Retinoblastoma is a rare cancer of the inner lining of the eye that primarily affects infants and young children.

In the United States, more than 95% of patients survive, most retaining their eyes with functional vision. But outcomes are highly dependent on early recognition and treatment — if the cancer spreads outside the eye, the prognosis is poor, especially if it spreads to the brain.

Globally, a large percentage of children from middle- and lower-income countries die each year due to the late recognition of retinoblastoma and/or a failure to receive the appropriate referral and care. Even when a diagnosis of advanced retinoblastoma is made and the eye is removed (enucleated), there is often a lack of clarity on how to proceed after microscopic review of the eye.

The decision to offer adjuvant chemotherapy and radiotherapy depends on what the individual treatment center defines as histopathologic high risk. Disparities can lead to wide variation in clinical practice and resulting outcomes.

To determine if regional disparities exist — and get a handle on how big they might be — researchers developed a web-based, non-validated, anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma and sent it to ocular oncologists, ocular pathologists and medical oncologists across 25 countries and six continents.

Responses from 27 practitioners representing 24 treatment centers and 16 countries revealed little uniformity in their definition of high-risk retinoblastoma, with postlaminar optic nerve infiltration, involvement of optic nerve transection and extrascleral tumor extension being the only features acknowledged as high risk for metastasis across all oncology practices. Consensus on over a dozen other clinical features varied widely, suggesting many patients are being overtreated or undertreated.

A study based on the responses was recently published in JAMA Ophthalmology.

For Dr. Patricia Chévez-Barrios, an ophthalmic pathologist at the Houston Methodist Research Institute and a co-author of the study, the survey represents an important first step towards recognizing variability and establishing international consensus definitions.

"You have to acknowledge there's a problem before you can identify solutions," says Dr. Chévez-Barrios, also research co-director at the Retinoblastoma Center of Houston, a collaboration involving Houston Methodist, MD Anderson Cancer Center, Baylor College of Medicine and Texas Children's Hospital). "The survey results reflect the reality of what's happening around the world — how everyone has their own ideas based on their experience and acts accordingly."

"Ideally, a consensus based on prospective systematic studies is a better approach," adds Dr. Chévez-Barrios. "However, this study highlights the current status and lays the groundwork for change."

Dr. Chévez-Barrios was instrumental in establishing the Children's Oncology Group (COG) protocol, which is currently used to guide treatment of high-risk retinoblastoma across North America and other countries. The protocol came out of the landmark 2019 paper A Study of Unilateral Retinoblastoma with and without Histopathologic High-Risk Features and the Role of Adjuvant Chemotherapy. Dr. Chévez-Barrios was the paper's lead author.

We sat down with Dr. Chévez-Barrios to discuss implications from the recent survey, lessons learned from the COG study and the next steps in the search for global consensus.

Q: Why is identifying high-risk retinoblastoma (RB) so important?

High-risk RB puts approximately 24% of children with RB at risk for developing systemic metastasis and indicates when chemotherapy and radiotherapy are needed as an adjuvant treatment to enucleation of the eye. Studies have shown that adjuvant therapy may reduce the potential of systemic metastasis to less than 7%. Global disparities in the definition of high-risk RB make it difficult to compare outcomes across various treatment centers. When basic definitions for risk vary, results are not comparable and drawing meaningful conclusions from multi-center studies is a challenge. So that means, not only are we probably not identifying some patients who may benefit from adjuvant treatment now, we are also losing opportunities to study and understand true high-risk retinoblastoma and make headway in defeating the cases that currently have no good therapies, such as those that have metastasized to the brain/central nervous system.

Q: Why is it difficult to come to a consensus on the high-risk features?

In the United States and globally, until recently, we didn't have studies on children with RB that were prospective and large enough to tell us what the "bad" histopathologic features were. We started planning the COG trial in 2004 and didn't publish it until 2019. That is partially because the number of patients with RB is so small. However, eventually we overcame that with the participation of other countries like India. It was also difficult to complete the study because of the time it took to review, interpret and work with the statistics to find which features were associated with high(er) risks for metastasis.

Historically, patients were seen and treated by ophthalmologists, not oncologists, and that can account for the late incorporation of RB patients into the COG trials. COG is a pediatric oncologists' group that has developed clinical trials with central histopathological review (by expert pathologists on the topic) to reach consensus on any childhood cancers they study. We unexpectedly also learned from this trial that there was a lack of standards on how to handle and study eyes enucleated for retinoblastoma to better interpret and diagnose high-risk features. In part, this is because of the lack of human resources in the field of ophthalmic pathology. There are very few pathologists in the world who have ocular pathology training. From our lessons learned at COG and together with the International Retinoblastoma Staging Working Group, we published a consensus statement in 2009 that has served as the guidelines for pathologists since then.

Q: Are there certain features you identified as highest risk?

In the COG trial we identified a group of patients with especially poor outcomes: those whose tumor invades the vascular coat of the eye (choroid) that surrounds the optic nerve head; whose tumor invasion covers more than 3 mm; and whose tumor simultaneously invades the optic nerve and passes through the lamina cribrosa for more than 1.5 mm. Patients with all three of these characteristics had the greatest metastasis into the brain, in spite of adjuvant chemotherapy, and likely need the most aggressive treatments available.

Q: Now that you have published this research, what's next?

Our hope is that this paper will serve as a starting point for international centers to cooperate in a prospective study with agreed-upon high-risk features to test patient outcomes. The first author of the recent JAMA Ophthalmology paper, Dr. Swathi Kaliki from the LV Prasad Eye Institute in India, is planning to retrospectively compare treatment outcomes based on each international participant institution's definitions of high-risk features.

In our own research at the Retinoblastoma Center of Houston, we are interested in studying current treatments and effect on tumor progression and ocular toxicities. Retinoblastoma is one of the few cancers that cannot be biopsied because if the tumor is dragged outside the eye by a needle, it will become recurrent and metastatic. However, accessing the anterior chamber fluid of the eye — separated from the location of the tumor — is a safe practice performed during intravitreal chemotherapy treatments for retinoblastoma. In preliminary studies, fragments of cell-free DNA have been recuperated from this anterior chamber fluid. Analysis of the cell-free DNA shows a correlation with tumor progression and aggressiveness. In the future, we would like to focus more on this kind of research — distinguishing the population of children with RB that can safely continue eye-sparing treatments from those that require prompt enucleation of the eye to prevent possible metastasis.