Shedding New Light on Wet AMD Therapy
Oraya Therapy works with a stereotactic, low-voltage X-ray irradiation system designed specifically for the treatment of neovascular AMD. This system consists of the following components:
- Precision-controlled X-ray tube
- Patient interface
- Eye stabilizing device
- Eye tracking module
- Intuitive operator interface
The IRay System is designed to deliver three overlapping X-ray beams to the macula, each 4 mm in diameter. The beams are directed into the eye while the patient sits comfortably in a chair, with the head positioned on a chin rest. The entire procedure takes about 20 minutes and the patient can go home after the appropriate post- treatment evaluations are made. The actual treatment time is approximately four minutes.
Principles of Radiation Treatment for Wet AMD
Radiation has a long history in the treatment of cancer. It is very effective in the destruction of rapidly dividing tumor and vascular cells. Unlike ablative therapies such as laser photocoagulation, only a small amount of energy is delivered to the cells leaving them largely intact and functioning. However, ionizing radiation can disrupt DNA to such an extent that the cell is no longer able to divide. Cells undergoing rapid growth (such as in tumors or neovascular tissues) are more radiosensitive than those that are senescent or reproducing slowly enough to repair the damage from the radiation.
Mechanisms of Action of Radiation Therapy
Ionizing radiation is used medically for its anti-angiogenic, anti-inflammatory, and anti-fibrotic effects, which most likely play a role in its impact on wet AMD.1
Cells undergoing mitosis must pass enzymatic checkpoints to verify that their chromosomes are acceptable for reproduction. Radiation can create enough DNA damage to prevent successful completion of a checkpoint, causing the cell to undergo apoptosis. Non-mitotic cells (such as nerve cells) remain largely unaffected. Slowly replicating cells (such as normally proliferating vascular endothelial cells) generally have time to repair the damage or to be replaced by recruitment from outside the target region.
AMD is an inflammatory disease, and a substantial fraction of the therapeutic value of radiation is related to the reduction of inflammation. This may occur directly by the disruption of cytokines and leukocytes or indirectly through the death of neovascular endothelial cells which express the pro-inflammatory cytokines.
Radiation can inhibit the fibrosis that leads to the disciform scarring associated with AMD. It may prevent the metaplasia of endothelial cells into fibrotic glia by causing them to undergo apoptosis. Additionally, fibrovascular growth is reduced by interrupting angiogenesis.
A meta-analysis of published papers was performed in 2010 by the Cochrane Collaboration, which examined the effects of radiotherapy on wet AMD in more than one thousand patients.2 The radiotherapy was delivered using high-energy external beam systems (with the exception of one study that used brachytherapy), and doses ranged from 7.5 to 24 Gy. The analysis determined that no patients suffered radiation retinopathy, optic neuropathy or malignancy.
Three-year safety data of epiretinal brachytherapy using a 24 Gy dose also showed a positive safety profile.3
Oraya Therapy has been tested in clinical trials at 16 and 24 Gy doses in hundreds of patients, many who have now been monitored for several years. There have been no clinically significant radiation or procedure-related adverse events.4-7
The Oraya device uses a proprietary narrow, low-energy (100 kVp) X-ray beam to treat a small volume of the macula. The X-ray beam is incident onto an integrated beam-stop, so scattered radiation levels are very low and additional shielding is not necessary. The highly collimated beams, 4 mm in diameter, allow precise targeting of the macula while minimizing dose to other tissues. The patient total-body effective dose is only about 0.3 mSv, comparable to a head radiography series, or one-tenth of a head CT scan. This is approximately the same background radiation dose as a person would naturally receive in a month.
The system also includes a number of safety features to protect both patient and operators. System input is limited to globe axial length, and no patient-specific dose planning is required. The eye position is monitored in real-time, and if there is excessive eye motion, the beam is automatically shut off. A shielded partition protects the operator during treatment.
1Silva, R. A., Moshfeghi A. A., et al. “Radiation Treatment for Age-Related Macular Degeneration.” Semin Ophthalmol 26.3 (2011):121-30.
2Evans, J. R., Sivagnanavel V., et al. “Radiotherapy for Neovascular Age-Related Macular Degeneration.” Cochrane Database Syst Rev 5 (2010):CD004004.
3Avila, M.P., et al. “Three-year safety and visual acuity results of epimacular 90Strontium/90Yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.” Retina 32 (2012):10-18.
4Canton, V. M., Quiroz-Mercado, H., et al. “24-Gy Low-Voltage X-Ray Irradiation with Ranibizumab Therapy for Neovascular AMD: 6-Month Safety and Functional Outcomes.” Ophthalmic Surge Lasers Imaging 43.1 (2012):20-4.
5Canton, V. M., Quiroz-Mercado, H., et al. “16-Gy Low-Voltage X-ray Irradiation With Ranibizumab Therapy for AMD: 6-Month Safety and Functional Outcomes.” Ophthalmic Surge Lasers Imaging 42.6 (2012):468-73.
6Moshfeghi, A. A., Morales-Canton, V.M., et al. “16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a ‘radiation-first’ strategy.” Br J Ophthalmol 96.10 (2012):1320-4.
7Jackson, T. L., Chakravarthy, U., et al. “Stereotactic Radiotherapy for Neovascular Age-Related Macular Degeneration: 52-Week Safety and Efficacy Results of the INTREPID Study.” Ophthalmology Epub 2013 Mar 12