Inside This Issue 

JUST RELEASED

Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration. The CATT Research Group. New England Journal of Medicine. 2011 (10.1056/NEJMoa1102673) accessed on line April 28, 2011, at NEJM.org

On April 28, 2011 The New England Journal of Medicine released the much awaited CATT Study (The Complications of Age-Related Macular Degeneration Treatment Trial). This study evaluated 1208 patients randomly assigned to receive intravitreal injections of either ranibizumab (Lucentis) or bevacizumab (Avastin) on either a monthly schedule or as needed with monthly evaluations. The primary outcome was the mean change in visual acuity at 1 year, with a non-inferiority limit of 5 letters on the eye chart.

Results reveled Avastin administered monthly was equivalent to Lucentis administered monthly, with 8.0 and 8.5 letters gained respectively. Avastin administered as needed was equivalent to Lucentis as needed, with 5.9 and 6.8 letters gained respectively. Lucentis given as needed had effects that were equivalent to Lucentis administered monthly. The comparison between Avastin as needed and monthly Avastin was inconclusive. The mean decrease in central retinal thickness was greater in the Lucentis monthly group (196 µm) than in the other groups,(152 to 168µm). Rates of death, myocardial infarction, and stroke were similar for patients receiving either agent; however the proportion of patients with serious systemic adverse events, primarily hospitalization, was higher with Avastin than with Lucentis (24.1vs. 19.0%). The authors suggested this requires further study.

One last finding compared the cost of the drugs per patient for year. This cost was $23,400 in the Lucentis monthly group; $13,800 in the Lucentis as needed group; $595 in the Avastin monthly group; and $385 in the Avastin as needed group. This cost differential has important economic implications when extrapolated to the estimated 250, 000 patients with neovascular AMD that are treated annually in the US.

Results for the second year of the study will be released next year.

Submitted by Steven Ferrucci, O.D., F.A.A.O.
ORS Fellow

A copy of the article may be accessed at http://www.nejm.org

CLINICAL PEARLS

ANSWER TO "YOU MAKE THE DIAGNOSIS"

This photo represents and amelanotic melanoma. Malignant melanoma of the choroid is a rare occurrence but it is the most common adult primary intraocular tumor in the United States. It has been reported that 1200 to 1500 new cases are diagnosed each year, with the incidence increasing as patients age. The median age at the time of diagnosis is about 55 years with men and women equally. Choroidal melanomas are much more common in white individuals than non-whites (8 times more common) and are rarely bilateral in presentation.

Choroidal melanomas are proposed to arise from pre-existing choroidal nevi. Choroidal nevi unlike melanomas are fairly common benign tumors of the posterior pole and have a variety in color presentation from a pigmented slate-grey to an amelanotic yellowish-white. Choroidal nevi increase in prevalence as patients age and has been reported to be as low as 6.5% and as high as 33% in the 6th to 9th decade of life with only 5-6% of these lesions being amelanotic in appearance. Nevi are rare in childhood. Nevi, like melanomas, are more common in whites than non-whites and most typically range in size from 1 to 10 mm in size, with the majority between 1.5 and 5 mm. Most nevi are generally flat with only 4.5 to 14.2% of nevi exhibit growth during a 5-year period. The majority of nevi remain benign with the risk of a "suspicious" nevus transforming into a malignant melanoma is approximately 0.02% over a 10 year period. Nevi are often associated with overlying drusen (incidence ranging from 27-50%) and more frequently observed in elevated nevi. The appearance of overlying drusen suggests chronicity to the lesion and is typically considered a good sign and a distinguishing feature from melanomas.

Like choroidal nevi, choroidal melanomas can range in color tremendously ranging from a dark brown to an amelanotic yellowish-white. The incidence of amelanotic melanomas has been reported to be 20-25% of all melanomas, and it is thought that amelanotic melanomas may arise from amelanotic nevi. Where drusen and RPE proliferation usually signify dormancy and associated with nevi, prominent vascularity, subretinal fluid and lipofuscin are indications of growth and potential malignancy. Lipofuscin is thought to be secondary to degeneration of the RPE within macrophages and manifests as orange clumps on the surface of melanomas. In amelanotic melanomas the lipfuscin may have a more golden brown appearance.

Choroidal melanomas may have a variety of symptoms depending on the size and location. Approximately 40% of cases of choroidal melanomas are asymptomatic at the time of diagnosis, while some patients experience photopsia, visual field defects, metamorphosis and decreased VA. Pain is not a characteristic symptom experienced. Choroidal melanomas typically appear as a discrete solid elevated subretinal mass. Multifocal melanomas are extremely rare. It is sometimes difficult to distinguish a small melanoma from a large nevus. The presence of orange lipofuscin pigment on the surface of the tumor or accumulation of subretinal fluid around the base of the lesion typically suggests malignancy. In approximately 20% of cases, a melanoma may break through Bruch's membrane becoming mushroom-shaped as it extends into the subretinal space. This mushroom configuration is characteristic of choroidal malignant melanomas and rarely seen in other choroidal tumors.

The Collaborative Ocular Melanoma Study (COMS) defined choroidal melanomas as small, medium and large.

Tumor size is strongly correlated with survival with the larger the tumor the greater chance of mortality. Small melanomas tend to be comprised of spindle cells and have a much more favorable prognosis of survival than larger tumors which are more likely to contain epithelial cells and carry the worst prognosis. The 15-year mortality rate for patients with small, spindle cell melanomas was 12% as compared to 75% for patients with large, mixed cell tumors. Pigmentation of the tumor has also been associated with survival. Heavy tumor pigmentation has been associated with poorer prognosis although not as significantly as compared to tumor size or cell type. The reported mortality for amelanotic lesions is approximately 19% and increases to 39% for lightly pigmented and 65% for heavily pigmented tumors.

Management of choroidal nevi typically consists of documentation (photos) and observation. Non-suspicious nevi should be observed on a yearly basis with fundus photography. Suspicious nevi should be documented with fundus photography and followed every 6 months for any changes in size. Fluorescein angiopgraphy and ultrasonography should also be used to monitor suspicious nevi for any growth changes.

Plaque radiotherapy (or brachytherapy) is currently the most common form of treatment for choroidal melanomas. Typically, small melanomas and most medium to large melanomas in eyes with some salvageable vision and any melanoma that occurs in a patients only useful eye. Iodine plaques are the most common radioactive source and possible complications include retinopathy, cataract formation, vitreous hemorrhage, anterior uveitis and scleral necrosis. Transpupillary thermotherapy (TTT) is a relatively new alternative treatment for small choroidal melanomas located in the posterior pole. The tumor is heated with near infrared radiation therapy delivered by a diode laser with the goal of creating a flat chorioretinal scar. Enucleation is reserved for approximately 20% of melanomas today and is typically for those tumors that are very large, or advanced. Enucleation is the preferred therapeutic modality when a lesion is too large for radiotherapy, has poor visual prognosis, involved the optic nerve and/or has produced a severe secondary glaucoma.

Metastatic assessment is mandatory for every patient diagnosed with a choroidal melanoma and should be repeated every 6-12 months. Despite treatment, up to 50% of patients with a choroidal melanoma will die from metastases within 10 years of diagnosis. the liver is the most common site of metastatic involvement but other organs such as the skin, lungs and bone may be affected.

Choroidal melanomas are a relatively rare but potentially fatal intraocular problem. Early diagnosis is a crucial component to the overall survival of the patient

As an aside, the patient was seen the next day by a local retinal specialist, who confirmed our findings. A referral was made to an ocular oncologist who confirmed an amelanotic melanoma, and the patient was scheduled for a radiation plaque. The patient unfortunately passed away prior to the surgery taking place.

Blair Lonsberry, M.S., O.D., MEd., F.A.A.O.
ORS Fellow

Corticosteroid Implant More Effective In Patients With Longer Duration Of DME

Two phase 3 clinical trials showed that patients who received fluocinolone acetonide implants for diabetic macular edema achieved better visual results if they had longer disease duration before treatment, Andrew N. Antoszyk, MD, said at the Association for Research in Vision and Ophthalmology meeting.

The FAME study included 956 patients with DME who were randomized to receive either 0.2 µg or 0.5 µg Iluvien (sustained release fluocinolone acetonide, Alimera Sciences) or control treatment.

Dr. Antoszyk presented results for a subgroup that included 536 patients who had been diagnosed with DME for 3 years or more at baseline and 416 patients who had been diagnosed for less than 3 years.

Of patients with DME for 3 years or more, 33.6% of those in Trial A (P < .001) and 42.4% of those in Trial B (P < .001) achieved a best corrected visual acuity improvement of at least 15 letters at 30 months. Positive visual acuity results maintained statistical significance at 36 months, Dr. Antoszyk said.

Researchers did not observe statistically significant gains in visual acuity in patients with DME for less than 3 years.

Adverse events occurred at nearly the same rate as those in the full study population and did not affect visual outcomes, according to Dr. Antoszyk. IOP increases of at least 30 mm Hg were observed in 14.8% of patients, of whom 5.3% underwent surgery to reduce IOP. Cataracts requiring surgery occurred in 85% of patients in the subgroup who had a natural lens in their eye at the start of the study.

Alimera has submitted a new drug application to the U.S. Food and Drug Administration for regulatory approval of low-dose Iluvien, as it met the primary endpoints for both Trial A and Trial B of the FAME study.

Anti-VEGF Agent Improves Visual Acuity, Quality Of Life In CRVO Patients

VEGF Trap-Eye was found to improve visual acuity in patients with macular edema secondary to central retinal vein occlusion, according to Julia A. Haller, MD, OSN Retina/Vitreous Board Member, said at the Association for Research in Vision and Ophthalmology meeting.

The COPERNICUS trial, a randomized, double-masked controlled phase 3 trial, included 189 patients who received six monthly 2-mg injections of VEGF Trap-Eye (aflibercept ophthalmic solution, Regeneron).The control group included 74 patients who received sham injections.

After the primary endpoint of 24 weeks, 56.1% of patients in the treatment group gained at least 15 letters of vision. Only 12.3% of patients in the sham treatment group achieved the same end result (P < .0001), Dr. Haller said.

Patients in the treatment group had a mean gain of 17.3 letters, compared with a mean loss of 4.0 letters in the sham treatment group.

The results echo the positive results of the GALILEO study.

Dr. Haller also noted a rapid decrease in central retinal thickness of 457.8 µm in the treatment group, compared with 144.8 µm in the sham group.

Quality of life, according to the NEI VFQ, significantly increased, improving 7.2 points in the treatment group and only 0.8 points in the sham group, Dr. Haller said

Wills Eye Institute, Retina Implant Plan First North American Clinical Trial Of Subretinal Implant

Retina Implant, the developer of a subretinal implant for the visually impaired, has chosen Wills Eye Institute to be the lead site of the first clinical trial of the device in North America, the company announced in a news release.

Retina Implant's proprietary technology will be evaluated in patients with retinitis pigmentosa, the release said.

"The results of the subretinal approach in Europe demonstrate the great potential this implant has to impact dramatically the quality of life for our patients here in the United States," Julia A. Haller, MD, ophthalmologist in chief at Wills Eye Institute, said in the release. "Patients involved in previous clinical trials have achieved extraordinary success in their ability to regain useful vision. It is this life-changing success we hope to replicate with our own patients as Wills becomes the first institution in the U.S. to offer Retina Implant's technology."

Retina Implant's subretinal implant technology has been in clinical trials for more than 6 years in Germany. The firm plans to expand its second human clinical trial into the United Kingdom this summer.

Results of Retina Implant's first human clinical trial showed that placement of the implant below the retina, in the macular region, enabled patients to recognize foreign objects and read letters.

MS Drug May Increase Risk Of Macular Edema In Patients With Diabetes, Uveitis

A newly approved multiple sclerosis drug poses a potential risk of macular edema in patients with diabetes mellitus and a history of uveitis, Robert C. Sergott, MD, said at the Wills Eye Institute Alumni Conference .

Gilenya (fingolimod, Novartis) is the first oral medication approved by the U.S. Food and Drug Administration for relapsing-remitting MS. The active ingredient regulates lymphocyte distribution and is believed to thwart lymphocyte migration from the lymph nodes and into the central nervous system.

Data on ocular complications were culled from two phase 3 FDA clinical trials for fingolimod. A 2-year trial compared fingolimod with placebo, and a 1-year trial compared fingolimod with interferon beta-1a, Dr. Sergott said.

Fingolimod was administered in 0.25-mg and 1.25-mg doses.

Fingolimod reduced the MS relapse rate and increased the percentage of patients without an MS relapse in both studies. The differences were statistically significant (P < .001).

In the 2-year trial, macular edema occurred in 0.4% of patients treated with fingolimod and 0.1% of patients who received the placebo, Dr. Sergott said.

Patients should undergo ophthalmic examination 3 or 4 months after initiation of fingolimod therapy; patients with diabetes mellitus or history of uveitis should have regular ophthalmic exams, Dr. Sergott said.

Visual acuity should be monitored at baseline and during routine exams, he said.

Ranibizumab Yields 15-Letter Gain In VA In Patients Treated For DME, Study Shows

Results of the second of two phase 3 clinical trials showed that ranibizumab met its primary endpoint in patients being treated for diabetic macular edema, according to a news release from Genentech.

The study showed a significant gain in visual acuity among patients who received injections of Lucentis (ranibizumab, Genentech) compared with patients who received sham injections, according to the release.

At 24 months, 42 of 125 patients (33.6%) who received a 0.3-mg injection of ranibizumab and 58 of 127 patients (45.7%) who received a 0.5-mg injection gained at least 15 letters of best corrected visual acuity over baseline. In contrast, 16 of 130 patients (12.3%) who received sham injections gained 15 lines or more.

Safety results were consistent with previous ranibizumab phase 3 trials, the release said.

Results of the study are scheduled to be presented in May at the Euretina meeting in London.

Results of the first phase 3 trial of ranibizumab for DME showed a rapid and sustained improvement in visual acuity that began 7 days after treatment and persisted for 24 months.

Both trials are being undertaken to support U.S. Food and Drug Administration approval of DME as an indication for ranibizumab. The anti-VEGF agent is approved by the FDA for wet age-related macular degeneration.

Expanded 2-year Follow-up Supports Ranibizumab for DME

Consistent best corrected visual acuity and safety results suggest that ranibizumab should be considered for the treatment of diabetic macular edema, a study in Ophthalmology found.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) multicenter, randomized clinical trial assessed 854 eyes treated with either sham injection with prompt focal/grid laser, intravitreal 0.5 mg Lucentis (ranibizumab, Genetech) with prompt or deferred laser, or 4 mg triamcinolone with prompt laser.

At 24 months, the ranibizumab plus prompt laser group and the ranibizumab plus deferred laser group achieved mean visual acuity improvements of 3.7 and 5.8 letters, respectively, greater than improvements in the sham plus prompt laser group. Conversely, mean visual acuity for the triamcinolone group, compared with the sham plus laser group, was 1.5 letters lower. On average, patients in the ranibizumab plus prompt or deferred laser groups underwent two to three injections, and no systemic events that could be attributed to treatment were observed.

However, three eyes in the ranibizumab groups experienced injection-related endophthalmitis, while cataract surgery and elevated IOP were more prevalent in the triamcinolone group.

Pain Caused By Intravitreal Injection May Be Lessened Through Topical Anesthesia

Topical anesthesia may limit pain caused by intravitreal injections, a study in Retina found.

The prospective masked study used a randomized block design. Twenty-four patients were intravitreally injected four times in combination with four different types of anesthesia: topical proparacaine, topical tetracaine, lidocaine pledget and a subconjunctival injection of lidocaine. To prevent bias, the order of injections was different for each patient.

All patients received at least one intravitreal injection before the study, with a mean of 12.9 previous injections. Immediately after injection, patients were asked to grade their pain on a 0 to 10 scale for the injection as well as the anesthesia. The average combined pain scores for injection and anesthesia were 3.5 for proparacaine, 4.1 for tetracaine, 4.4 for lidocaine pledget and 3.8 for subconjunctival lidocaine.

Differences in pain grade were not statistically significant; neither were the individual injection or anesthesia pain scores.

Fifty-four percent of eyes that received subconjunctival lidocaine experienced subconjunctival hemorrhage. However, none of the other anesthesia methods was associated with this complication or any other complication.

The study authors suggested that future analyses assess pain experienced after the immediate post-injection period.

Anti-VEGF Monotherapy May Improve Visual Acuity More Effectively Than PDT Combined With Anti-VEGF

A study in Retina suggested that ranibizumab monotherapy may improve visual acuity to a greater extent than verteporfin photodynamic therapy in combination with ranibizumab for patients with neovascular age-related macular degeneration.

The open-label, prospective study included 20 eyes of 17 patients assigned to Lucentis (ranibizumab, Genentech) monotherapy and 20 eyes of 13 patients assigned to PDT with Visudyne (verteporfin, Novartis) in combination with intravitreal ranibizumab. Follow-up was 1 year.

Eyes in the monotherapy group received three monthly, consecutive ranibizumab injections, while eyes in the combination therapy group received a single session of verteporfin PDT with ranibizumab. Patients in each group were given as-needed ranibizumab injections during follow-up.

Although anatomical improvement was similar for the two groups, mean gain in visual acuity was 12 letters for the monotherapy group and 3.2 letters for the combination therapy group. Only one eye in the combination group lost more than 15 letters.

Despite better visual acuity outcomes, the monotherapy group was associated with a shorter interval between initial treatment and re-treatment, as well as more ranibizumab injections during re-treatment.

The study authors encouraged larger trials with longer follow-up to confirm these findings.

Vitamin D Shows Protective Effect Against Early AMD In Women

High concentrations of serum 25-hydroxyvitamin D may protect against early age-related macular degeneration in women younger than 75 years, according to a large observational study in Archives of Ophthalmology.

"Inflammation is thought to be involved in the pathogenesis of AMD. Vitamin D, because of its anti-inflammatory, immune-modulating properties, may suppress the cascade of destructive inflammation that occurs at the level of the retinal pigment epithelium-choroid interface in early stages of AMD," the authors said.

The Carotenoids in Age-Related Eye Disease Study (CAREDS) included 1,313 women aged 50 to 79 years who were enrolled in the multicenter Women's Health Initiative Observational Study (WHIOS).

Researchers evaluated samples from serum 25(OH)D assays, which reflect vitamin D exposure from food, supplements and sunlight. Stereoscopic fundus photographs determined early AMD status in 241 subjects.

Although multivariate models did not reveal a significant relationship between early AMD and 25(OH)D, there was a significant age interaction (P =.002) that suggested a selective mortality bias in older women, the study found.

Serum 25(OH)D decreased the odds of early AMD in 968 women younger than 75 years (P = .02) and increased the odds in 319 women older than 74 years (P = .05). Adjusting for body mass index and physical activity, which are predictors of 25(OH)D, attenuated the association in the younger age group.

Multivariate models also revealed that oral intake of vitamin D decreased the odds of AMD in subjects younger than 75 years, but direct sunlight exposure did not.

According to the authors, a prospective study is needed to confirm the association between vitamin D and AMD, and to understand how vitamin D and genetic and lifestyle factors could affect early AMD risk.

Brimonidine Reduces Subconjunctival Hemorrhage After Intravitreal Injection

Brimonidine 0.15% administered before intravitreal injection decreased the incidence, size and severity of post-injection subconjunctival hemorrhage, a study found.

Investigators set out to study vasoconstrictive effects produced by brimonidine. Brimonidine is most commonly used to reduce IOP, but it is also used to minimize bleeding in LASIK, cataract and strabismus surgery.

The prospective, randomized, double-masked study included 244 eyes of 244 patients who underwent injections of Avastin (bevacizumab, Genentech). Mean patient age was 61 years. A study group of 126 patients received Alphagan (brimonidine 0.15%, Allergan) 30 minutes before intravitreal injection. A control group of 118 patients received normal saline.

Size and severity of subconjunctival hemorrhage were assessed at 1 day and 7 days after injection. Hemorrhage severity was graded on a scale of 1 (mild) to 3 (severe).

Study results showed that 13.5% of eyes in the brimonidine group and 29.7% of eyes in the saline group developed subconjunctival hemorrhage after intravitreal injection. The difference was statistically significant (P = .003).

Subconjunctival hemorrhage remained in 14 eyes in the brimonidine group (11.1%) and in 26 eyes in the saline group (22%) at 1 week. The difference was statistically significant (P = .025), the authors reported.