May 2010




AMD options after anti-VEGF

by Rich Daly EyeWorld Contributing Editor


Targeted radiation therapy may eliminate the need for frequent anti-VEGF injections

Left, AMD eye with subretinal hemorrahge. Right, same eye with no residual subretinal hemorrhage 5 months after IV Avastin treatment Source: Henry Muller, M.D.

Medical therapy for neovascular age-related macular degeneration (AMD) has advanced in recent years to give real hope to many patients. However, the continuing limitations of those treatments have kept open the door for adjunctive therapies.

One alternative where researchers are finding some success in curbing the indefinite use of anti-vascular endothelial growth factor (anti-VEGF) agents is radiation therapy.

Epimacular brachytherapy treats AMD using a new surgical device to deliver targeted beta radiation to active AMD lesions. Radiation therapy differs from anti-VEGF agents in that it aims to eliminate choroidal neovascularization (CNV) vessels permanently, rather than only suppress them. This potential effect creates the possibility that patients could undergo a single treatment procedure rather than a lifetime of intravitreal injections that carry with them large costs, patient inconvenience, and a small but cumulative risk of complications.

“While the current treatment with anti-VEGF therapy is very effective at maintaining vision, it imposes a large burden on patients who require monthly hospital review and regular intravitreal injections,” said Tim Jackson, Ph.D., F.R.C.Ophth., consultant ophthalmic surgeon and honorary senior lecturer, King’s College Hospital, London, and radiation researcher.

Research shows promise

Previous attempts to deliver radiation using external beams had uneven success, possibly due to collateral damage to the healthy tissue surrounding the small CNV lesions targeted for treatment.

The difference in epimacular brachytherapy is that beta radiation is delivered through a vitrectomy procedure, which potentially allows highly precise delivery of beta radiation without surgical damage to the retina.

The novel epimacular brachytherapy tool—developed by NeoVista (Fremont, Calif.)—aims to allow intraocular, epimacular, focal delivery of radiation to CNV lesions and minimize the amount of radiation delivered to surrounding tissues.

The surgery uses a hand piece with a 20-gauge cannula, which contains a retractable radiation source, inserted through a pars plana vitrectomy. After vitreous removal, the device is placed in the mid-vitreous cavity and the radioactive source is moved down the cannula into position.

Fluorescein angiography is then used to position the cannula directly over the CNV lesion, where it is held for about 4 minutes. Dr. Jackson described the surgery as “not technically difficult.”

Initial trials suggest the treatment is safe and effective, with results remaining stable over time. Recent trials of epimacular brachytherapy have included injections of an anti-VEGF agent at the time of surgery and again one month later on the belief that they have a synergistic effect. Further anti-VEGF injections were offered as required by lesion activity, at the discretion of the investigator.

The study results suggest that the treatment is sustainable, with most patients (76%) not requiring repeated anti-VEGF injections at 1 year, in one small study. The elimination of anti-VEGF injections—often recommended as at least monthly—could be significant for people in rural areas or who have other chronic conditions that complicate regular treatment.

“Some patients are good candidates for monthly therapy or frequent injections and they are fine with the current approach, but there are a number of patients who are not,” said Jeff Heier, M.D., assistant professor of ophthalmology, Tufts Medical School, Boston, and a former investigator of a radiation therapy treatment. “That’s where something like combination radiation therapy can be important.”

The Phase II study of epimacular brachytherapy with an anti-VEGF injection among 30 AMD patients found a positive treatment response. The mean visual acuity improved by 6.6 ETDRS letters, 93% of patients maintained vision (less than a 15 letter loss), and 37% gained three lines (15 or more letters). Researchers noted that a significant finding of the study was that most patients (73%) did not require further anti-VEGF injections after the first two mandated by the protocol.

The positive results have been praised by U.S. and international surgeons for showing the potential of the treatment but many remain cautious.

“The fact that relatively few treatments or injections [were needed] for the maintenance of good vision for a long period of time is interesting,” Dr. Heier said. “But I always qualify radiation therapy by saying we need to see those results replicated in the larger trials.”

The largest trial to date is expected to have results in early 2011. The Phase III CABERNET study of treatment-naive patients with CNV secondary to AMD treated with radiation is a multicenter, randomized, active-controlled trial. The large international study randomized patients to standard treatment with ranibizumab (Lucentis, Genentech, South San Francisco, Calif.) alone, or epimacular brachytherapy with one ranibizumab injection at the time of surgery and a second injection 1 month later.

Research has not yet identified any serious safety concerns from the procedure, including no cases of radiation retinopathy or other adverse events attributable to intraocular radiation exposure. “We have been very pleased that to date no cases of radiation retinopathy have been reported,” Dr. Heier said. “But there are patients who are coming up on 3 years now, and that is when we would anticipate it.”

The most common adverse effect was cataract, which occurred in 25% of phakic patients. Researchers said the cataracts likely stemmed from the vitrectomy rather than the radiation, with high rates of nuclear sclerosis regularly occurring within 2 years of vitrectomy. Further research will also need to address how to treat patients with recurrences after epimacular brachytherapy. Patients treated with radiation cannot be retreated if they develop additional lesions.

“The flip side is that in many patients, gaining a year to a year and a half is significant if they are sick—such as those going through cancer therapy—and can’t come in,” said Dr. Heier. “If we can stabilize their eye for a year and a half, [then] that can be very meaningful.”

Editors’ note: Drs. Jackson and Heier have financial interests with NeoVista (Fremont, Calif.).

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