Off-label drug use draws interest at Macula 2006

From tumor treatment to reclassifying what to use to determine treatment options, physicians covered the spectrum of macular diseases.

NEW YORK – Retina specialists should assume that treatment of retinal diseases with the oncology drug bevacizumab will not be covered by Medicare, according to a physician speaking here.

Off-label use of Avastin (bevacizumab, Genentech) for the treatment of age-related macular degeneration was one of the topics that drew heavy interest from attendees at Macula 2006, a meeting sponsored by the Manhattan Eye, Ear and Throat Hospital.

Avastin is approved in the United States for the treatment of colorectal cancer. Genentech has another drug, Lucentis (ranibizumab), awaiting regulatory approval for the treatment of AMD. But recently there has been interest among retinal specialists in use of the already-approved drug in an off-label fashion as a systemic or intravitreal treatment for AMD.

“Avastin seems to work, there are no apparent adverse effects, and it’s inexpensive, so what’s the problem?” George A. Williams, MD, asked rhetorically here at the meeting. One problem, he said, is that Medicare and private insurance carriers are not reimbursing for the use of the drug for this indication.

George A. Williams

Before administering the drug intravitreally for treatment of retinal disease, the physician should first give patients who are Medicare beneficiaries an Advance Beneficiary Notice informing them that the procedure will likely not be covered by Medicare, Dr. Williams said.

He said one reason Medicare may be unwilling to cover off-label use of Avastin is that it could set a precedent for off-label uses of other oncologic drugs.

In addition, Dr. Williams said he received an e-mail message from a medical director of an insurance carrier saying that the company would not cover Avastin for the treatment of AMD because it was considered investigational.

Furthermore, Dr. Williams said, the Health Insurance Portability and Accountability Act has created a new crime called health care fraud, and his closing message was, “Buyer beware.”

Following are other highlights from the Macula 2006 meeting. These items originally appeared as daily coverage from the meeting on OSNSuperSite.com.

Treatment of uveal melanoma

The identification of two distinct forms of molecules in uveal melanoma may lead to significant advances in the treatment of the disease, said William Harbour, MD. Tumors containing class 1 and class 2 molecules differ in degree of severity due to biological differences, he said.

“The biology of class 1 and class 2 is very different,” he said.

Dr. Harbour explained that researchers have not observed any tumors with class 1 molecules that have metastasized, while 75% of those with class 2 molecules have.

He also said that class 2 molecules are associated with smaller, malignant tumors and are correlated with metastatic death as well as the presence of monosomy 3, a known predictor of poor prognosis.

He said class 2 molecules have a superior predictive value, and tumors containing them are worthy of “intensive surveillance.”

“Don’t wait to treat uveal melanoma until we have a cure — it doesn’t make sense,” he said.

Dr. Harbour said that clinical trials for molecule-targeting therapies should include only class 2 molecules due to their risk for metastasis.

One question for future research, he said, is how best to treat small tumors.

“Are they the same at the onset and then develop into either class 1 or class 2, or do they differ from day 1?” he asked. “We can begin to answer these questions if we develop noninvasive testing techniques.”

Early AMD treatment

Treatments that focus on subretinal mechanisms, such as fluid passage through Bruch’s membrane, may allow earlier treatment of AMD, a speaker suggested.

John Marshall, PhD, said it may be possible to delay the onset of AMD by delaying some of the aging processes in posterior segment structures.

“We are probably treating [AMD] too late,” he said. “I would like to see prophylactic treatment either with laser treatment or with newer therapies.”

Biomechanical changes connected with collagen cause initial aging of the retina, and later aging is caused by an increase in the presence of lipid under the retina, Dr. Marshall said. There is an increase in the presence of lipids in Bruch’s membrane as patients age, he said, and as a result fluid transport and carrier transport of proteins decay exponentially with age.

Laser treatment of Bruch’s membrane might help clear out the lipids, he suggested. Selective treatment of the retinal pigment epithelium with short laser pulses placed marginally, away from the macula, could cause a “major” change in the rate of fluid movement, he said.

Better retinoblastoma classification

A modified classification system for retinoblastoma may improve treatment of the disease and allow ophthalmologists to save more eyes, according to one retina specialist.

“Our understanding of choroidal retinoblastoma continues to improve,” Carol Shields, MD, said. “But we need to improve treatment for eyes with advanced tumors.”

She described a modified classification system that has been proposed to help identify the most severe cases. The new system has five categories with increasing severity. Lesions that fall into category A are 3 mm or smaller, while those in category E cover more than 50% of the globe with opaque media.

Dr. Shields applied the system in a study of 249 cases treated with chemotherapy reduction in six cycles of vincristine, etoposide and carboplatin. Success was defined as an avoidance of radiation therapy and no enucleation.

Classifying the results using the new system, all eyes in group A were saved with chemoreduction. In group B, defined as lesions larger than 3 mm with subretinal fluid, 90% of eyes were saved. In group D, however, which includes lesions with diffuse seeds, only 47% of eyes were saved.

This study, she said, was preliminary to a larger study called the National Retinoblastoma Study.

Isoflavone for diabetic retinopathy

A nutritional supplement extracted from soybeans may potentially help delay early progression of diabetic retinopathy, laboratory testing suggests.

Where most therapies focus on advanced stages of diabetic retinopathy, the isoflavone genistein could help prevent early disease progression, said Mike Cooney, MD, who described experimental work with the compound.

“Nutritional supplements for diabetic retinopathy must focus on the compound that focuses on oxidative stress,” he said.

Dr. Cooney said genistein has good bioavailability and a good safety profile. It works as a strong antioxidant as well as an inhibitor of aldose reductase, the enzyme that changes glucose into sorbitol, a sugar alcohol that can lead to retinopathy and neuropathy in large quantities, he said.

In experimental ischemia studies, genistein was shown to inhibit protein tyrosine kinase pathways and to provide neuroretinal protection, Dr. Cooney said.

He said it also has been shown to reduce activated vascular endothelial growth factor receptors.

The potential benefits of genistein could have a “major public health impact,” he said.

Retinal thickness important

Including retinal thickness analysis in studies of new therapies for AMD may provide physicians with a more comprehensive picture than just lesion size and type, said one surgeon. Jason Slakter, MD, said retinal thickness measurements can provide a third element in analysis of clinical trial data.

“We must look at the amount of retinal thickening in interpreting the outcome of data,” Dr. Slakter said.

He said that a “three-dimensional approach” can have benefits when evaluating new therapies.

For instance, he said, in some studies, patients who were thought to have small, recent lesions, were shown later to have extensive leakage, and many had cystoid macular edema.

Dr. Slakter also suggested that clinical trials should measure the efficacy of therapies in relation to the natural history of the disease, which he called a fourth dimension.

“Retinal thickness is important for clinical management and for future clinical designs,” he said.

For Your Information:

• Jared Schultz is an OSN Staff Writer who covers all aspects of ophthalmology. He focuses geographically on Europe and the Asia-Pacific region.