Treating AMD a major focus for retinal surgeons

"Wonder drugs,” and safety issues with intravitreal injections highlighted the ASRS Masters meeting.

RIO GRANDE, Puerto Rico – After the annual meeting of the American Society of Retina Specialists in August 2005, a majority of physicians said they began using intravitreal bevacizumab to treat age-related macular degeneration and other retinal diseases. At that time, some physicians were calling Genentech’s Avastin (bevacizumab) a “wonder drug” for AMD treatment. At the 2006 Masters of the American Society of Retina Specialists meeting, a select group of about 50 physicians gathered to share their experiences with the drug and to discuss other surgical techniques and pharmaceutical treatments and methods for AMD and complications of diabetes.

The following items were originally published on the OSN SuperSite.

Medical treatments

Use of Avastin

Paul E. Tornambe

An informal poll of retina’s leading thinkers showed about 85% believe intravitreal bevacizumab is safe enough to use on their parents, and more than 90% believe in the drug’s ocular safety. Paul E. Tornambe, MD, recapped highlights of this year’s Masters of the American Society of Retina Specialists meeting. This year, the main focus was on Genentech’s Avastin (bevacizumab) and Lucentis (ranibizumab), both for the treatment of age-related macular degeneration.

“The gold standard of treatment for AMD will probably be Lucentis,” he said. Avastin most likely will continue to be used intravitreally after Lucentis receives U.S. approval “for non-AMD treatments.”

The retinal community is still debating the dosage levels appropriate for Avastin, Dr. Tornambe said. “We have no science behind what we’re using. Can we go even lower than what we’ve been using?” he asked.

Another issue facing retinal specialists about Avastin is its duration of action. None of the attendees would re-inject a patient at 4 weeks, but the majority would re-inject at 6 weeks, with about 20% holding off until week 8 for the second injection. Most surgeons said they would inject three times and “see what happens.”

When combination therapy is being discussed, about half the physicians would use photodynamic therapy and Avastin as a primary treatment for AMD, while the other 50% would use intravitreal triamcinolone and Avastin.

“It seems most of us will use Macugen (pegaptanib, Pfizer/OSI) if the patient responds,” he said. Macugen may be beneficial beyond salvage therapy, he said.

While Dr. Tornambe advocated a comparison study between Lucentis and Avastin, Stephen Sinclair, MD, voiced concern that with all the attention being paid to the two medical therapies, insurance companies will be hesitant to reimburse for other drug therapies.

“We need to make insurance companies recognize there are multiple drugs available, and they should pay for whatever the physician believes will help the patient,” he said.

Tracking Avastin events

A growing concern over potential ocular and systemic safety issues of intravitreal bevacizumab has led to an online registry to track adverse events, Andrew Moshfeghi, MD, said. To date, 68 centers have supplied information to the registry, which is headed by Anne Fung, MD, Dr. Moshfeghi said. It includes information on 4,869 patients who have undergone 6,584 injections.

“What we’ve seen so far with adverse events are two cases of endophthalmitis, three retinal detachments and 11 abrasions,” he said.

With intravenous Avastin (bevacizumab, Genentech) for the treatment of metastatic colorectal cancer in conjunction with 5-FU chemotherapy, systemic adverse events have included a rise in blood pressure and stroke.

Dr. Moshfeghi also recommends keeping the diluted Avastin for a maximum of 2 weeks. He advised physicians to tell retinal patients there is a reported increased risk of arterial thromboembolic events (including stroke) when relatively large doses of Avastin are given intravenously with traditional chemotherapy to patients with end-stage colorectal cancer every 2 weeks, but that it is not known what risk, if any, is associated with intravitreal delivery of minute quantities of Avastin in relatively healthy patients every 4 to 8 weeks.

"If a patient has a stroke 2 to 4 weeks after being injected with intravitreal Avastin, then [most studies would consider the event as possibly/probably] drug related," he said. However, this informal survey of retinal physicians captured data for all systemic adverse events and asked the respondent to then characterize the time-frame of the adverse event, so there was no pre-specified time-frame in which an adverse-event was considered "related."

Stabilizing SPED

Intravitreal Avastin may improve and stabilize vision in patients with serous pigment epithelial detachment, one speaker said.

Ayala Pollack, MD, analyzed data from 17 eyes of 17 patients who underwent an intravitreal injection of Avastin in an IRB-approved, open-label, uncontrolled study in Israel. Patients had to fail other therapies before enrollment in this trial, she said. Seven eyes had serous pigment epithelial detachment (SPED), five had choroidal neovascularization due to age-related macular degeneration, and two had angioid streaks.

“The patients had to have CNV unresponsive to other therapies and had to have subretinal fluid,” Dr. Pollack said. Patients were injected with 1.25 mg of Avastin, and follow-up was at 1 day, 1 and 4 weeks and 2 months, she said.

Of seven eyes at 1 week, three had improved between 8 and 15 letters, three showed no improvement, and one regressed, “but that eye had hyphema,” she said. Optical coherence tomography showed three eyes improving, two eyes without a change and two eyes regressing.

“The need for re-treatment was based on visual acuity measurement, evidence of subretinal fluid on clinical examination and OCT or leakage on fluorescein angiography,” she said.

Of the seven eyes with SPED, three showed visual acuity improvement. “One eye improved by four lines,” she said. Four eyes maintained vision at all follow-up points.

Ten eyes had a mild conjunctival injection on the first postop day that resolved spontaneously. None of the eyes showed an increase of IOP, Dr. Pollack said.

“Overall, VA did improve, but regression may occur,” she said.

Proliferative diabetic retinopathy

In patients with proliferative diabetic retinopathy, an intravitreal injection of Avastin “induced a rapid regression of retinal and iris neovascularization,” Robert L. Avery, MD, said.

He used intravitreal Avastin on 45 eyes of 32 patients with proliferative diabetic retinopathy. The average patient age was 58 years.

“We used lower and lower doses [of Avastin] and still saw a dramatic result,” he said.

If the patient needs surgery, Dr. Avery recommended surgeons inject Avastin before vitrectomy surgery to reduce potential leakage, and he said surgeons should proceed with caution. The drug may penetrate the fovea, and the level of penetration may be dose-related. He recommended injecting between 3 and 10 days preoperatively.

“These are very short-term results,” he said. “The lower dose may be effective, but longer-term follow-up is still needed.” Early results indicate intravitreal dosing has been successful, and in some cases one injection was sufficient to eliminate rubeosis.

“Patients with diabetic macular edema do not respond as well,” he cautioned. For those patients, he recommended using intravitreal triamcinolone.

Triple therapy for CNV

A treatment regimen that combines dexamethasone, anti-VEGF injection and photodynamic therapy is showing promising results at the 4-month follow-up in choroidal neovascularization patients with age-related macular degeneration, said Indre Offermann, MD. A total of 46 patients have undergone the treatment so far, she said. All had either occult or classic lesions; the mean visual acuity at baseline was 20/100, and the mean patient age was 76.2 years.

“We began with PDT, then added 1.25 mg of Avastin and 800 µg of dexamethasone,” she said. “With only one treatment cycle, the mean visual acuity increased 1.89 lines.”

By week 18, none of the patients had regressed to pre-treatment visual acuity, she said. None of the patients reported any side effects from the triple therapy, she added.

“We use dexamethasone instead of intravitreal triamcinolone because there’s less potential of an IOP spike,” she explained during a question and answer period.

Surgical Techniques

23-gauge vitrectomy system

Keith A. Warren

Using a 23-gauge vitrectomy system on patients with various retinal pathologies may involve a surgeon learning curve, but it is “an effective alternative for sutureless vitrectomy,” said Keith A. Warren, MD.

The typical 20-gauge vitrector is about 1 mm in diameter, Dr. Warren said. The typical 25-gauge is about 0.5 mm in diameter, and the 23-gauge is somewhere in between, he said. Both the 20- and 25-gauge systems involve increased surgical times or reduced flow in some surgeries, he said.

Dr. Warren retrospectively reviewed 31 patients who underwent vitrectomy with a 23-gauge system (DORC). Of the patients, 10 were being treated for diabetic vitreous hemorrhage, seven had diabetic tractional detachment, five had primary retinal detachment, and five had macular holes. The other patients had macular pucker, diabetic cystoid macular edema, or branch retinal vein occlusion or hemorrhage, Dr. Warren said.

All patients were treated preoperatively with Vigamox (moxifloxacin HCl ophthalmic solution 0.5%, Alcon) and then underwent a standard three-port vitrectomy. Eleven patients had a visual acuity between 20/40 and 20/60 preop; the mean preop IOP was 18 mm Hg. Postoperative IOP dropped to 17 mm Hg, Dr. Warren noted. Patients were followed for at least 3 months.

“None of the patients had hypotony,” he said. “None of the patients had to be converted to a 20-gauge vitrectomy,” although two patients had serious complications – vitreous hemorrhage and peripheral retinal tear. Five patients had minor subconjunctival hemorrhages, and one had subconjunctival gas.

“The retinal tear was on the periphery – at 11 o’clock, away from the trocar,” he said.

“It’s an easy learning curve from 20- or 25-gauge,” Dr. Warren added. “You need prophylactic antibiotic for the endophthalmitis risk.”

Rheopheresis treatment

An outpatient procedure that takes about 3 hours has shown demonstrable results in lowering plasma levels and treating age-related macular degeneration, said Frank H.J. Koch, Prof. Dr. med.

Rheopheresis is “the elimination of rheologically relevant high molecular plasma proteins” from the eye, Dr. Koch said. For nonexudative AMD, the target for a single rheopheresis treatment is “100% of the individual plasma volume, with a minimum of 70%,” he said. Repeated, pulsed reduction of the blood and plasma viscosity leads to rapid alteration of the blood flow, he said, which induces a “continuing improvement of the microcirculation.”

Frank H.J. Koch

Ophthalmologists need to work with an internist for the most successful experience, Dr. Koch said. He recommended rheopheresis for patients with dry AMD, soft drusen, mild pigment distribution or initial atrophy, with a visual acuity between 0.1 and 0.6.

In Frankfurt, Germany, 128 eyes of 91 patients underwent one treatment of rheopheresis. At the 23-week follow-up, none of the patients had lost any lines of vision, 7% gained at least three lines, 39% had a one-line gain, 12% had a two-line gain, and 7% lost one to two lines. The outcomes match results from other centers as well, Dr. Koch said.

“This is not a treatment option for patients with exudation, bleeding, progressive atrophy or fibrosis,” he said. “Late AMD in the fellow eye is not a contraindication, however.”

In Europe, each treatment costs around 10,000 euros (US $11,963).

“Success can be dramatic and correlated very well with a loss of drusen, or it can be dramatic and not correlate that much with a loss of drusen,” Dr. Koch said.

Oblique incision preferred

Regardless of which vitrectomy system a retinal surgeon prefers, using an oblique incision instead of a straight incision will help the cannula stay in better, Dr. Koch said. He presented his observations with the II 4000 high-resolution endoscope on the Alcon, Bausch & Lomb, DORC and Midlab vitrectomy systems.

“All systems have to be handled differently to have an optimized profit from each of them,“ he said.

Straight vitrectomy systems – such as the Alcon and Bausch & Lomb – should be inserted obliquely anyway, Dr. Koch said.

“Don’t forget to displace the conjunctiva,” he warned.

Once the incision is made, surgeons need to determine how much screwing of the port is necessary, he said. He recommends 20° to 25°.

“Using an oblique angle is easier,” he said. “But when does incarceration happen? How much do we need? How much can we tolerate?” Once a surgeon pulls back the trocar, in most cases, he said, vitreous will be incarcerated in the cannula.

“The size of the cannula is not important,” he said.

He urged surgeons to clean the ports at the beginning and end of the surgery.

“Use an oblique insertion, clean the entry port, keep pressure on the eye during explantation,” he said.

“In short, different mini-gauge approaches afford completely different strategies to perform a successful pars plana vitrectomy,” he said. Surgeons should consider using oblique insertion of ports rather than straight, cleaning ports and entry sites, and maintaining pressure during explantation to have a successful surgery.

Tamponade not necessary

Pseudophakic rhegmatogenous retinal detachment can be repaired with pars plana vitrectomy alone, without a tamponade agent in the postoperative period, one surgeon said.

Vicente Martinez-Castillo, MD, described a prospective study of 60 eyes of 60 patients who underwent PPV. The inclusion criterion was primary pseudophakic rhegmatogenous retinal detachment; all patients had a follow-up period of at least 1 year. Patients ranged in age from 39 to 85 years, 70% were men, and 35 were myopic. Posterior chamber IOLs had been implanted in 56 patients, and an anterior chamber IOL had been implanted in one patient. The average time between cataract extraction and retinal detachment was 34 months, Dr. Martinez-Castillo said.

“The key is to perform the vitrectomy with perfluorocarbon liquid and use a transscleral diode laser,” he said. At the end of the procedure, the vitreous cavity was filled with balanced salt solution, he said.

The initial reattachment rate was 98.3%, with a final reattachment rate of 100%. No patient developed proliferative vitreoretinopathy in the postop period, he said.

“Until the gas is absorbed or the oil removed, surgeons don’t know for sure if the retina is reattached,” he said.

When performing a PPV for rhegmatogenous retinal detachment, “it’s possible to have a sealed choroid adhesion intraoperatively,” Dr. Martinez-Castillo said. Using perfluorocarbon “obviates the need for [silicone] oil,” he said.

Surgeons should inject the perfluorocarbon liquid, ensuring maximum drainage of the subretinal fluid, should ensure the entire retinal break is attached to the retinal pigment epithelium and retinopexy should be done with a diode laser, he said.

Miscellaneous

Retirement considerations

Retinal surgeons “will fail retirement” if they do not create a formal structure for the achievement of new goals and challenges, said Jerald A. Bovino, MD, who was keynote speaker of this year’s conference.

“You can’t retire from something,” he said. “You have to retire to something.” Dr. Bovino, who retired from a successful practice in Illinois to Aspen, Colo., several years ago, found himself “bored after 4 weeks.” Since his retirement, he has earned his private pilot’s license, started a newspaper column, become a partner in a spring water business and become the host of a local TV show.

“We are all ‘type A’ personalities,” he said, and failure to plan or structure how to spend the retired years “is a plan for disaster.”

Dr. Bovino offered his 10 steps for achieving financial success before the thought of retirement can even be considered. Among them: Start saving early, and invest in what is familiar.

“Avoid ‘hot’ stock tips,” he said. “Anyone who really knows something hot about a stock is not allowed by law to tell you.”

Diversify holdings and “get rich – slowly,” he said. “There’s no easy way to make money without working for it.”

Consider where to live as part of an overall retirement strategy. “Do you like where you live? Then stay,” he said. Continue with hobbies and maintaining friendships, he suggested.

For Your Information:

• Michelle Dalton is Managing Editor of OSNSuperSite.com. She writes daily updates on developments in all aspects of ophthalmology.