A chemo combo pioneered at St. Jude retains a high cure rate for retinoblastoma while preserving usable vision and lowering future cancer risk.
Like most 1-year-olds, Alissa Galindo loves flipping through board books, cruising along furniture and playing with her older siblings. But Alissa’s life has already veered sharply from the typical because of her battle with retinoblastoma, a rare eye cancer that affected the center of vision in her left eye and some peripheral vision in her right.
Alissa was diagnosed at 3 months old, after photos revealed the cancer’s telltale white glow in her eyes. She and her family came directly to St. Jude Children’s Research Hospital for a triple-drug chemotherapy regimen. Pioneered at St. Jude, the drug combo not only offers a high cure rate, but ups the odds Alissa will have usable eyesight that will carry her into old age.
Affecting the light-sensing tissue at the back of the eye, retinoblastoma strikes about 250 to 300 infants and young children in the U.S. each year. Many, like Alissa, carry a mutation in their RB1 gene that predisposes them to the cancer.
“The doctors feel she can see really well, and I know she can because she picks up small objects,” says Alissa’s mom, Megan Blair. “I don’t know if it’s perfect vision, but she does see.”
Drug swap offers advantages
Alissa’s parents leapt at the chance for their child to receive the St. Jude three-drug chemotherapy regimen for retinoblastoma. St. Jude now substitutes the drug topotecan for another called etoposide. This change has lowered children’s risk of developing treatment-related leukemia.
In the Journal of Clinical Oncology, St. Jude scientists recently described a 10-year follow-up study that outlined the advantage of topotecan use. The research showed for the first time that using topotecan as a first-line drug, along with vincristine and carboplatin, was superior to placing etoposide in the mix.
The drug switch sustained high cure rates for retinoblastoma. Those cure rates exceed 95 percent in the U.S. for children like Alissa, who have advanced disease that is still confined to the eyes; all patients survived on the St. Jude study. The newer triple-drug therapy was also more successful than standard chemotherapy at helping survivors retain measurable vision. Eighteen of the 24 children who completed therapy had near-normal vision in at least one eye after treatment.
To Megan and her husband, Daniel Galindo, these benefits clearly outweighed a minor downside of topotecan’s use. The study required more chemotherapy cycles, and topotecan can trigger more short-term side effects than etoposide. These side effects include low blood cell counts, diarrhea, rash and fever. But since Alissa’s RB1 gene mutation also confers a higher risk of later cancers, cutting the odds of treatment-related leukemia was crucial.
Envisioning optimal treatment
Given retinoblastoma’s impressive cure rate, St. Jude researchers have turned their focus to making treatment safer and preserving sight.
More than a decade ago, Michael Dyer, PhD, chair of St. Jude Developmental Neurobiology, began lab research that laid the foundation for the recent clinical trial. Topotecan had shown promising results in treating other solid tumors, including brain cancer. This encouraged the study’s senior authors, Carlos Rodriguez-Galindo, MD, Global Pediatric Medicine chair, and Matthew Wilson, MD, of Surgery, to work with Dyer and his team to explore whether it might be a better choice than etoposide for retinoblastoma patients.
Dyer praised the constant dialogue between lab and clinic that helped shape efforts on both sides and speed the timeline for testing the new triple-drug option with St. Jude patients.
“Retinoblastoma is a success story in terms of childhood cancer and survival rates,” says Dyer, who identified an effective dose of topotecan in the lab before the clinical trial was launched. “But one of the things I really came to appreciate at St. Jude is thinking beyond survival and thinking about quality of life for kids. In this case, it’s very direct and very clear—it’s about saving vision.”
Avoiding surgery and radiation
Dyer’s sentiment is shared by lead study author Rachel Brennan, MD, of St. Jude Oncology. When topotecan was substituted for etoposide, fewer retinoblastoma patients required the surgical removal of an eye or the use of external beam radiation to stop the tumor from worsening. To provide further consolidation, Wilson used focal therapy with extreme heat or cold to target any lingering tumor cells.
The trial’s success is measured in the number of eyes saved and how well they function. More than 75 percent of eyes with advanced disease were saved with treatment that included topotecan. That compares to reports from prior research of 30 to 60 percent saved when etoposide was used—treatment that often included radiation.
Avoiding radiation and surgery are both key goals, but for different reasons. Radiation can damage surrounding bone and tissue and even trigger secondary cancers. Meanwhile, surgery becomes an option if nothing else seems to control tumor growth or spread. But prosthetics, while realistic-looking, “aren’t the native eye and have no potential for vision,” Brennan explains.
Perhaps most striking, Dyer and Brennan say, is 75 percent of St. Jude patients finished the topotecan-combo treatment with measurable vision.
“Our No. 1 goal is still patient survival, but we need to take it one step further—to save eyes. And not just save an eye, but save an eye with vision,” Brennan says.
Evaluating the results of their work demands Dyer and Brennan to take both a short- and long-term view. The pair say they hope other pediatric cancer programs won’t shy away from using topotecan as standard treatment for retinoblastoma. At some hospitals, treatment includes pumping a highly toxic chemotherapy drug known as melphalan directly into the small vessels surrounding the eyes, an approach not advocated at St. Jude.
The three-drug combo substituting topotecan for etoposide has already become the standard treatment at St. Jude, which Dyer notes is one of the few institutions able to run clinical trials for retinoblastoma.
“By having all this data and infrastructure, it becomes the gold standard,” he says. “It’s not an anecdotal report with one patient here or there doing better. It’s a well-designed clinical trial with all the appropriate benchmarks. Since other centers are having frustrations with melphalan, I think the timing is actually good for seeing this sort of a transition.”
Brennan says the St. Jude research is especially valuable because its 10- year follow-up period “evaluates a long-term cure with long-term vision that impacts patients through the lifespan.”
She adds that delayed gratification is important in retinoblastoma.
“You have to be mindful of the footprint you make on the lives of these children, and the only way to do that is to follow them closely,” she says. “That’s why we’ve carefully followed these patients and tracked every outcome.”
But even as they celebrate their recent victories in retinoblastoma outcomes, St. Jude researchers have already cast wider nets. In developing nations, for example, many children still die of retinoblastoma, with published research indicating survival rates average from 40 to 79 percent in lower- and middle- income countries. Dyer and Brennan would like to extend St. Jude resources to these children to bring their outcomes more in line with the U.S.
“I’m hoping over the next several years to bring this therapy globally through our international outreach efforts,” Dyer says. “I want to extend this beyond the U.S. to around the world because the vast majority of retinoblastoma patients are in less-developed countries.”
Brennan agrees and calls the new St. Jude research “a good first step.” But she’d also like to identify targeted therapies that will work just as well against retinoblastoma but with lower toxicity than conventional chemotherapy, further reducing side effects.
“I’m not losing sight of what we’ve done, but I know the story’s not over yet,” she says, noting that much will be revealed in another decade, after the children who’ve undergone topotecan therapy grow older.
“With the vision we’ve been able to provide for them and the emphasis we have on the whole patient, I hope they know they don’t have to be limited,” Brennan remarks. “You hear about the patient who’s a gymnast or a wide receiver, or see the child in clinic who had awful disease in both eyes, but who is picking up ladybugs off the sidewalk or riding a bike.
“These children have figured out how to be amazing,” she continues. “I’m interested to see in another 10 years what these survivors are doing with their lives and their vision.”
From Promise, Winter 2017