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News Epimacular Brachytherapy for Age-Related Macular Degeneration (AMD)
OCULAR SURGERY NEWS U.S. EDITION January 25, 2010
Strontium-90 epimacular brachytherapy was found to be safe in patients requiring frequent, persistent therapy with anti-VEGF to treat neovascular AMD.
Epimacular brachytherapy, when used to treat patients requiring chronic anti-VEGF therapy, may reduce the burden of treatment for neovascular age-related macular degeneration.
According to results from a study presented at the joint meeting of the American Academy of Ophthalmology and Pan-American Association of Ophthalmology, a single procedure of epimacular brachytherapy can further improve visual acuity in a majority of this patient population while decreasing the number of injections required. Most important, 63% of patients enrolled in the study experienced improvement in their visual acuity while 50% of patients gained five or more letters of visual acuity at 6 months.
Preliminary results indicate that epimacular brachytherapy may help reduce treatment burden in a population of patients that are at high risk for visual decline, even if they are undergoing sustained anti-VEGF monotherapy, according to Pravin U. Dugel, MD, of Retinal Consultants of Arizona.
"The problem is not really giving an injection twice or thrice. The problem is giving this injection 15 times or 20 times," Dr. Dugel said. "Most of the injections I do, most of the injections that most of my colleagues do, are not in treatment-naïve patients. They are in patients who have significant disease with persistent fluid. And that's where the treatment burden is."
Interim study results
The interim study results were from the MERITAGE I (Macular epiretinal brachytherapy in treated age-related macular degeneration patients) trial, which enrolled 50 patients.
Patients in the trial were required to have undergone a loading phase of three anti-VEGF injections over 3 consecutive months along with either a minimum of five injections over the course of 12 months or three injections over 6 months preceding enrollment. The study enrolled patients who had as many as 23 injections of anti-VEGF therapy before receiving epimacular brachytherapy.
Re-treatment was based on strictly defined protocols related to visual changes and/or presence of fluid on optical coherence tomography or fluorescein angiography.
"The main goal of this study was to reduce the treatment burden by reducing the frequency of injections while maintaining the baseline vision," Dr. Dugel said.
In the first 6 months of the study, patients required an average of two injections, which compared favorably with the four-injection average in the 6 months leading up to enrollment and a 12-injection average in the 12 months preceding enrollment. During the study period, 88% of patients maintained visual acuity, indicating that the study met its primary endpoint. Visual acuity data was based on 16 patients with complete data at the time of reporting.
However, in an unexpected finding, 63% of patients gained visual acuity, with 50% gaining five or more letters (one line).
"We didn't expect that vision would improve in a significant number of patients," Dr. Dugel said. "There was a population of patients who experienced significant vision gains."
Safety data, taken from 49 patients treated under the MERITAGE I protocol so far, indicate that the treatment was well tolerated. Cataract progression was noted in three patients, subconjunctival hemorrhage occurred in 10 patients and ocular pain was reported by seven patients, but all other adverse events were unremarkable.
Adverse events seen in the study were most likely attributable to the pars plana vitrectomy that was performed to clear the vitreous cavity for epimacular brachytherapy. Rates of complications were no higher, Dr. Dugel said, than would be expected in a similar population of patients undergoing vitrectomy for any reason.
It is also notable that no cases of radiation retinopathy were reported in the current study and, Dr. Dugel said, there has been no radiation retinopathy in patients from other studies that have been followed for up to 3 years. To date, epimacular brachytherapy has been performed safely in over 400 patients worldwide.
The gain in visual acuity in the MERITAGE I trial is not surprising given that brachytherapy is delivered precisely in a focused manner to the macula rather than a plaque application or external beam used to treat melanoma and other such ocular conditions, where radiation retinopathy is a prominent concern. The agent used, strontium-90, also has a rapid dispersion of energy, penetrating about 2 mm from the point of application and dropping off about 10% for every 0.1 mm from the center of the source.
"Does that mean epimacular brachytherapy is safe? It is still early," Dr. Dugel said. "I think we can confidently say that the data so far is encouraging."
Triad of synergistic effects
The application of epimacular brachytherapy may be beneficial because of what Dr. Dugel calls "a triad of synergistic effects." Anti-VEGF agents only block VEGF, which is a predominant growth factor in the angiogenesis cascade but is not the only chemical factor involved, especially in more advanced cases of wet AMD that include fibrotic changes on the macula.
The second component of the treatment is the application of brachytherapy, which disrupts secondary and tertiary chemical pathways that lead to angiogenesis, including those inducing fibrosis.
Thirdly, the vitrectomy that is performed to access the macula with the epimacular probe may, in fact, increase oxygenation and enhance the effects of radiation on the choroidal neovascularization lesion.
HORIZON, an extension study of the ANCHOR (Anti-VEGF antibody for the treatment of predominantly classic CNV) and MARINA (Minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular AMD) trials, showed that even after 2 years of monthly dosing, patients were prone to a significant decline in visual acuity with as-needed therapy in the third year of treatment.
"These data in particular suggest that anti-VEGF monotherapy has to be administered on a regular basis indefinitely," Dr. Dugel said. "It's just not sustainable from a patient, physician and health economic point of view."
Although Avastin (bevacizumab, Genentech) has recently gained popularity even though it is not approved by the U.S. Food and Drug Administration for ophthalmic use, current treatment practices are largely based on studies of anti-VEGF therapy with Lucentis (ranibizumab, Genentech), which is approved by the FDA and is more expensive. And although upcoming clinical trials, such as CATT (Comparisons of AMD treatments trials), will help answer questions about the comparative efficacy of the two agents, current clinical data suggest that monthly injections with anti-VEGF monotherapy may be needed to sustain a fluid-free retina and to maintain vision.
Aside from the high cost to the health care system, monthly dosing places a significant strain on both the provider and the patient in terms of co-pays, out-of-pocket expenses, and time lost from work for patients and/or care providers.
"Anti-VEGF therapy is an effective treatment that simply cannot be given the way it was intended to be administered in this economic climate," Dr. Dugel said.
The results reported at the AAO/PAAO meeting from the MERITAGE I trial are a 6-month interim analysis of an ongoing 1-year trial, and while encouraging, "it's way too early to make any conclusions," Dr. Dugel said.
However, he added, there is an unmet need in the treatment of neovascular AMD today. The current protocol is simply not sustainable. So far, epimacular brachytherapy combined with anti-VEGF therapy has shown promise in treatment-naïve patients (phase 2 NVI-111) and in patients who have received treatment with anti-VEGF agents previously (MERITAGE I).
Based on the phase 2 data from the NVI-111 study, the phase 3 multicenter, randomized, controlled, pivotal CABERNET (CNV secondary to AMD treated with beta radiation epiretinal therapy) trial was initiated in treatment-naïve patients. This trial has completed enrollment (n = 450) and the initial data should be available in about 1 year.
A new multicenter, randomized, controlled clinical study in patients who have received treatment with anti-VEGF agents previously, MERITAGE II, is in the planning stages and will be restricted to patients with pseudophakic lens status at baseline in an effort to better understand visual changes.
"[MERITAGE I] is important, exciting and encouraging, but it is preliminary," Dr. Dugel said. "It is a necessary investigation in order to address the current unmet need in the treatment of neovascular AMD."
- by Bryan Bechtel
* Pravin U. Dugel, MD, can be reached at Retinal Consultants of Arizona, 1101 E. Missouri Avenue, Phoenix, AZ 85014; 602-222-2221; fax: 602-266-2044; e-mail: firstname.lastname@example.org. Dr. Dugel is a consultant for Alcon, Genentech, MacuSight and NeoVista.
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