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Noninvasive radiotherapy reduces need for repeated anti-VEGF injections in AMD
A new system delivers the minimal patient-effective dose to the targeted area without affecting other eye structures.
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MILAN — One-year results of the phase 3 INTREPID trial on stereotactic radiotherapy showed that this treatment modality can be an adjuvant of anti-VEGF therapy in neovascular age-related macular degeneration.
Anti-VEGFs have been a big advance in the treatment of AMD, but the need for frequent follow-up visits and re-treatments is a burden for patients and the health care system. Combination treatment with radiotherapy is one possible way to reduce the number of anti-VEGF injections.
“AMD is a neovascular process, which also involves fibrosis and inflammation. Radiation targets all these components, as it is anti-angiogenic, anti-fibrotic and anti-inflammatory,” Timothy L. Jackson, PhD, FRCOphth, said at the Euretina meeting here.
Devices available in the past were primarily meant to treat tumors and did not have the micron dimension precision that was needed to treat the back of the eye, he said. External beam radiation therapy for AMD seemed promising initially, but randomized trials showed minimal functional benefits.
“The systems available at the time could not deliver precise collimated doses of ionizing radiation to small targets. The entire posterior globe had to be included in the field of radiotherapy, which precluded the use of sufficient doses because of the risk of inducing radiation optic neuropathy and retinopathy. Accurate placement of the beam could not be confirmed either,” Jackson said.
The new IRay device (Oraya Therapeutics) delivers sequentially three X-ray beams that converge on the macula. Each beam measures 4 mm at the fovea. A low-energy X-ray source is utilized to provide the therapeutic dose, enabling precise dose delivery, according to Oraya. A minimal dose of radiation reaches non-targeted areas, such as the optic disc and crystalline lens, and the patient effective dose is roughly equivalent to one-tenth of the radiation used for a head CT scan.
“The procedure is noninvasive and takes about 20 minutes of office time, with less than 4 minutes of radiation delivery,” Jackson said.
Study outcomes
The aim of the randomized, double-masked, sham-controlled INTREPID study was to evaluate the safety and efficacy of radiotherapy with the IRay system in patients with neovascular AMD. Primary outcome was the number of as-needed 0.5-mg Lucentis (ranibizumab, Genentech) injections over 52 weeks. Secondary outcomes included gain or loss of 15 letters of ETDRS visual acuity. Neovascular lesion size was measured using fluorescein angiography, and retinal thickness was measured using optical coherence tomography. Adverse events associated with the treatment were evaluated.
Two hundred thirty patients were divided into three groups and followed for 12 months. The dose of delivered radiation was 16 Gy, 24 Gy or sham.
“Inclusion criteria were similar to those of many AMD trials: AMD diagnosed within the previous 3 years, more than 50 years of age, BCVA between 75 and 25 ETDRS letters. Patients were required to have had at least three anti-VEGF injections in the previous year, had a wet macula and still needed anti-VEGF treatment at enrollment,” Jackson explained.
After radiotherapy, patients were seen monthly for refraction, best corrected visual acuity, biomicroscopy and OCT examination. Anti-VEGF re-treatment was administered whenever a 100 µm increase in central subfield thickness from best previous OCT was found or when there was new or increased macular hemorrhage and a more than five-letter decrease in vision since the previous visit or baseline.
“Patients had received a mean of 5.6 injections in the previous year, 77% with ranibizumab, 30% with bevacizumab and 3% with pegaptanib. A statistically significant reduction in demand for anti-VEGF therapy of 30% to 35% was found after radiotherapy and compared with controls. Depending on the dose of radiation, patients had a mean of 2.4 to 2.6 injections in the study year. Patients in the active arms were two times more likely to receive no injection over the course of the year and approximately half as likely to need four or more injections over the course of the year compared with controls,” Jackson said.
No loss of BCVA letters was reported. Jackson noted that visual acuity was possibly slightly better in the active arms of the study than in the sham group.
OCT showed twice the reduction of central subfoveal thickness compared with controls. No radiation retinopathy or other severe adverse events were reported in the study eyes, Jackson said.
Prognostic factors for best results
Subgroup analysis was carried out on the best responders to see if prognostic factors for best results with radiotherapy could be found. Amount of fluid, measured in terms of macular volume on OCT, and lesion size were considered as potential parameters.
“We found that the eyes with small active lesions and no existing fibrosis were those that did better,” Jackson said.
A 55% reduction in the number of injections and a gain of six letters over controls was found in the patients with macular volume of 7.4 mm3 or greater and lesion size of 4 mm or less, which comprised 26% of the study population.
“The study hit its first endpoint, as there was a significant reduction in the number of injections used, and though mean BCVA was equivalent, there was a suggestion that subgroups with specific characteristics may also gain vision. Twice a reduction in OCT thickness was obtained with radiotherapy, and a favorable safety profile was found,” Jackson said.
The study will continue to monitor the potential long-term effects of radiation. – by Michela Cimberle