Low-Voltage X-Ray Combined with Anti-VEGF Therapy in the Treatment of Neovascular AMD
Intravitreal injection of an anti-vascular endothelial growth factor (anti-VEGF) agent is the standard of care for the treatment of neovascular age-related macular degeneration (AMD). Patients with neovascular AMD treated with anti-VEGF therapy frequently gain and maintain favorable visual acuity outcomes. However, “real-world” outcomes with anti-VEGF therapy have been reported to be substantially worse than those achieved in clinical trials and many patients experience suboptimal visual outcomes.1,2 Some patients fail to respond optimally to anti-VEGF therapy, either initially or over time.3
Ionizing radiation (IR) has been proposed as an adjunct to anti-VEGF therapy in the long-term management of patients with neovascular AMD. IR disrupts cell mitosis and acts preferentially on cells with rapid cell division cycles, including vascular endothelial cells associated with choroidal neovascular (CNV) lesions. Mature cells and cells that are mitotically inactive engage intracellular mechanisms to repair DNA damage and remain viable.4 The IRay system (Oraya Therapeutics, Newark, CA) is commercially available in Europe, and delivers robotically controlled, microcollimated 100 kV X-ray irradiation to the retina using stereotactic technique.
The INTREPID study of stereotactic radiotherapy (SRT) using IRay was a randomized, double-masked, sham-controlled study among patients treated previously for neovascular AMD of the effect of SRT plus pro re nata (PRN) anti-VEGF therapy versus sham SRT plus PRN anti-VEGF therapy. The primary endpoint was the mean number of anti-VEGF injections at 1 year. The study met its primary endpoint; patients who received SRT were treated with 33% fewer anti-VEGF injections at 1 year (P = .001), while maintaining equivalent visual acuity outcomes, compared to patients who received sham radiation.5
Post hoc analysis of baseline characteristics showed that the greatest benefit was seen in eyes with a CNV lesion of 4 mm or less in greatest linear dimension (corresponding to the size of the X-ray beam diameter) and significant exudation (as evidenced by abnormal macular volume on OCT) at the time of irradiation. In these so-called “best responder” eyes, there was a 55% reduction in the number of anti-VEGF injections (P = .0002) and a greater letter gain of visual acuity in eyes that received SRT compared to eyes that received sham SRT (P =.028).6 The treatment benefits persisted through year 2, with 25% and 45% reductions in the number of anti-VEGF injections in the full cohort and the best-responder group, respectively.7
One challenge of integrating the IRay into practice is to determine which patients to treat and when. Most users typically select patients who meet the “best responder” profile.8 The question of when to use SRT was not fully answered by INTREPID. In my opinion, SRT may be helpful in three groups of patients:
Patients treated with anti-VEGF therapy who have experienced inadequate improvement or worsening in visual acuity or retinal morphology. These patients may be identified after as few as three monthly anti-VEGF injections.9,10 Adjunctive use of SRT would be intended to bring the disease under control, thus permitting anti-VEGF therapy to maintain a dry macula.
Patients whose AMD may be controllable with anti-VEGF, but who require more frequent injections than can be administered/tolerated. Adjunctive use of SRT would be intended to reduce treatment burden.
Patients at initial diagnosis or during a disease recurrence after extended quiescence, to help reduce the rate of inadequate response and prolong visual acuity gains with fewer anti-VEGF injections.
In a short-term economic model, for patients with a CNV lesion ≤4 mm in diameter and with high exudative activity, the cost savings over 2 years from fewer anti-VEGF injections offset the costs of SRT therapy in a German practice setting.11
Anti-VEGF monotherapy has been demonstrated to be associated with a significant improvement in visual acuity outcomes for many patients with neovascular AMD. Adjunctive use of SRT has been reported to be effective in neovascular AMD, especially in patients who respond suboptimally to anti-VEGF therapy and who have a CNV lesion ≤4mm in diameter with high exudative activity.
Reference(s):1. Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015;99(2):220-226.
2. Tufail A, Xing W, Johnston R, et al; Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity. Ophthalmology. 2014;121(5):1092-1101.
3. Amoaku WM, Chakravarthy U, Gale R, et al. Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond). 2015;29(6):721-731.
4. Chakravarthy U, Klein SB. Radiation Biology of Choroidal Neovascularisation of Age-Related Macular Degeneration. In Age-related Macular Degeneration: Current Treatment Concepts. Alberti WE, Richard G, Sagerman RH, eds. 2000, Springer-Verlag Berlin and Heidelberg GmbH & Co. KG. p. 8.
5. Jackson TL, Chakravarthy U, Kaiser PK, et al; INTREPID Study Group. Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week safety and efficacy results of the INTREPID study. Ophthalmology. 2013;120(9):1893-1900.
6. Jackson TL, Shusterman EM, Arnoldussen M, et al; INTREPID Study Group. Stereotactic radiotherapy for wet age-related macular degeneration (INTREPID): influence of baseline characteristics on clinical response. Retina. 2015;35(2):194-204.
7. Jackson TL, Chakravarthy U, Slakter JS, et al; INTREPID Study Group. Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study. Ophthalmology. 2015;122(1):138-145.
8. Jackson TL, Rennie I, Aslam T, Hatz K, Grisanti S, Brand C. See the Impact of Oraya Therapy on Wet AMD patients. Presentation at 14th EURETINA Congress 13 September 2014, London.
9. Korb C, Zwiener I, Lorenz K, et al. Risk factors of a reduced response to ranibizumab treatment for neovascular age-related macular degeneration--evaluation in a clinical setting. BMC Ophthalmol. 2013;13:84.
10. Stellungnahme der Retinologischen Gesellschaft, der Deutschen Ophthalmologischen Gesellschaft und des Berufsverbands der Augenärzte Deutschlands zur Strahlentherapie bei neovaskulärer altersabhängiger Makuladegeneration. Der Ophthalmologe. 2015;112(11):912-916.
11. Neubauer AS, Reznicek L, Minartz C, Ziemssen F. Economic short-term cost model for stereotactic radiotherapy of neovascular AMD (Oraya system). Klin Monatsbl Augenheilkd. 2016, in press.
About our author(s):
Aljoscha Steffen Neubauer,
Mahdy Ranjbar, MD