NEWS

Advances in Treatment for Eye Cancer Bring Visible Benefits

Tom Reynolds

Patients with ocular cancers used to have little choice but to sacrifice the eye for a chance to save their life. But treatment innovations have allowed many to preserve their eyes and, in some cases, vision.

Removal of the eyeball, known as enucleation, is still commonly used for large tumors. But radio-, cryo-, and thermal therapies have expanded the arsenal over the past 2 decades.

While a variety of cancers — breast, lung, lymphomas, leukemias — occasionally metastasize to the eye, melanoma is the most common primary eye cancer in adults. Most melanomas occur in the area of the eye called the uvea, consisting of the iris, ciliary body, and choroid. Iris tumors are the least threatening, in part because unlike other uveal tumors they are visible, small in size, and usually are diagnosed relatively early. Tumors of the choroid account for 85% of uveal melanomas.Go



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A pigmented choroidal melanoma can be seen beneath the retina. Tumor thickness and the presence of subretinal fluid are also important diagnostic criteria for choroidal melanoma.

Photo courtesy of the Eye Cancer Network, http://www.eyecancer.com)

 
Radiotherapy was introduced widely in eye cancers in the 1970s, and is usually delivered to the eye in the form of plaque brachytherapy. A dish-shaped radiation source containing radioactive seeds (usually iodine-125) is sewn to the eye over the tumor.

Since 1986, the Collaborative Ocular Melanoma Study has investigated the role of radiotherapy in that disease. The primary intent of COMS has been to assess the outcome of the treatment comparing I-125 brachytherapy with enucleation surgery for medium-sized tumors. Recruitment is complete, but results are several years off. Experience has convinced many ophthalmologists that survival is virtually equivalent for the two treatments. As a result, there is a tendency to use radiation unless the tumor is so large that the dose required would destroy the eye.

Another COMS trial also assessed the impact of adding preoperative radiation to enucleation for large ocular melanoma. In June 1998 the National Eye Institute announced that after 5 years of follow-up, the radiation treatment appeared to have no effect on survival.

Palladium-103 Radiotherapy

Paul T. Finger, M.D., calls himself a champion — or more accurately, the champion — of palladium-103 in radiotherapy of eye melanomas, which he said should reduce the chance of common side effects such as neovascular glaucoma, cataract, hemorrhage, and neuropathy compared with I-125. The lower-energy photons generated by palladium-103 are more rapidly absorbed in tissue. The result is that the same dose at the apex — the target point for the radiation — results in a higher dose to nearby tissue and a lower dose to more distant healthy tissue than I-125 would give.



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Dr. Paul T. Finger

 
"I've drawn hundreds of melanomas in theoretical eyes" on computer modeling programs, said Finger, director of the Ophthalmic Oncology Center at the New York Eye and Ear Infirmary, "and I haven't found one that wouldn't be better treated with palladium than iodine. For me it's a no-brainer."

Despite these putative advantages — and despite palladium's widespread use against tumors such as lung and prostate — Finger believes he is the only physician in the world using it for eye cancer. He said the decision to use I-125 in the COMS studies led the rest of the country and much of the world to follow, and few have looked beyond it.

William F. Mieler, M.D., an ocular oncology specialist at the Cullen Eye Institute at Baylor College of Medicine in Houston, conceded that palladium has theoretical advantages, though he continues to treat melanomas with I-125. He said the wider availability of I-125 seeds combined with more extensive experience is the main reason ophthalmologists choose them.

High-Temperature Therapy

The latest innovation in eye cancer, introduced about 5 years ago by a team of researchers at Leiden University in the Netherlands, is transpupillary thermal therapy, which uses a diode laser to generate heat of 55 to 60 degrees Celsius, heating the tumor and destroying it.

TTT is "a very focused treatment that can avoid excessive damage to the retina and the optic nerve that can occur with radiotherapy," said J. William Harbour, M.D., director of the Center for Ocular Oncology at Washington University in St. Louis.



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Dr. J. William Harbour

 
But Mieler cautioned that the high temperatures used in TTT may pose their own risks of retinal damage, meaning patients must be selected carefully. He said uncertainty remains about whether TTT truly improves outcomes and lessens morbidity.

Harbour is among the most experienced users of TTT in the United States. Although more confident that the treatment is a genuine advance, he agreed with Mieler that the precise indications for the therapy are still being defined. He said the consensus seems to be that TTT will work in tumors up to around 3 mm thick, accounting for roughly a third of ocular melanoma patients.

"I've only had one patient who has failed this treatment so far," he said, "and that patient had a tumor with a thickness of 4.2 mm. That confirmed for me that thickness is a key indicator of whether it will be successful."

For very small melanomas in the eye (which may actually be benign nevi — the difference is not clear-cut), Harbour said a trial of immediate TTT versus initial observation could help clarify treatment questions. But the large numbers of patients required and the rarity of the tumor make such a trial difficult to mount.

For retinoblastoma, the most significant recent treatment trend is the resurgence of interest in chemotherapy, in response to the second-cancer risk and cosmetic damage caused by radiotherapy in children. Although chemotherapy was once abandoned as ineffective in this disease, Harbour said, "the difference now is that we have good local therapies. Once the tumor shrinks under chemotherapy, we use local therapies like laser and cryotherapy to kill the residual tumor before it can grow back."

"Within this century, we've gone from a survival of around 5% to greater than 95%," he added. "It's really one of the success stories in childhood cancer." Unfortunately, patients who survive hereditary retinoblastoma face a lifetime of increasing cancer risk, from rare, fatal pineal gland tumors in childhood to osteosarcoma in adolescence to melanoma in adulthood. About 40% have a second cancer by age 40.

Genetic Testing

Genetic testing is potentially useful in retinoblastoma, but so far is largely impractical. For instance, traditional linkage analysis is rarely useful since only about 7% of new retinoblastoma patients have a positive family history and not all of these will have sufficient numbers of affected members with useful genetic information, Harbour said.

Testing would also be useful in patients newly diagnosed with unilateral retinoblastoma, to determine whether they have a germline mutation and hence a high risk for tumors in the other eye and elsewhere. But the Rb gene is so large and mutations so widely spread out that it has been difficult to create a test to detect them all. A team of scientists in Germany can find about 80% of mutations by searching the genome for point mutations and sequencing the mutated piece of DNA. But this method is time-consuming, expensive, and may be inconclusive, Harbour said. More work needs to be done to find better approaches like those that have been successful in other cancers, such as looking at Rb protein length in blood cells, which is abnormally short in the mutated form.

Whether a patient has a hereditary (germline) or somatic mutation has important treatment implications.

With unilateral cases, if you know there is no germline mutation, "you're more likely to remove that eye — especially with very large tumors — and not take any chances with the infant's life," Harbour explained. "But if you knew the patient had hereditary disease and just hadn't developed tumors in the other eye yet, you might be more aggressive in trying to save the eye." Also, knowing that a child has a germline mutation would make a doctor less likely to use radiation therapy, since this can increase the risk for subsequent cancers.



             
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