Office-based External Beam Radiation Therapy for Age-related Macular Degeneration
Office-based External Beam Radiation Therapy for Age-related Macular Degeneration
JASON HSU, MD ∙ CARL D. REGILLO, MD
With the advent of intravitreal anti-vascular endothelial growth factor (VEGF) therapies bevacizumab (Avastin, Genentech) and ranibizumab (Lucentis, Genentech), ophthalmologists are now able to prevent significant vision loss in the majority of patients who develop neovascular age-related macular degeneration (AMD).1,2 However, the effects of these medications are short-lived and do not seem to cause complete involution of choroidal neovascularization (CNV). For example, in the clinical trials with Lucentis, monthly injections were found to be superior to quarterly injections.3 Therefore, in order to sustain the treatment benefit, most patients require repeated injections for an indefinite period of time. As a result, adjunct treatments that might provide a synergistic effect with Avastin or Lucentis are being explored. One area of interest for combination therapy involves the use of localized ionizing radiation.
Jason Hsu, MD, and Carl D. Regillo, MD, are retinal specialists at Wills Eye Institute in Philadelphia and Mid Atlantic Retina. They have no direct financial interest in the products mentioned in this report. The Retina Service of Wills Eye receives significant research support from NeoVista. Dr. Hsu can be reached via e-mail at firstname.lastname@example.org.
A SHORT HISTORY OF RADIATION
The idea of radiation as a treatment modality for wet AMD has been around for years. Local radiation therapies have been shown to prevent proliferation of vascular tissue via inhibition of neovascularization.4,5 Following exposure to low-dose radiation, vascular endothelium undergoes morphologic and DNA changes, inhibition of replication, increased cell permeability, and ultimately apoptosis.6-13 In addition, the proliferation of fibroblasts and formation of fibrosis, often seen in end-stage wet AMD, is inhibited.
Since CNV contains proliferating endothelial cells, it is preferentially more sensitive to radiation treatment compared to the nonproliferating capillary and larger vessel endothelial cells.14 Several clinical studies have supported the use of ionizing radiation alone for the treatment of neovascular AMD. The Age-Related Macular Degeneration Radiotherapy Trial suggested that external beam radiation with five fractions of 4 Gy had a modest but short-lived benefit in preserving visual acuity.15 Another randomized clinical trial enrolled 161 patients with subfoveal CNV Patients randomized to four fractions of 2 Gy (8 Gy total) and four fractions of 4 Gy (16 Gy total) showed a reduction in visual acuity loss during the 18 months of follow-up compared to control.16
However, others have shown no benefit as monotherapy.17 One randomized clinical trial of 83 eyes with subfoveal CNV showed no benefit or harm of seven fractions of 2 Gy (14 Gy total) by one-year follow-up.18 Another trial involving 203 patients randomly assigned to six fractions of 2 Gy (12 Gy) total vs observation showed no significant benefit in terms of moderate or severe vision loss at 24 months.19 A review of 11 randomized controlled clinical trials involving 1078 patients with external beam dosages ranging from 7.5 to 24 Gy revealed that most trials found effects that favored treatment though the results were not always significant.20 The authors concluded that more evidence was needed to support external beam radiotherapy as an effective treatment for neovascular AMD.
Clinical studies with ionizing radiation alone that have shown a benefit still fail to produce the results found in the Lucentis studies. However, intravitreal anti-VEGF therapies alone do not seem to cause complete involution of CNV, with recurrence often occurring after the injections are stopped. Radiation therapy has the theoretical benefit of more permanent CNV closure. Combining the two treatments may allow for a synergistic effect leading to more long-term visual benefits with fewer repeated intravitreal injections required.
One such clinical study that demonstrated this potential benefit involved a strontium 90 applicator (NeoVista, Fremont, CA) that can deliver a targeted dose of 24 Gy to the center of the CNV following a pars plana vitrectomy. When this device was combined with intravitreal Avastin, the 12-month results showed that 91% of patients lost <3 lines of vision and 38% gained ≥3 lines of vision. No further injections beyond 2 initial ones given 1 month apart were required in 26 of 34 patients (76%).21 A phase 3 multicenter, randomized, controlled study is currently underway to evaluate the effects of this strontium 90 applicator when combined with intravitreal Lucentis injections compared to Lucentis monotherapy.
OFFICE-BASED EXTERNAL BEAM RADIATION THERAPY
Unlike the strontium 90 applicator designed by NeoVista, an office-based radiotherapy treatment known as the IRay system (Oraya Therapeutics, Inc., Newark, CA) is being developed (Figure 1). This device is capable of delivering a highly localized dose of low-energy X-ray radiation to the macula. The eye to be treated is carefully stabilized using a specially designed mechanical arm that applies applanation force (Figure 2). Using a robotic device to keep the eye properly aligned, the X-ray beams are maneuvered such that they enter the eye through the pars plana region and target the macula.
Figure 1. The office-based IRay system designed by Oraya Therapeutics, Inc.
Figure 2. The I-Guide allows precise alignment of the eye to more accurately deliver the external beam radiation to the macula while avoiding other structures such as the lens and optic nerve.
The angle of beam entry was chosen to minimize collateral damage to radiosensitive structures, especially the lens and optic nerve (Figure 3).22 Each treatment involves three fractionated doses of 8 Gy for a total of 24 Gy in order to replicate the findings from the NeoVista study. One beam will enter approximately at mid-quadrant inferonasally; the second beam will enter inferiorly at 6 o'clock; and the third beam will enter approximately at mid-quadrant inferotem-porally Depending on the vertical tilt of the optic nerve, the inferotemporal beam has the highest risk of exposing the optic nerve to a maximum of 1.7 Gy that is well below the mean dose of 8 Gy, which is felt to be the minimum potentially deleterious exposure level.23
Figure 3. Illustration of the trajectory of the external beam radiation through the pars plana region into the macula, avoiding the lens and optic nerve.
The benefits of an office-based procedure are numerous. Oraya Therapeutics estimates that each procedure should take only 10 to 20 minutes to complete, allowing for significant time savings in comparison with surgery. Since it is noninvasive, there is no additional risk of infection, hemorrhage, retinal tears, or retinal detachment. In patients who are phakic, the requirement for pars plana vitrectomy with the strontium 90 applicator increases the rate of cataract formation. Since the beam path with the IRay system avoids the lens, the rate of cataract formation should not be overly influenced. Without the need for operating room personnel, radiation oncologists, anesthesia, and instrumentation, the IRay system may also be more cost-effective.
To date, no clinical data have been published about the IRay system. A feasibility trial is currently underway and has shown that the device is well tolerated with only topical anesthesia and has not been associated with any short-term complications. The results of a large-scale randomized clinical trial will be necessary to determine if the IRay system in combination with intravitreal anti-VEGF injections provides any additional benefits.
POTENTIAL BENEFITS OF STRONTIUM 90 APPLICATOR
However, the strontium 90 applicator procedure may hold its own benefits when compared with the IRay system. Strontium 90 has a very rapid fall-off in radiation delivery, losing approximately 10% of its energy for every 0.1 mm away from the source. As a result, the radiation exposure to collateral structures such as the lens and optic nerve is well below the threshold of tolerance. The IRay system exposes all structures in its beam path to radiation, including the entry conjunctiva and sclera, which could theoretically increase the risk of unwanted side effects. Fortunately, the 8 Gy fraction is below the usual dose that causes severe damage to these structures.24 An additional potential benefit is the need for vitrectomy prior to insertion of the strontium 90 applicator over the macula. Previous studies have suggested that vitrectomy alone may produce some degree of CNV regression, perhaps due to increased oxygenation.25,26 In addition, enhanced oxygenation may improve the therapeutic effect of radiation.27
FUTURE ROLE OF RADIATION THERAPY FOR AMD
The potential role of radiation therapy for AMD hinges on the results of larger randomized clinical trials. Based on the early trials with the strontium 90 applicator, radiation therapy holds the greatest promise as part of a combination approach with anti-VEGF injections. If radiation therapy can be proven to decrease the number of required anti-VEGF injections while still maintaining results similar to the clinical trials with monthly intravitreal Lucentis injections, then this combination could significantly reduce the tremendous cost associated with treating neovascular AMD. An office-based system, such as the IRay, could provide even further benefits due to its noninvasive nature, relative ease of delivery, and time savings. However, further studies will be necessary to confirm a clinical benefit of this system before any conclusions can be made. RP
- Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1432-1444.
- Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431.
- 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.
- Krishnan L, Krishnan EC, Jewell WR. Immediate effect of irradiation on microvas-culature. Int J Radiat Oncol Biol Phys. 1988;15:1447-1450.
- Chakravarthy U, Gardiner TA, Archer DB, Maguire JF. A light microscopic and autoradiographic study of non-irradiated and irradiated ocular wounds. Curr Eye Res. 1989;8:337-348.
- Mooteri SN, Podolski JL, Drab EA, et al. WR-1065 and radioprotection of vascular endothelial cells, II: morphology. Radiat Res. 1996;145:217-224.
- Rosander K, Zackrisson B. DNA damage in human endothelial cells after irradiation in anoxia. Acta Oncol. 1995;34:111-116.
- Rubin DB, Drab EA, Kang HJ, Baumann FE, Blazek ER. WR-1065 and radioprotection of vascular endothelial cells, I: cell proliferation, DNA synthesis, and damage. Radiat Res. 1996;145:210-216.
- Verheif M, Koomen GCM, van Mourik JA, Dewitt L. Radiation reduces the cyclooxygenase activity in cultured human endothelial cells at low doses. Prostaglandins. 1994;48:351-366.
- Hosoi Y, Yamamoto M, Ono T, Sakamoto K. Prostacyclin production in cultured endothelial cells is highly sensitive to low doses of ionizing radiation. Int J Radiat Biol. 1993;63:631-638.
- Hallahan D, Clark ET, Kuchibhotla J, Gewertz BL, Collins T. E-selectin gene induction by ionizing radiation is independent of cytokine induction. Biochem Biophys Res Commun. 1995;217:784-795.
- Eissner G, Kohluhuber F, Grell M, et al. Critical involvement of transmembrane tumor necrosis factor-alpha endothelial programmed cell death mediated by ionizing radiation and bacterial endotoxin. Blood. 1995;86:4184-4193.
- Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy-clinical histopatho-logical, ultrastructural and experimental correlations. Eye. 1991;5:239-251
- Maguire AM, Schachat AP. Radiation retinopathy. In: Ryan SJ, ed. Retina. St Louis, MO: Mosby; 1994.
- The AMDRT Research Group. The Age-Related Macular Degeneration Radiotherapy Trial (AMDRT): one year results from a pilot study. Am J Ophthalmol. 2004; 138:818-828.
- Valmaggia C, Ries G, Ballinari P. Radiotherapy for subfoveal choroidal neovascularization in age-related macular degeneration: a randomized clinical trial Am J Ophthalmol. 2002;133:521-529.
- Hoeller U, Fuisting B, Schwartz R, Roeper B, Richard G, Alberti W. Results of radiotherapy of subfoveal neovascularization with 16 and 20 Gy. Eye. 2005; 19:1151-1156.
- Marcus DM, Sheils WC, Johnson MH, et al. External bean irradiation of subfoveal choroidal neovascularization complicating age-related macular degeneration. Arch Ophthalmol. 2001;119:171-180.
- Hart PM, Chakravarthy U, Mackenzie G, et al. Visual outcomes in the subfoveal radiotherapy study. Arch Ophthalmol. 2002;120:1029-1038.
- Sivagnanavel V, Evans JR, Ockrim Z, Chong V Radiotherapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004004.
- Avila MP, Farah ME, Santos A, et al. Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal stron-tium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol. 2009;93:305-309.
- Lee C, Chell E, Gertner M, et al. Dosimetry characterization of a multibeam radiotherapy treatment for age-related macular degeneration. Med Phys. 2008;35: 5151-5160.
- Girkin CA, Comey CH, Lunsford LD, Goodman ML, Kline LB. Radiation optic neuropathy after stereotactic radiosurgery. Ophthalmology. 1997;104:1634-1643.
- National Council on Radiation Protection and Measurements. Biological Effects and Exposure Limits for Hot Particles. Report No. 130. Bethesda, MD: National Council on Radiation Protection and Measurements; 1999.
- Ikeda T, Sawa H, Koizumi K, Yasuhara T, Yamasaki T. Pars plana vitrectomy for regression of choroidal neovascularization with age-related macular degeneration. Acta Ophthalmol Scand 2000;78:460-464.
- Stefansson E, Landers MB, Wolbarsht ML. Vitrectomy, lensectomy, and ocular oxygenation. Retina. 1982;2:159-166.
- Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in squamous cell carcinoma of the head and neck. Radiother Oncol. 1996;41:31-39.
Retinal Physician, Issue: September 2009