It’s been more than a year since basketball player Derek Fisher brought national attention to children with retinoblastoma and a treatment called direct intra-arterial chemotherapy.
After his 10-month-old daughter Tatum’s treatment by Y. Pierre Gobin, MD, at Memorial Sloan-Kettering Cancer Center and New York Presbyterian Hospital, Mr. Fisher flew back to Salt Lake City with his family, arriving just in time to play in a Jazz game. In a moment of candor after the game, he told his family’s story in a live television interview, which brought wide attention to retinoblastoma and the new tech nique of delivering localized chemo therapy via the ophthalmic artery. According to some ophthalmologists, this technique may provide a new direction for the treatment of retinoblastoma.
The Conventional Approach
Retinoblastoma is a rare eye cancer that affects an estimated 5,000 children a year worldwide. Survival rates are highest in the United States, with more than 95 percent of children surviving (compared with fewer than 50 percent worldwide). Yet the standard treatments can be a bitter pill to swallow, and include systemic chemotherapy, radiation and, often, enucleation.
Although it can be curative, radiation is now known to increase the risk of secondary cancers. And systemic chemotherapy, while it can shrink tumors, also may have significant side effects. Plus, the treatment can take up to nine months with costs exceeding $150,000 per patient, according to David H. Abramson, MD, chief of the ophthalmic oncology service at Memorial Sloan-Kettering and professor of ophthalmology at Weill-Cornell Medical School.
Enucleation can prevent progression to metastatic disease in almost all cases, but it also can compromise orbital bone growth in young children, he noted, and the loss of an eye presents life-long challenges.
The Ophthalmic Artery Technique
In 2006, Dr. Abramson and a team of clinician-scientists at Memorial Sloan-Kettering, including interventional neuroradiologist Dr. Gobin and pediatric oncologist Ira J. Dunkel, MD, set out to use a technique that could selectively infuse a chemotherapeutic agent through the ophthalmic artery—hopefully with minimal ocular and systemic toxicity—to treat children with advanced retinoblastoma. “The technique has totally transformed our practice,” Dr. Abramson said. “Very few eyes in our practice now have to be enucleated.”
The results from a phase 1/2 trial involving treatment of their first 10 patients were published in Ophthalmology last year.1 All the children had Reese-Ellsworth V retinoblastoma and were slated for enucleation. After treatment with the drug melphalan (Alkera and others) via cannulation of the ophthalmic artery using a femoral artery approach, the team saw dramatic regression of tumors, vitreous seeds and subretinal seeds in nine of the 10 patients. In two cases, intra-arterial carboplatin (Paraplatin) also was added because the eyes had such advanced disease. An arterial anomaly disqualified one child, who was then enucleated.
The number of treatment sessions ranged from two to six for each eye, but Dr. Abramson noted that each tumor showed more than a 50 percent reduction after just one injection. None of the nine children had a cancer recurrence. Two children underwent enucleation because of concerns regarding persistent retinal detachment and suspected tumor recurrence; however, histopathological examination found no viable tumor.
There were no severe systemic side effects, although one child did develop neutropenia. After a mean follow-up of 8.8 months, the researchers found little toxicity associated with the treatment. Three patients developed conjunctival and lid edema that resolved without treatment. One previously irradiated eye developed retinal ischemia, and another eye developed radiation-like retinopathy after subsequent brachytherapy. Although generally poor, vision did stabilize or improve in all but one patient after treatment.
The Memorial Sloan-Kettering researchers chose to use melphalan because it is highly effective against retinoblastoma. Normally, it cannot be given intravenously to children with the disease because of potential bone marrow toxicity. Although the concentration given via the ophthal mic artery is high, the total dose to the rest of the body is very low, Dr. Abramson said.
He and his colleagues have now done the procedure successfully more than 100 times and have seen elimination of the tumor with as few as one or two injections, he said. The standard treatment they have developed for most patients, however, involves three injections. Dr. Abramson noted that the technique cannot be used on children younger than 6 months old because their ophthalmic arteries are too small.
Despite the success of the New York team, some ophthalmologists sound a note of caution about localized delivery of chemotherapy to the eye.
This approach is very exciting, said Carol L. Shields, MD, professor of ophthalmology at Thomas Jefferson University and surgeon at the ocular oncology service at Wills Eye Hospital. None theless, she said, it still has risks, including vascular spasms with ischemic events, toxicity to the eye and brain and potential for ultimate fibrosis of the artery. “New techniques are exciting until you face a serious complication. The limitations of this technology still await definition,” she said.
The Germ of the Idea
The idea of delivering localized doses of chemotherapy for retinoblastoma originated in Japan 15 years ago, where there is significant cultural opposition to the removal of patients’ eyes, even if it can cure the retinoblastoma.
The Japanese technique, however, involved infusing melphalan into the carotid artery. A balloon catheter was then passed into the internal carotid artery and inflated to occlude the artery and allow the medication to perfuse the eye without reaching the brain.
In Japan, investigators have reported more than 900 infusions in 160 children, but no data have been published on visual results, electroretinogram testing, pupil testing or ocular side effects.
Moreover, while Japanese researchers have documented low rates of complications and excellent clinical outcomes, they also treat their patients with hyperthermia and external beam radiation, making it difficult to assess the contribution of the carotid artery infusion. Infusion through the carotid artery also may affect intra cranial vascular territories through the branches of the internal carotid, Dr. Abramson noted in the Ophthalmology paper.
Where We Are Now
The New York researchers are now treating patients with less-advanced disease (Reese-Ellsworth III and IV retinoblastoma). They also have treated patients with bilateral disease—usually infusing chemotherapy to both eyes at the same sitting. For advanced cases, they also are using two drugs at the same sitting, infused minutes apart. “Theoretically, using two drugs is more powerful than one,” Dr. Abramson said, noting that they have tried topotecan (Hycantin) as an additional agent with favorable results and also are investigating other agents.
“We are now into a new world of treating retinoblastoma. The majority of eyes that we would have enucleated in the past can now be saved. And not only are we saving patients’ eyes, but their lives as well,” Dr. Abramson said.
“While clinicians are still evaluating this innovation, I am 99 percent certain that if they had a child with retinoblastoma in their own family they would choose the intra-arterial technique over systemic chemotherapy,” he said. “Every one of them would want to try and save the eye before removing it.”
However, Dr. Shields believes that the ophthalmic artery technique is best used for those who have failed conventional therapies or have advanced disease. “There is still a role for radiotherapy and enucleation for some children,” she said. Plaque radiotherapy takes only two to four days, can be utilized with no risk for second cancer and has a high success rate, she said. “Children with massive retinoblastoma and no hope for sight are best managed with enucleation, without the serious risks of brain cannulation.”
In addition, Dr. Shields noted that systemic chemotherapy can be lifesaving in some cases. “For patients who have bilateral disease with germline mutation and who are thus at risk for brain tumors and second cancers, we have good evidence that systemic chemotherapy can minimize the risk of metastatic disease and pinealblastoma. The intra-arterial route will not provide this systemic protection.”
Still, Dr. Shields feels that localized delivery of chemotherapy for retinoblastoma is in the forefront of new developments for treating this eye cancer and needs to be explored. She is so interested in the concept that she is now using a technique to deliver localized intra-arterial chemotherapy to children with retinoblastoma with IRB approval. The use of the technique at the Wills Eye Institute is under way. “This isn’t a technique that can be used for every child. But it’s an exciting part of what the future may hold in terms of retinoblastoma treatment,” she said.
___________________________ Drs. Abramson and Shields report no related financial interests.