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Advancements in retinoblastoma have occurred in the areas of treatment, genetic testing, and diagnostic imaging.
Reviewed by Jonathan W. Kim, MD
Advances in treatment for retinoblastoma offer better safety than systemic chemotherapy and radiation and result in higher globe salvage rates without compromising patient survival, said Jonathan W. Kim, MD.
“Intra-arterial chemotherapy is now rivaling systemic chemoreduction as a primary treatment modality for retinoblastoma, and intravitreal chemotherapy has replaced external beam radiation as a salvage therapy for vitreous seeding,” said Dr. Kim, director, Retinoblastoma Service, Children’s Hospital Los Angeles. “Treatment of extraocular retinoblastoma is also much different now as it is based on high-dose multiagent chemotherapy with stem cell rescue rather than deforming orbital surgery and radiation.”
Dr. Kim credited David Abramson, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), New York, as a leader in developing the modern technique of direct ophthalmic artery infusion of melphalan. He worked with Dr. Abramson to salvage 7 of the first 9 treated eyes at MSKCC. Two eyes were removed due to persistent subretinal fluid, Dr. Kim said.
Ocular oncologists at MSKCC have the largest experience with intra-arterial chemotherapy. In a series including almost 500 patients treated from 2011 to 2015, patients received a median of three infusions given at monthly intervals with a dose averaging 4 mg.
“Their group reported a 29% incidence of Grade 3 neutropenia, and that speaks to the fact that melphalan is a very powerful drug and that some of it does get out into the systemic circulation,” Dr. Kim said.
Figure 1. Retcam fundus photograph of the left eye of a 10-month-old child with unilateral Group D retinoblastoma. Courtesy of Jonathan W. Kim, MD
In the series, 79% of patients avoided enucleation or radiation. Carol L. Shields, MD, of Wills Eye Hospital, Philadelphia, reported a 91% salvage rate in a series of unilateral Group D disease.
“These outcomes compare favorably to the approximately 50% salvage rate associated with systemic chemotherapy alone,” Dr. Kim said.
A paper by Yousef et al. that reviewed 12 published series of intra-arterial chemotherapy reported salvage rates of 66% overall and 57% in Group D/E eyes. This may be because most papers included in the review were older series whereas more recently, salvage rates are higher, Dr. Kim said.
Intra-arterial chemotherapy complications include periorbital edema and erythema along with lash loss, all of which are transient. Rare, serious events include avascular retinopathy, sectorial choroidal vascular occlusion, and stroke.
Data indicate the metastatic disease rate with intra-arterial chemotherapy is about 4%. “This rate is comparable to that reported for patients who have undergone enucleation even though intra-arterial chemotherapy is salvaging eyes with more advanced disease,” Dr. Kim said.
The Munier protocol for administering intravitreal melphalan has advanced the treatment of vitreous seeding. Melphalan is injected into a tumor-free quadrant of the eye using a 32-gauge needle and after removing 0.10 cc of aqueous humor through a paracentesis. Cryotherapy is applied as the needle is withdrawn, and the eye is shaken to distribute the melphalan.
Figure 2. Retcam fundus photograph of the same patient after 3 cycles of intra-arterial chemotherapy using melphalan demonstrating excellent tumor regression. Courtesy of Jonathan W. Kim, MD
Since publication of the technique in 2012, Dr. Kim rarely uses radiation for vitreous seeding.
Most centers performing intravitreal chemotherapy administer weekly melphalan injections between 20 and 30 mcg and show about 90% of eyes are salvaged.
Reports about the Munier protocol from users outside of Japan show it is associated with very few complications and no cases of extraocular spread. One issue that emerged was the development of severe hemorrhagic retinopathy, which Dr. Kim believes is due to melphalan getting behind the posterior vitreous face.
He started to deliver the injection more anteriorly to try to solve the issue, but that approach is associated with cases of cataract development, which may be a bigger problem as it precludes fundus exam.
Retinoblastoma experts are fine-tuning the technique to optimize tumor response and decrease complications, he continued. Extraocular tumor spread has not been encountered.
“A more recent analysis of the data for Group D eyes at our center has revealed that combining systemic chemotherapy and intravitreal melphalan injections led to a 75% globe salvage rate,” he said.
Genetic testing, imaging
Currently, RB1 gene testing performed using quantitative multiplex polymerase chain reaction and sequencing is the gold standard. Next-generation sequencing is on the horizon and is faster and perhaps less expensive.
Optical coherence tomography has also emerged as a helpful tool in retinoblastoma where it can detect very small tumors that can be missed on clinical exam and is being used to follow treatment response.
Jonathan W. Kim, MD
This article was adapted from Dr. Kim’s presentation during the Ocular Oncology and Pathology Subspecialty Day at the 2016 meeting of the American Academy of Ophthalmology. He has no relevant financial interests to disclose.