Some 50 years after Eli Lilly and Co. began selling vincristine, the chemotherapy drug is still widely used to treat cancers in children.
While often effective, a vincristine regimen is sometimes accompanied by neuropathy – side effects in the nervous system that can range from jaw pain to foot drop to severe constipation.
For most patients the effects go away when the drug treatment ends, but for others the damage is long term. For some the problems are tolerable, for others they are much more of a struggle. To date, it’s been difficult or impossible to predict who will suffer – and how much – from the side effects, and who will not.
Moreover, it’s not easy, particularly with younger patients, to determine quickly who is suffering from the onset of complications.
“When you ask a two-year-old if they have numbness or tingling or even pain, it’s a real challenge,” said Dr. Renbarger, Nora Letzter Scholar in Pediatrics and assistant professor of pediatrics and of medicine.
So she and University of Michigan researcher Ellen Smith are developing a tool to help physicians accurately assess the level of nervous system side effects – neuropathies – that might be affecting a child receiving vincristine for acute lymphoblastic leukemia.
The two have taken an existing neuropathy assessment tool and adapted it for use with vincristine and with children, adding relevant issues such as hoarseness and constipation. They have, as Dr. Renbarger put it, “put this tool through the wringer,” testing it on about 100 young patients. They hope to make it available to doctors later this year.
Earlier and better diagnosis of existing complications will be good. So would predicting, and preventing, future complications.
For that, Dr. Renbarger and teams of researchers at Michigan, Vanderbilt University, Children’s National Medical Center at George Washington University and Penn State University are collaborating on a long-term study to gather medical, pharmacological and genetic data that they hope will enable physicians to determine, in advance, how susceptible individual patients may be to vincristine side effects, and how effective a treatment vincristine is likely to be.
The research, which will last about five years, will follow children from the time they are diagnosed with acute lymphoblastic leukemia until a year after their vincristine treatment ends.
It’s a complicated situation – not only do patients react differently to vincristine, but there is a broad range of aggressiveness in leukemia.
And so, asks Dr. Renbarger, “are there children who are particularly sensitive to neuropathy, but have a less aggressive disease? Could we lower their dose to spare them some of the toxicity?
“At the other end of the spectrum, are there kids with very high risk disease who won’t experience significant neuropathies – who could tolerate a more intensive dose?”
Some answers may be emerging now in Kenya, where the IU School of Medicine conducts an international medical program in partnership with the Moi University School of Medicine. Dr. Renbarger and graduate fellow Jodi Skiles, M.D., have begun a study of Kenyan children undergoing vincristine treatment. That study grew out of previous observations that some children produce more of a particular enzyme that is more efficient in breaking down – metabolizing – the vincristine. As a result, the children with that genetic makeup have fewer side effects from the drug. Research showed that African-American children were more likely to have more of the highly efficient form of the enzyme.
The Kenya study has enrolled 65 children so far, “and we’ve seen virtually no neuropathy. Two children with extremely minimal neuropathy,” said Dr. Renbarger. And this being a neuropathy study, they’re looking carefully to find it.
In a similar group of US children receiving vincristine, she said, “We would be finding subtle changes in 90 percent of the patients.”
If the trend holds up as the research continues, the implication in Africa, at least, is that many children could tolerate higher doses of vincristine that could make the drug more effective for them.
In addition, the Kenya study should add genetic and clinical data to help answer the broader question of which young patients are more likely to be negatively affected by vincristine, and which might benefit from an even larger dose.
Dr. Renbarger’s research also points to other factors that may play roles. For example, younger children tend to metabolize the drug faster than older ones. Research is pointing to several other genetic differences that may play a role. And differences in how the drug is administered – how often, in what doses, and so on, may also be significant. The interaction of such factors will take time to sort out, but the result will hopefully be more effective cancer treatment with fewer side effects.
Said Dr. Renbarger, who is associate director of the Indiana Institute for Personalized Medicine and a member of the Indiana University Melvin and Bren Simon Cancer Center: “That’s my long term goal – to optimize how we give vincristine.”