Radiation therapy has been evaluated extensively as a treatment for choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) because of its antiangiogenic, antifibrotic, and anti-inflammatory properties.1-3 Historically, radiation for AMD has been delivered with two broad approaches: (1) radiotherapy with external beam (megavoltage x-rays, proton beam) and (2) brachytherapy with radioactive isotopes (strontium-90, palladium-103).4-11
Clinical studies of external beam radiation in neovascular AMD have produced mixed results, leaving retina specialists undecided about whether it is a viable treatment option. Because the delivery of external beam radiation is not localized, it has limited ability to target only affected cells without collateral damage to healthy tissue. Low-dose beta radiation inhibits angiogenesis and has been used in the treatment of ocular tumors.12
The effects of radiation on neovascularization are usually delayed, sometimes by several months. During this period, the choroidal neovascular membrane can continue to grow and cause retinal damage, leading to a reduction in visual acuity before the radiation effect begins. Due to its time-of-onset limitation, radiation for wet AMD is ineffective as a monotherapy in the majority of patients.
TARGETED DELIVERY
Two companies, NeoVista, Inc. (Fremont, CA), and
Oraya Therapeutics, Inc. (Newark, CA), are evaluating
technologies designed to provide more targeted delivery
of radiation. The Vidion Anti-Neovascular (ANV;
NeoVista) therapy system utilizes a surgically inserted
device to deliver intraocular exposure of radiation to
the macula with strontium-90 in an epiretinal plaque
brachytherapy technique over leaking blood vessels that
affect central vision without causing damage to surrounding
tissues. The IRay system (Oraya) is an investigational,
stereotactic, radiosurgical device that uses a
noninvasive, robotically controlled platform to deliver
low-energy x-rays.
EPIMACULAR BRACHYTHERAPY
In epimacular brachytherapy, a three-port pars plana
vitrectomy allows the Vidion ANV to deliver beta radiation.
The Vidion ANV comprises a strontium-90 source
within an endoscopic probe that is held over the AMD
lesion for approximately 4 minutes and then removed
from the eye. According to the company, the Vidion
ANV is designed to deliver targeted beta radiation to
leaking blood vessels that affect central vision without
causing damage to surrounding tissues. The treatment
delivers the highest dose (24 Gy) to the center of the
lesion, but the optic nerve receives only 2.4 Gy and the
lens 0.0006 Gy. Stronium-90, with the proper dose rate
and fractionation, enables epimacular brachytherapy
with the Vidion ANV to deliver high doses of radiation
to treat the lesions without causing damage to the surrounding
tissues.
ROBOTICALLY-CONTROLLED X-RAY
IRRADIATION THERAPY
The IRay system is designed to deliver low-energy
x-rays precisely and reproducibly to the macula of
patients with wet AMD in an office-based setting.
According to Oraya, treatment planning with the IRay
includes an A-scan ultrasound for axial length and the
optic disk edge-to-fovea center distance. To limit radiation
exposure to the optic nerve, patients with an optic
disk edge-to-fovea center distance greater than 3 mm
are ineligible for treatment.
When treatment is initiated, the robotically controlled device moves the x-ray point source 150 mm from the plane of the macula following a predetermined offset directly over the macula. Three 3.5-mm beams are introduced through the inferior pars plana at the 5-, 6-, and 7-o'clock positions. Each beam consists of 5.33 Gy at a distance of 150 mm from the point source. The beams overlap precisely on the macula to achieve a single 4-mm spot of total dose (16 Gy).13 A lid speculum pulls the lower eyelid out of the path of radiation. The I-Guide (Oraya) suction-based contact lens system ensures that any eye movement is accounted for in the treatment. Less than 1 Gy is delivered to the optic nerve.13
CLINICAL TRIALS
NeoVista is currently conducting three clinical trials—
MERLOT, MERITAGE, and CABERNET—in which
epimacular brachytherapy with the Vidion ANV is performed
in patients with AMD. Preliminary observations
of MERITAGE suggest that a single procedure of epimacular
brachytherapy reduced patients' need for
ongoing anti-vascular endothelial growth factor (anti-
VEGF) therapy, indicating that the Vidion ANV system
may potentially reduce the burden of treatment in
these resource-intensive patients while maintaining
good visual outcomes.14 Additionally, 63% of patients
showed some improvement in visual acuity, with 50%
gaining at least five letters at 6 months.14 The 12-month
results of CABERNET are expected to be available early
next year.
More than 60 patients have been treated in a phase 1 study of the IRay device, and results from that trial led to the initiation of a masked, sham-controlled phase 3 study designed to demonstrate the efficacy and safety of radiation therapy for wet AMD. The phase 3 clinical trial is being conducted at seven European sites and will include a minimum of 150 patients previously treated with ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech), with approximately one-third of patients receiving sham treatment and the remainder receiving traditional radiation dosing with the IRay system.
CONCLUSION
Currently, neither therapy is approved by the US
Food and Drug Administration for use in humans in
the United States. Results of large clinical trials, as well
as outcomes following approval, will be important to
determine what long-term effects may exist with these
novel radiation delivery systems for patients with
AMD.
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