Until the early 1990s, external beam radiotherapy and enucleation were the cornerstones of treatment for intraocular retinoblastoma. But that paradigm was shattered with the recognition that many children who were cured of their retinoblastoma were placed at greater risk for developing subsequent fatal nonocular cancers.
Today there has been a shift to the initial use of systemic chemotherapy in the hope of salvaging eyes without using external beam radiation therapy (EBRT). But systemic chemotherapy carries its own set of risks, and ocular oncologists are keeping watch for long-term complications among these children. In the meantime, they are looking for new ways to shrink retinoblastoma tumors with fewer systemic side effects and less risk for late complications.
Sounding the Alarm
Using the data generated from research conducted by Algernon B. Reese, MD, Robert M. Ellsworth, MD, and David H. Abramson, MD, it was Dr. Abramson who highlighted the serious long-term risks of treating infants with EBRT. Looking back at the records of a large population of patients treated in his practice, Dr. Abramson, chief of the ophthalmic oncology surgical service at Memorial Sloan-Kettering Cancer Center in New York, discovered that among those who received radiotherapy, the risk of developing a second primary cancer was about 1 percent per year. Irradiation in the first year of life appeared to pose the greatest risk.
Radiation, though effective in treating retinoblastoma tumors, interacts with Rb1—the so-called retinoblastoma gene. Dr. Abramson calls Rb1 the “genetically determined time bomb” that predisposes these children to developing other cancers outside the eye. Rb1, located within the q14 band of chromosome 13, is a tumor suppressor gene. Researchers now know that the gene is expressed in various types of cells beyond the eye as well, and the Rb protein is inactivated in the majority of human adult and childhood solid cancers. Rb1 deletions or mutations can lead to loss of tumor suppression in nonocular cells and, in turn, to the development of other types of cancer, such as sarcomas (especially osteosarcoma) and malignant melanoma. Radiation exposure from EBRT exacerbates the problem.
With the realization that EBRT can influence the development of second primary cancers, researchers once again turned to chemotherapy. Chemotherapy was investigated in the 1950s, noted J. William Harbour, MD, but researchers found that after an initial shrinkage, the tumor almost invariably grew back.
“When chemotherapy was tried again in the early 1990s, the difference from earlier efforts was that once the tumor had shrunk, it was treated almost immediately with local modalities such as laser or cryotherapy,” said Dr. Harbour, associate professor of ophthalmology, cell biology and molecular oncology and director of the ocular oncology service at Washington University in St. Louis. “Almost overnight there was a dramatic shift away from radiation and to chemotherapy followed by local consolidative treatment.”
Dr. Abramson noted that in about two-thirds of patients, chemotherapy produces a “very gratifying, dramatic reduction in tumor size”—rendering the tumor small enough to yield to laser, freezing or radioactive plaques. EBRT usually is reserved for patients in whom chemotherapy has failed.
Chemo’s Mixed Blessing
Chemotherapy regimens are based on carboplatin (Paraplatin), vincristine (Oncovin and others) and etoposide (Etopophos and others), which are used in various combinations at different centers. Carboplatin is the mainstay and is sometimes used alone. Chemotherapy is given intravenously every three weeks, for as many as nine cycles.
Despite chemotherapy’s ability to save some eyes and to avoid EBRT in many patients, it’s a mixed blessing, according to Dr. Abramson. “The chemotherapy does have some toxicity. We are now seeing children with infections, low blood counts—some requiring transfusions—and even some deaths.”
Dr. Harbour noted an increasing number of reports of treatment-related leukemia. “It’s not a flood of patients, but clearly some kids are developing leukemia after chemotherapy for retinoblastoma.” Etoposide is known to increase the risk of leukemia, he added. “So some centers never use it. Others use carboplatin alone, and some use all three. There’s really no scientific rationale for any of the current regimens because there has never been a trial to determine which agents are best. We don’t know if all three agents are needed in every patient or not, and that is a major concern.”
Looking back at the changes in retinoblastoma treatment over the last 10 years, Dr. Harbour wonders if the pendulum has swung too far. Today radiation has been nearly abandoned in favor of chemotherapy, he said. But radiation is more effective in advanced cases, and the long-term risks of chemotherapy are still unknown. Radiation may yet have a role, particularly in patients older than 1 year of age.
“Almost all the risks of second cancers have been in children who were irradiated when they were under 1 year old,” Dr. Harbour pointed out. “So we really have many unanswered questions. Even though we can cure more than 98 percent of retinoblastomas, we still don’t know what the best treatment is in a particular setting because the treatments have never been compared scientifically.”
More New Developments
Periocular chemotherapy. Researchers are investigating the use of periocular chemotherapy as a means of avoiding systemic chemotherapy’s side effects. In this approach, carboplatin is injected around the eye every three weeks for one to seven cycles. The injected chemotherapy has no systemic side effects, but it does cause some scarring and swelling around the eye. Like systemic chemotherapy, periocular chemotherapy by itself rarely cures the retinoblastoma, but it may shrink the tumor enough to save the eye.
Transpupillary thermotherapy (TTT). This has been used alone and in conjunction with chemotherapy to treat retinoblastoma. Dr. Abramson’s group has reported that TTT alone can successfully treat new or newly growing tumors less than 1.5 disc diameters. In a recent study, the investigators treated 24 patients (91 tumors in 22 eyes) with the Iridex diode laser (810 nanometers) on continuous mode with a 1.2-millimeter spot size.1 TTT alone cured 84 tumors (92 percent); seven tumors (8 percent) were cured with TTT and salvage therapy (one to five treatments with cryotherapy, systemic chemotherapy, EBRT or periocular chemotherapy). TTT also is being combined with systemic chemotherapy to treat small- to medium-sized tumors.
Treating metastatic disease. Investigators at several centers are using intensive chemotherapy and autologous stem cell rescue to manage extraocular retinoblastoma. Chemotherapy regimens have included courses of carboplatin and etoposide alternating with cyclophosphamide (Cytoxan, Neosar), etoposide and either carboplatin or cisplatin (Platinol). Dr. Abramson noted that the majority of patients treated with the intensive chemotherapy and stem cell rescue are cured and survive. In some published series, all treated patients have survived 10 to 15 years.
Need for Collaboration
The one thing that is missing in this promising research is clinical trials to compare the effectiveness and long-term complications of these emerging therapies. Dr. Harbour said that it is imperative for ophthalmologists who specialize in retinoblastoma to come together in a collaborative way to begin performing these trials.
He also emphasized how quickly retinoblastoma treatment is changing and the importance of specialized treatment for these young patients. “It’s still important that these children be managed in centers that have extensive experience [in the disease]. The treatment is changing so rapidly and the standard of care has changed so much that I think it’s hard for someone who sees one or two patients every year or so to keep up with what’s going on.”
1 Abramson, D. H. and A. C. Schefler. Ophthalmology 2004;111(5):984–991.