Retinoblastoma is the most common intraocular cancer in children. While more than 9 out of 10 children in the U.S. with retinoblastoma are cured, the outlook is not as good if the cancer has spread outside of the eye. For two decades, intravenous chemotherapy was the mainstay of therapy, but it led to immunosuppression, infection, transfusions and increased risk of subsequent cancers.
“In advanced intraocular retinoblastoma, intravenous chemotherapy success rates were under 35 percent for more advanced cases and came with significant toxicities,” said Anthony Daniels, M.D., chief of the Division of Ocular Oncology and Pathology at the Vanderbilt Eye Institute. “We knew there must be a better way.”
Sparing Children the Effects of Chemotherapy
The multidisciplinary ocular oncology team at Monroe Carell Jr. Children’s Hospital at Vanderbilt was one of the first to adopt intra-arterial chemotherapy (IAC), where chemotherapy is delivered into the ophthalmic artery through an endovascular microcatheter. The team has also incorporated intravitreal chemotherapy, in which the drug is injected directly into the eye.
Vanderbilt is currently the only center in the Mid-South and one of a handful in the U.S. offering both IAC and intravitreal chemotherapy for ocular cancer. The success rate has been high.
“Since we began using these advanced therapies, we’ve successfully eradicated 100 percent of tumors in retinoblastoma.”
“Targeting the ocular tumor spares the rest of the child’s body from the toxic effects of chemotherapy,” Daniels said. “The increased efficacy of IAC is especially evident for eyes with more advanced disease, such as difficult-to-treat group D retinoblastoma. Since we began using these advanced therapies, we’ve successfully eradicated 100 percent of tumors.”
Hard-to-Treat Ocular Cancers
The “cavitary” form of retinoblastoma is a rare subtype that has historically demonstrated minimal treatment response with intravenous chemoreduction (IVC), showing less robust regression and less reduction in tumor size. In a recent study published in Ophthalmology Retina, Vanderbilt researchers reported excellent treatment response of cavitary retinoblastoma tumors to IAC. One hundred percent of the cavitary tumors regressed (8/8 tumors, in 6/6 eyes), 100 percent of vitreous and subretinal seeds regressed, with 100 percent globe salvage. None of the tumors recurred, and no patients developed metastases.
Looking at all forms of retinoblastoma in a retrospective cohort study of patients undergoing IVC or IAC, Vanderbilt researchers found that total unintended healthcare encounters, unplanned hospitalizations, episodes of low blood counts and transfusions were all lower with IAC than IVC. At three years, globe salvage was 100 percent with IAC and 58 percent with IVC.
Uveal Melanoma in Adults
Daniels also treats adults with ocular cancers. “Uveal melanoma is by far the most common eye cancer in adults,” he said. “While we have excellent success rates for treating the intraocular tumor using implanted, plaque-based radiotherapy – almost 100 percent here at Vanderbilt – many patients end up losing vision as a result of this treatment, and many still go on to develop metastatic disease.”
Historically, large and very large melanomas were treated with enucleation. A pilot study led by Daniels demonstrated that a technique called fractionated stereotactic radiosurgery (fSRS) could cure very large uveal melanomas without enucleation. At the primary study endpoint of one year, 100 percent of tumors were successfully eradicated, and 100 percent of eyes saved. Most patients retained good visual acuity years after treatment.
None of the fSRS-treated patients developed metastases during the first three years of follow-up. “SRS allows us to save many eyes that previously would have been deemed unsalvageable because of the massive size of the melanoma,” Daniels said.
“SRS allows us to save many eyes that previously would have been deemed unsalvageable because of the massive size of the melanoma.”
Discovering Novel Agents
Daniels’ laboratory research focuses on developing new, molecularly targeted therapies for ocular cancers. His lab has developed the first small animal model of intra-arterial chemotherapy to test the safety and efficacy of new chemotherapy compounds. They have also identified several agents that are just as effective as currently used regimens, but without the associated ocular toxicities.
A multicenter phase II study of a the immune checkpoint inhibitor pembrolizumab in patients with metastatic uveal melanoma demonstrated that pembrolizumab has a more significant and durable clinical benefit if metastases are found early before high-volume liver tumors develop.
“The problems I study are those that I see with my patients in clinic and in the OR,” Daniels said. “My discoveries in the laboratory are geared toward directly helping these patients and others with the same diseases.”