November 2010, Issue 47
Novel Radiation Technique for the Treatment of Neovascular Age-Related Macular Degeneration
Marcos Ávila, MD
Federal University of Goiás
Radiotherapy for neovascular age-related macular degeneration (AMD) has been studied since the early 1990s. One of the studies considered to be a more “modern” review of external beam radiation for neovascular AMD was published in 1996.1 Although there was a good amount of optimism for this concept early on, it has been difficult to assess the efficacy of radiation for neovascular AMD because the studies that have been performed offer no consensus. For example, there are as many published studies that show a positive effect2-8 as those showing an equivocal or no effect.9-14 The various studies used differing doses and fractionations of radiation and this may explain why the results are so variable.
The main challenge in many of these studies that focus on the use of radiation for the destruction of angiogenic cells has been avoiding damage to other areas of the retina. External beam radiation is not precisely localized, which reduces the efficacy and the ability to target a specific area with a high dose of radiation.
The method of radiation delivery, type of radiation administered, and the dose delivered are very important factors in determining therapeutic outcomes. The biggest difference between the various types of radiation is their penetrating power. Alpha particles penetrate poorly and can be stopped by a piece of paper. Gamma rays require large lead-lined, lead-and-concrete-mixed walled rooms to protect those outside the room when the radiation is taking place. The penetration of beta rays falls between alpha and gamma rays and can be stopped by fairly simple measures. Strontium 90 beta radiation is most intense at the source and, within a few millimeters, there is very little radiation present. Beta radiation penetration can be halted by surrounding tissue in the retina, which is essentially water. Therefore, it is appropriate for targeted delivery to the retina.
The Epimacular Brachytherapy System (Neovista, Fremont, CA) uses 24 Gy strontium 90 brachytherapy. The device brings the actual radiation to the lesion itself with a rapid falloff. The volume of tissue affected by the radiation is small, along the order of a few millimeters.
The majority of clinical trials that used radiation for AMD in the past did so with external beam delivery. It is very difficult to deliver a precise dose of radiation using external beam techniques to volumes smaller than 4 centimeters in diameter.
Epimacular brachytherapy has shown promising results in pilot studies.15-16 The safety and efficacy of this intervention is being evaluated further in two large phase III randomized trials.15-16
The CABERNET trial (n=450), which is the pivotal phase III, multicenter (45 sites) trial, is designed to evaluate the safety and visual acuity outcomes of treatment-naïve patients in two arms: patients treated with the Epimacular Brachytherapy System and two intravitreal injections of ranibizumab 1 month apart, and patients treated with intravitreal ranibizumab monthly for the first three injections, then followed by quarterly injections. Both groups receive ranibizumab rescue treatment based on predefined retreatment criteria
The MERLOT trial has a target recruitment of 363 subjects and is based in the United Kingdom. The trial receives support from the National Institute for Health Research (NIHR) via the Comprehensive Clinical Research Network (CCRN). The CCRN aims to provide support for studies that are scientifically robust, and address areas of importance to the National Health Service. Patients in the MERLOT study are randomized to either epimacular brachytherapy or anti-VEGF monotherapy (control). Both groups receive ranibizumab rescue treatment based on predefined retreatment criteria. The co-primary outcome measures are mean number of anti-VEGF injections over 12 months, and mean ETDRS visual acuity.
Radiation preferentially damages the cells that mediate vision loss in neovascular AMD. It was, therefore, somewhat unexpected that early studies of external beam radiation failed to show significant benefit. Interest in radiation treatment of neovascular AMD has recently been rekindled, using devices that provide more focal delivery and less collateral damage than external beam radiation therapy. Large randomized clinical trials of epimacular brachytherapy are underway.
- Hart PM, Chakravarthy U, MacKenzie G, Archer DB, Houston RF. Teletherapy for subfoveal choroidal neovascularisation of age-related macular degeneration: results of follow up in a nonrandomized study. Br J Ophthalmol. 1996;80(12):1046-1050.
- Bergink GJ, Deutman AF, van den Broek JF, van Daal WA, van der Maazen RW Radiation therapy for subfoveal choroidal neovascular membranes in age-related macular degeneration. A pilot study. Graefes Arch Clin Exp Ophthalmol. 1994;232(10):591-598.
- Finger PT, Berson A, Sherr D, Riley R, Balkin RA, Bosworth JL. Radiation therapy for subretinal neovascularization. Ophthalmology. 1996;103(6):878-889.
- Matsuhashi H, Takahashi D, Noda Y, Mariya Y, Tarusawa N, Yoshimoto H, Matsuyama S. Lowdose radiation, therapy for choroidal neovascularization in age-related macular degeneration. [Article in Japanese] Nippon Ganka Gakkai Zasshi. 1996;100(10):803-809.
- Freire J, Longton WA, Miyamoto CT, Brady LW, Augsburger J, Brown G, Micaily B, Unda R. External radiotherapy in macular degeneration: technique and preliminary subjective response. Int J Radiat Oncol Biol Phys. 1996;36(4):857-860.
- Schwartz LH, Schmitt T, Benchaboun M, et al. Radiotherapy and age-related macular degeneration: a review of the literature. [Article in French] Cancer Radiother. 1997;1(3):208-212.
- Jaakkola A, Heikkonen J, Tommila P, Laatikainen L, Immonen I. Strontium plaque irradiation of subfoveal neovascular membranes in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 1998;236(1):24-30.
- Brady LW, Freire JE, Longton WA, et al. Radiation therapy for macular degeneration: technical considerations and preliminary results. Int J Radiat Oncol Biol Phys. 1997 1;39(4):945-948.
- Valmaggia C, Bischoff P, Ries G. Low dosage radiotherapy of subfoveal neovascularization in age-related macular degeneration. Preliminary results. [Article in German] Klin Monatsbl Augenheilkd. 1995;206(5):343-346.
- Valmaggia C, Bischoff P, Ries G. Low dosage radiotherapy of subfoveal neovascularizations in age related macular degeneration. Results after 6 weeks and 6 months. [Article in German] Klin Monatsbl Augenheilkd. 1996;208(5):315-317.
- Stalmans P, Leys A, Van Limbergen E. External beam radiotherapy (20 Gy, 2 Gy fractions) fails to control the growth of choroidal neovascularization in age-related macular degeneration: a review of 111 cases. Retina. 1997;17(6):481-492.
- Roesen B, Scheider A, Kiraly A, Gofferjé MA, Feldmann HJ. Choroid neovascularization in senile macular degeneration. 1 year follow-up after radiotherapy. [Article in German]
- Ophthalmologe. 1998;95(7):461-465.
- Spaide RF, Guyer DR, McCormick B, Yannuzzi LA, Burke K, Mendelsohn M, Haas A, Slakter JS, Sorenson JA, Fisher YL, Abramson D. External beam radiation therapy for choroidal neovascularization. Ophthalmology. 1998;105(1):24-30.
- Bergink GJ, Hoyng CB, van der Maazen RW, Vingerling JR, van Daal WA, Deutman AF. A randomized controlled clinical trial on the efficacy of radiation therapy in the control of subfoveal choroidal neovascularization in age-related macular degeneration: radiation versus observation. Graefes Arch Clin Exp Ophthalmol. 1998;236(5):321-325.
- Avila MP, Farah M, 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 choroidal neovascularization secondary to age-related macular degeneration. Retina. 2009;29(2):157-169.
- Avila MP, Farah ME, Santos A, Duprat JP, Woodward BW, Nau J. Twelve-month short-term safety and visual acuity results from a multicentre prospective study of epitretinal strontium-90 brachytherapy with bevaciumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol. 2009;93(3):305-309. Epub 2008 Nov
Ingrid U. Scott,
MD, MPH, Editor
Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine