Issue: March 2016
March 14, 2016
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Epimacular brachytherapy with anti-VEGF not superior to anti-VEGF monotherapy for wet AMD

Patients in the epimacular brachytherapy arm received no fewer anti-VEGF injections and lost more letters of vision than those in the ranibizumab arm.

Issue: March 2016
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Macular epiretinal brachytherapy combined with ranibizumab did not reduce the number of ranibizumab injections that patients required for the treatment of neovascular age-related macular degeneration, according to a study.

Principal investigator Tim Jackson, PhD, FRCOphth, outlined results of the MERLOT study at the Euretina meeting in Barcelona, Spain.

“Unfortunately, epimacular brachytherapy doesn’t reduce anti-VEGF therapy, and the visual acuity is certainly no better, probably worse, than standard of care with monthly as-required Lucentis,” Jackson said. “Small and classic lesions appear to respond better to radiation, but they don’t respond better than they would if they had anti-VEGF therapy.”

Tim Jackson, PhD, FRCOphth

Tim Jackson

Epimacular brachytherapy is performed after pars plana vitrectomy. An endoscopic probe is passed into the vitreous cavity and held over the macula for 3 or 4 minutes to deliver 24 Gy of radiation, Jackson said.

“There’s a much higher dose at the center that tails off exponentially as you get further from the probe,” he said.

Study design

The MERLOT study, a phase 3 randomized controlled trial conducted at 24 centers in the United Kingdom, included 363 patients previously treated for wet AMD. Patients were randomized 2:1 to undergo epimacular brachytherapy combined with as-needed Lucentis (ranibizumab, Genentech/Novartis) or as-needed ranibizumab alone.

Primary outcome measures were mean number of as-needed ranibizumab injections (superiority) and mean change in ETDRS visual acuity (non-inferiority) over 12 months.

Secondary outcomes included visual acuity loss of less than 15 letters, gain of 0 or more letters, gain of 15 or more letters, total lesion size, choroidal neovascularization size and foveal thickness.

To qualify for the study, patients had to have completed an induction phase and had to have received at least three consecutive monthly ranibizumab injections. In addition, patients had to have received two maintenance injections in the 6 months before enrollment or four maintenance injections in the 12 months before enrollment.

Patients with visual acuity worse than 6/96, previous treatment other than anti-VEGF, subfoveal scarring, diabetes, previous radiation to the head or neck, or expected cataract surgery were excluded.

Re-treatment criteria were loss of five letters from baseline, an increase of at least 50 µm in central retinal thickness, new or increased hemorrhage, and new neovascularization identified on fluorescein angiography.

Results

Jackson said that 350 patients (96%) were followed for 12 months.

“Unfortunately, we had disappointing results,” he said. “Regarding visual acuity, we didn’t establish non-inferiority, and in fact, the visual acuity in the radiation arm was slightly worse than that in the control arm, so we missed that first primary endpoint. Unfortunately, there were slightly more injections in the epimacular brachytherapy arm. So, disappointing on both counts.”

Patients in the epimacular brachytherapy arm lost a mean of 4.8 letters, and patients in the ranibizumab monotherapy arm lost a mean of 0.9 letters.

Mean number of injections was 4.9 in the epimacular brachytherapy arm and 4.3 in the ranibizumab arm.

Subgroup analysis

Jackson and colleagues also performed a predefined subgroup analysis to determine factors that would predict response to treatment if a majority of patients missed the primary endpoints.

Baseline variables were lens status (phakic or aphakic), visual acuity, lesion type (classic, minimally classic or occult) and lesion size (greater or less than 3.5 disc areas).

“If you look at all those subgroups, there is some suggestion that certain lesions did better than others, but none of those did significantly better in terms of vision than they did with Lucentis monotherapy,” Jackson said. “If we look at the number of injections, again a similar pattern. It does seem that smaller lesions and classic lesions did better but not better than anti-VEGF monotherapy.”

Jackson said the INTREPID study, which used a different radiation delivery device and did not involve vitrectomy, showed that radiation reduced anti-VEGF therapy and improved visual acuity.

“What we take from this is that the mode of delivery for radiation is critical. The dose profile may be very important between these two studies,” Jackson said. “The other issue to consider is that the vitrectomy may reduce the drug half-life such that you therefore have to fight harder to maintain effectiveness if the drug doesn’t last long in the vitreous cavity.” – by Michela Cimberle and Matt Hasson

Disclosure: Jackson reports he received research funding from Oraya, NeoVista and Novartis.