A Combination of Anti-VEGF Therapy and Epi-retinal Radiation for the Treatment of Neovascular Age-related Macular Degeneration
Radiation therapy1 has been studied previously as a possible treatment for neovascular age-related macular degeneration (AMD).2-4 The use of radiation as a treatment modality is based on the concept that neovascular AMD is analogous to a proliferative wound healing process,5 and proliferating cells and inflammatory cells are sensitive to the effects of radiation.6-7 Choroidal neovascular membrane (CNV) complexes are histologically comprised of a vascular network, local inflammatory cell populations, and fibroblasts.8 The effects of radiation on normal and injured vasculature have been explored in multiple animal and human studies,9-10 mostly from the cardiovascular literature. Ionizing radiation acts by forming free radicals (primarily from water molecules) that cause irreparable damage (double strand breaks) to the DNA backbone and disrupt protein synthesis.11 The irradiated cell is unable to replicate; however, it does not lose its cellular integrity or undergo necrosis. Radiation has been shown to induce endothelial cell loss10 in vivo and collagen synthesis in cultured fibroblasts.12 The apoptotic effect on the vascular endothelium and reduction in fibroblast activity of the CNV complex do not manifest with the use of anti-VEGF therapy alone.
Unlike previous studies in which large areas of retinal tissue were irradiated to achieve a therapeutic dose to the lesion, the NeoVista System is an investigational device (intraocular strontium-90 applicator) that places the radiation source into close approximation with the CNV complex. This device allows for irradiation of a very focused area and small volume of retina tissue. This novel delivery method of delivering the source within the intraocular cavity is unprecedented. Plaque brachytherapy utilizes the same principle, although the source is placed outside of the sclera, underlying the lesion. The design of the plaque delivery method exposes the underlying structures of the retina such as the choriocapillaris to high doses of radiation to account for dose reduction at the CNV complex.
The rapid reduction in dose that is inherent to the strontium-90 radiation of the NeoVista system limits radiation exposure to the normal tissue surrounding the lesion (0.0039 Gy to the cornea, 0.0040 Gy to the conjunctiva, 0.0056 Gy to the lens, and 2.4 Gy to the optic nerve; NeoVista Inc., data on file). Treating a small area of the retina with the therapeutic dose of 24 Gy, as well as the small volume of retina actually receiving clinically relevant levels of radiation, may reduce or eliminate radiation retinopathy that has been seen with previous treatment methods utilizing ionizing radiation.
In a prospective, nonrandomized, multicenter pilot study, patients with predominantly classic, minimally classic, and occult (with no classic) CNV received a single treatment with 24 Gy brachytherapy using an investigational medical device (intraocular strontium-90 applicator; NeoVista, Inc., Fremont, CA) and two injections of the anti-VEGF antibody bevacizumab. Only one eye per patient received the investigational treatment. In the first 12 months of follow-up, there were no instances of radiation-induced toxicity or adverse events attributed to radiation exposure with the intraocular strontium-90 applicator. This is consistent with an earlier study with two year follow-up of patients treated with 24 Gy radiation delivered alone. Adverse events reported at month 12 included subretinal hemorrhage (1/34), retinal tear (1/34), subretinal fibrosis (2/34), epi-retinal membrane (1/34), and cataract (6/24; 24 patients were phakic at baseline). At month 12, the mean change in BCVA from the baseline visit in the Intent to Treat population (ITT-all available data; N=34) treated with 24 Gy brachytherapy and bevacizumab was a gain of 8.9 letters of vision. The peak mean BCVA for the population, a gain of over 15 letters (three lines), was reported at the month three visit. This is consistent with studies of anti-VEGF therapy, which demonstrated the most VA improvement within the first three months.13, 14, 15 At month 12, 91% (31/34) of patients treated with 24 Gy brachytherapy and bevacizumab lost fewer than 15 letters and 68% (23/34) had stable or improved vision. Nearly 40% (13/34) of patients experienced a clinically significant improvement in vision at month 12, defined as a gain of 15 or more letters (3 lines).
The rationale supporting a synergistic response with a combination regimen of radiation and antiangiogenic therapy is based on a two-pronged approach for treating the CNV complex: antiangiogenic therapy inhibits growth factors present in the local region and radiotherapy kills or disables the local inflammatory cell population and eventually the endothelial cells of the neovascular vessel. Together, the combination of these two effects may allow for faster and more complete recovery of functional vision. In the pilot studies discussed above, data showed encouraging results with a single application of epi-retinal beta radiation and two injections of anti-VEGF antibody. Based on the outcome of these studies this combination regimen is now being evaluated in a large, multicenter, phase III study - The CABERNET study.
Schmidt-Erfurth UM, Richard G, Augustin A, et al. Guidance for the treatment of neovascular age-related macular degeneration. Acta Ophthalmol Scand 2007;85:486-94.
Chakravarthy U, Houston RF, Archer DB. Treatment of age-related subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol 1993;77:265-73.
Finger PT, Berson A, Ng T, et al. Ophthalmic plaque radiotherapy for age-related macular degeneration associated with subretinal neovascularization. Am J Ophthalmol 1999;127:170-7.
Jaakkola A, Heikkonen J, Tommila P, et al. Strontium plaque irradiation of subfoveal neovascular membranes in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 1998;236:24-30.
Ambati J, Ambati BK, Yoo SH, et al. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol 2003;48:257-93.
De Gowin RL, Lewis LJ, Hoak JC, et al. Radiosensitivity of human endothelial cells in culture. J Lab Clin Med 1974;84:42-8.
Sagerman RH, Chung CT, Alberti WE. Radiosensitivity of ocular and orbital structures. In: Alberti WE, Sagerman RH ed.| Book Title|. Edition ed|. City|: Publisher| Year|:Pages|.
Grossniklaus HE, Martinez JA, Brown VB, et al. Immunohistochemical and histochemical properties of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 1992;114:464-72.
Waksman R, Bhargava B, Saucedo JF, et al. Yttrium-90 delivered via a centering catheter and afterloader, given both before and after stent implantation, inhibits neointima formation in porcine coronary arteries. Cardiovasc Radiat Med 2000;2:11-7.
Verin V, Popowski Y, de Bruyne B, et al. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. The Dose-Finding Study Group. N Engl J Med 2001;344:243-9.
Hosoi Y, Yamamoto M, Ono T, et al. Prostacyclin production in cultured endothelial cells is highly sensitive to low doses of ionizing radiation. Int J Radiat Biol 1993;63:631-8.
Kirwan JF, Constable PH, Murdoch IE, et al. Beta irradiation: new uses for an old treatment: a review. Eye 2003;17:207-15.
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-44.
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;145:239-48.
About our author(s):
Michael S. Ip, MD
Associate Professor of Ophthalmology
University of Wisconsin-Madison