve patients and did not meet its efficacy endpoint. Why might this be? The 3 most obvious reasons are vertical dose instability with EMBT with variation in the surgeon’s microscopic hand movements over 3 to 5 minutes, the CABERNET study’s evaluation of only treatment-naïve patients, and the possible confounding effect of pars plana vitrectomy on the study results with respect to possible altered pharmacokinetics of subsequent ranibizumab injections in the prn follow-up period.
In summary, there appears to be a role for radiation in the management of neovascular AMD. The NeoVista EMBT device did not meet its primary prespecified endpoint. As of March 2013, NeoVista is no longer operational.
Oraya’s device met its prespecified endpoints in the INTREPID study, and, is currently planning a pivotal trial. The first patient treated with the Oraya device outside a clinical trial occurred in February of 2013 in the United Kingdom, where marketing approval has been granted. The Oraya device has the CE Mark in the European Union and is available commercially in the UK and Switzerland.
Finally, a new entry into the radiation therapy arena, Salutaris MD (http://bmctoday.net/retinatoday/2013/01/article. asp?f=moorfields-eye-hospital-and-salutarismd-to-collaborateon- treatment-for-wet-amd), is evaluating a novel episcleral delivery device for its version of brachytherapy for wet AMD. After a positive small safety study in the United States, a larger trial is planned at Moorfields Eye Hospital in London.
- Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
- CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
- Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol. 2008;145:239-248.e5.
- Silva RA, Moshfeghi AA, Kaiser PK, Singh RP, Moshfeghi DM. Radiation treatment for age-related macular degeneration. Semin Ophthalmol. 2011;26(3):121-30.
- Avila MP, Farah ME, Santos A, et al. Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD. Retina. 2009;29:157-169.
- Avila MP, Farah ME, Santos A, Duprat JP, Woodward BW, Nau J. Twelve-month short-term safety and visualacuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol. 2009;93:305-309.
- Avila MP, Farah ME, Santos A, et al. Three-year safety and visual acuity results of epimacular 90 strontium/90 yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Retina. 2012;32:10-18.
- Dugel PU, Bebchuk JD, Nau J, et al; CABERNET Study Group. Epimacular Brachytherapy for Neovascular Agerelated Macular Degeneration: A Randomized, Controlled Trial (CABERNET). Ophthalmology. 2013;120(2):317-327.
- Dugel PU, Petrarca R, Bennett M, et al. Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety and efficacy results. Ophthalmology. 2012;119(7):1425-1431.
- Moshfeghi DM, Kaiser PK, Gertner M. Stereotactic low-voltage x-ray irradiation for age-related macular degeneration. Br J Ophthalmol. 2011;95:185-188.
- Moshfeghi AA, Canton VM, Quiroz-Mercado H, et al. 16-Gy low-voltage X-ray irradiation followed by as-needed ranibizumab therapy for AMD: 6-month outcomes of a “radiation-first” strategy. Ophthalmic Surg Lasers Imaging. 2011;42:1-8.
- VM, Quiroz-Mercado H, Velez-Montoya R, et al. 16-Gy low-voltage X-ray irradiation with ranibizumab therapy for AMD: 6-month safety and functional outcomes. Ophthalmic Surg Lasers Imaging. 2011;42:1-6.
- Canton VM, Quiroz-Mercado H, Velez-Montoya R, et al. 24-Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular AMD: 6-month safety and functional outcomes. Ophthalmic Surg Lasers Imaging. 2012;43:20-24.
- Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388- 1398.