American Academy of Ophthalmology Web Site: www.aao.org
News in Review
A Look at Today's Ideas and Trends
Retinoblastoma: When Tumors Shrink
There is perhaps no area of ophthalmology in which the consequences of therapeutic decisions seem so potentially tragic as when an infant has retinoblastoma. Desperate parents want their beloved child to survive, and in the last half of the 20th century ophthalmic oncologists learned how to grant parents their wish in about 95 percent of cases.
But the survival prescription—chemotherapy, radiation and, often, enucleation—is not easily endured by these tiny patients and those who love them.
So it was with excitement and with words like “dramatic” and “amazing” that ophthalmic oncologist David H. Abramson, MD, reported at the Academy’s 2007 Annual Meeting on successfully treating children’s tumor-ridden eyes with a few highly concentrated but small and localized doses of chemotherapy, avoiding both enucleation and systemic toxicity.
“There’s just nothing out there like this,” said Dr. Abramson, chief of the ophthalmic oncology service at Memorial Sloan-Kettering Cancer Center in New York City. “Perhaps the most amazing thing about this protocol is that, in cancer, never do you do something new where you have 100 percent response and no significant toxicity. This allows us to give doses that are devastating to the tumor but don’t harm the patient at all.”
He credits Japanese doctors with originating the idea of localized retinoblastoma chemotherapy, but he said problems with study design have made it difficult to evaluate those outcomes.
At the Annual Meeting in New Orleans, Dr. Abramson reported on his phase 1/2 study of intra-arterial chemotherapy in 10 children, ages 9 months to 2 years, with advanced retinoblastomas (Reese-Ellsworth stage 5). This IRB-approved study only allowed advanced eyes that were scheduled for enucleation to be treated.
With the children under general anesthesia, Dr. Abramson’s team threaded a 1.3-mm catheter through the femoral and internal carotid arteries to the ophthalmic artery. After placing the tip of a 0.4- or 0.5-mm microcatheter at the ophthalmic artery’s orifice, he infused the chemotherapy drug melphalan (3, 5 or 7 mg diluted into 30 cc saline) in pulses of one cc per minute for 30 minutes.
Every tumor, including those with advanced vitreous seeding, showed a more than 50 percent reduction in volume after one injection, he reported. Children were treated one to six times, but Dr. Abramson since has settled on three treatments, at three-week intervals, as sufficient.
Normally, melphalan is not used in children because of its bone marrow toxicity, he noted. With this intra-arterial approach, the only systemic side effect occurred during dose-escalation, when measurable signs of neutropenia indicated the need to reduce the drug dose, he said. The only local side effect was self-limiting lid or conjunctival edema in three children. The key concept here is that even though the local concentration of chemotherapy in the eye is very high, the total dose to the rest of the body is very low.
After follow-up as long as 18 months, none of the nine children on whom he reported has had a cancer recurrence. Two children underwent enucleation for other reasons, and they had no viable tumor in the treated eyes; and some of the previously unsalvageable eyes show improved electroretinogram readings, he said. Subsequently, there have been similar results in another nine children—some of them with parents who heard about intra-arterial chemo because of a professional basketball player, Derek Fisher.
The Utah Jazz guard arrived late for an NBA playoff game last May, at first angering fans but then winning their hearts after he revealed that he had been with his family as his 10-month-old daughter was treated for retinoblastoma. Her surgeon: Dr. Abramson, who worked closely with interventional neuroradiologist Pierre Gobin, MD, of New York Presbyterian Hospital in New York. As a result, the patient grapevine about intra-arterial chemo has been fed by sports fans, not ophthalmologists.
Such circumstances can be expected to raise the usual physician concerns about under-the-medical-radar popularization of new treatments. And, with retinoblastoma, the stakes are raised because of the tension between parents’ reservations about enucleation and the high five-year survival rate with the combination of systemic chemotherapy, radiotherapy and enucleation.
This explains why other ophthalmic oncologists have been cautious in their reaction and have told Dr. Abramson they want to see longer-term results before making a judgment. In the meantime, however, his paper’s significance is reflected in its acceptance for publication next month in Ophthalmology.
Gene Therapy Moves From Dogs to Phase 1 Trials
Six years after using the same method to restore sight in congenitally blind dogs, researchers at the universities of Florida and Pennsylvania have launched a human gene therapy trial that—if it works as well in people—might one day give ophthalmologists the means to cure blindness caused by missteps along the eye’s molecular pathways.
Although the new trial is a phase 1 human safety study, there is a small chance based on the dose size (about 600 billion copies of the gene) that these first patients might have some of their vision restored, said William W. Hauswirth, PhD, the Florida professor of ophthalmic molecular genetics whose lab developed the viral vector being used in the trial. In puppies, the gene therapy showed results within one to two months, he said.
“We’re chewing our fingernails to see if we get some restoration of vision,” Dr. Hauswirth said in December, as the team prepared to treat a second patient. “I’ve been working on this for three decades now. I didn’t have a clue that we’d ever be able to do this.”
Six adults and three children, ages 8 through 17, with Leber’s congenital amaurosis (LCA) are to receive the gene therapy over the next year. The first vitrectomy and subretinal gene-transfer injection was performed in November at the University of Florida by Shalesh Kaushal, MD, PhD, assistant professor of ophthalmology and chief of the vitreoretinal service. The lead investigator there is Barry J. Byrne, MD, PhD, professor of molecular genetics and microbiology and director of UF’s Powell Gene Therapy Center. Clinical exams are being conducted at the University of Pennsylvania, where Samuel G. Jacobson, MD, PhD, professor of ophthalmology, is principal investigator.
People with LCA commonly have severe loss of vision from birth or early childhood, complete night-blindness, extinguished rod electroretinography and severely reduced cone responses. In the trial, the subjects will receive a single, unilateral subretinal injection (150 µl) of an adeno-associated virus, in which most of the genetic material has been replaced with a gene for producing RPE65. This is the key isomerase in the visual cycle; without it, the retinal pigment epithelium cannot convert vitamin A to 11-cis retinal, the molecule necessary for regeneration of pigment in the photoreceptors.
How is this pioneering gene therapy experiment doing so far? In December, the Florida doctors were preparing for subject No. 2, after monitoring found no safety issues with the first patient, Dr. Hauswirth said. The team is moving slowly to guard against surprises and expects to have treated three or four subjects by the first quarter of this year.
Seeing ScotomasWouldn’t it be great if everyone over age 50 could, in a twinkle, find out quickly and easily if they have early glaucoma damage or incipient age-related macular degeneration?
The answer might come from the twinkle itself—that is, the “twinkle after-effect” visual illusion, according to U.S. and British scientists.1 The illusion foils the brain’s automatic “filling-in” of small blind spots in the visual field and so offers the possibility that patients could notice their scotomas earlier—perhaps leading them to early drug treatment and some preservation of vision.
“We have built-in mechanisms that prevent us from being aware of loss of vision. Even if you close one eye, the location of the physiological blind spot is still filled in,” said Peter J. Bex, PhD, assistant professor of ophthalmology at Harvard University and a scientist at the Schepens Eye Research Institute. “When you have a real disease with a blind spot, you may not be aware of it because filling in takes over.”
After recruiting eight patients with scotomas, most of them caused by macular degeneration, Dr. Bex and two colleagues at the University College London performed detailed microperimetry tests to map their scotomas. Four of the patients’ scotomas could not be measured with conventional campimetry because of filling in.
Then they tested the “twinkle after-effect” by first showing the subjects a large, touch-sensitive display screen of visual noise (like a detuned TV channel) for 15 seconds, followed by a solid gray screen for 15 seconds. After several cycles of this, the patient looked at the gray screen and was asked to draw around any area of the screen that appeared unusual. Patients described what they saw as an “aberration,” a “twinkling” or a “moving cumulus cloud.” The twinkling areas they saw corresponded well with the scotomas measured with microperimetry. Of the four subjects who could not be measured with conventional campimetric tests, three experienced the twinkle after-effect.
“Our aim is that we can adapt this system so that people can have a simple test to check their own vision at home,” said another of the researchers, Michael Crossland, PhD, who is in the ophthalmology department at University College London.
“This will ensure they come to the hospital or see a specialist in time for any possible treatment, giving them the very best chance of preserving their vision.”
Glaucoma Drug Goes Glam
Off-label use has always been widespread in ophthalmology. In a new twist: reports of ocular medications incorporated into cosmetic products to enhance eyelash growth. These products, which blur the lines between drugs and cosmetics, contain bimatoprost, a prostaglandin analog. As a glaucoma drug, bimatoprost has the side effects of causing changes to pigmentation of the iris, eyelashes and periorbital tissue, as well as causing eyelash growth.
In November, the FDA seized more than 12,000 applicator tubes of one product over concerns that it may lead to decreased vision in some users.
In a Nov. 19 letter posted on its Web site,1 the FDA expressed concern that persons using the drug as both an IOP-lowering medication and part of the enhanced cosmetic may be at increased risk of optic nerve damage. It said, “the extra dose of bimatoprost may decrease the prescription drug’s effectiveness.” The agency warned of other adverse effects, including macular edema and uveitis.
Debra A. Goldstein, MD, director of the uveitis service at the University of Illinois at Chicago, shares those concerns, the biggest of which is for persons with uveitis, hypotony or previous cataract surgery, since multiple trials have demonstrated breakdown of the blood-ocular barrier and the development of cystoid macular edema in pseudophakes on prostaglandin analogs.
Dr. Goldstein recommends avoiding these lash products after cataract or refractive lens exchange procedures. The same goes for anyone with a history of uveitis. “These agents may theoretically increase ocular inflammation and could certainly worsen preexisting hypotony,” she said.