Retinoblastoma: advances in diagnosis and therapy

Key Points

New Orleans-The pace of advances in the diagnosis and therapy of retinoblastoma rates "a solid C-minus," according to A. Linn Murphree, MD, speaking here at the annual meeting of the American Academy of Ophthalmology.

Little has changed in several decades, and some promising new approaches will be available only to a limited number of children with access to sophisticated treatment centers, according to Dr. Murphree, professor of ophthalmology, University of Southern California, Los Angeles, and director of ocular oncology at the Retinoblastoma Center, Children's Hospital Los Angeles.

Dr. Murphree cited a survey of almost 2,000 eyes at 18 centers around the world in which only about 25% of tumors had been diagnosed in stages A and B, the first two of five stages in a severity-based classification system. Centers experienced in treating ocular tumors can save nearly 100% of eyes with disease found at those stages, which is why it is disappointing that the majority of retinoblastoma cases are not diagnosed until later, he added.

Although such results would be atypical at an ocular oncology center in the United States, they are representative of outcomes in many developing countries, Dr. Murphree said.

"The point is that around the world, the chance of salvaging eyes is smaller as the disease grouping goes up," he added.

Advances in diagnosis have lagged for more than two decades, Dr. Murphree said. "I'm sorry to say that I don't think [there] has been almost any improvement in diagnosis. The reason is not related to ophthalmology. We see these patients when they can be referred to us. The future hope is to educate pediatricians as to the early signs and symptoms of retinoblastoma."

Although pediatricians may see a child as often as once a month during the first year of life, they frequently fail to diagnose retinoblastoma early because they conduct examinations in well-lighted rooms with open windows. Pupils are small under these conditions, so the clinician might not obtain reliable results when conducting examinations such as the red reflex test, Dr. Murphree said. For best results, the lights should be dimmed, he said, and, if necessary, the pupils can be dilated.

Advances in therapy also have been "minimal to miniscule," Dr. Murphree said. Among the successes, systemic chemotherapy has been used for nearly 20 years, and four Children's Oncology Group protocols open are evaluating minor variations in chemotherapy drugs. In addition, ophthalmologists have learned to delay radiotherapy in advanced cases until after a child is aged 1 year, which significantly reduces the risk of secondary malignant neoplasms.

The bottom line, however, is that the prevailing treatment involves "poisoning kids," Dr. Murphree said.

One form of experimental therapy under evaluation is the use of intra-arterial melphalan (Alkeran, GlaxoSmithKline). Promising results were reported recently in a small, phase I/II clinical trial of chemotherapy with melphalan; several eyes with advanced retinoblastoma were salvaged following a direct ophthalmic artery infusion.

According to Dr. Murphree, this method of administration is slightly more targeted but risky and amounts to "tweaking" of the disease rather than a breakthrough. "We're still giving a nonspecific treatment to a very small portion of the body. The eyes weigh, collectively, about 15 g. In a 10-kg child-that's 10,000 g-almost all of the chemotherapy treatment we give goes to toxicity, so we have to do a better job in delivering treatment for these problems in a targeted way," he said.

Even if intra-arterial delivery of melphalan or other chemotherapy agents were proven to be effective, it would have only a minor effect on retinoblastoma treatment worldwide, Dr. Murphree said, because it only could be administered at the most sophisticated medical centers.

Transscleral topotecan (Hycamtin) is another experimental treatment approach for retinoblastoma. A compressed topotecan wafer is applied to the episclera, where it slowly crosses into the eye. Although this technique is intriguing, it is applicable only to topotecan because the wafers cannot be made from other chemotherapy drugs, Dr. Murphree said.