Research aims to spare children from painful adverse effects of chemotherapy
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Survival rates for pediatric cancers have improved dramatically during the past 50 years. According to American Cancer Society, the 5-year survival rate for children with cancer has risen from 58% in the mid-1970s to 85% today.
However, many of these children live with immediate and late adverse effects of cancer treatment, in some cases for years after active treatment has ended.
“It’s nice to say that we have saved a child’s life and that the child is cancer-free, but what happens with the child after the cancer treatment is completed?” Hana Starobova, PhD, postdoctoral researcher at University of Queensland, told Healio. “The problem is, how do we treat children who have cancer, cure them of cancer, but limit those long-term impacts? The question becomes, what is the quality of life?”
Starobova, whose research focuses on chemotherapy-induced adverse effects, received a fellowship grant from Children’s Hospital Foundation to investigate approaches that relieve or prevent adverse effects of cancer treatment among children. Starobova spoke with Healio about her study, its potential impact and the need to differentiate the physiology of children from that of adults.
Healio: How do children respond differently to chemotherapy than adults?
Starobova: It’s important to remember that children are not little adults. They have a faster metabolism than adults, so chemotherapy drugs are metabolized and eliminated faster. This may result in two different outcomes.
Some specific chemotherapy drugs may be released from the body more quickly, making the effects of the drug — and the adverse effects — less intense.
However, some chemotherapy drugs build metabolites — different chemical substances that may cause adverse effects. So, because children’s metabolism is much faster, there are more of those metabolites that can cause adverse effects. It really depends on the chemotherapy drug we use.
To complicate things further, we never use only one chemotherapy drug — it’s always a combination. This is another difference between children and adults, because the types of cancers that children have are different than the types adults have. For example, blood cancers and brain cancers are very frequently diagnosed in children and less frequently in adults.
Another difference is in the immune systems of children vs. adults. Studies have shown that a child’s immune system is very different in terms of immune cell reactivity. The nervous system is another major difference. In children, the nervous system is still developing and more susceptible to damage, consequently changing the way pain and adverse effects develop and how children respond to chemotherapy.
When we talk about pain, it’s important to understand that each type of pain has a different mechanism. Pain that develops after surgery will have a fully different mechanism than pain after chemotherapy. Each type of pain needs to be approached as a different disease and in a specific way.
Healio: What types of adverse events might pediatric cancer survivors experience?
Starobova: When patients receive chemotherapy, some drugs can cause adverse effects and pain very quickly, as soon as 24 hours after the administration. These are a problem because we have no way to treat them. The guidelines currently recommend dose reduction or discontinuation of chemotherapy in this situation. If this happens, it drastically decreases the patient’s chances of survival.
The second type of adverse effects are late effects. Those occur after chemotherapy is completed and can be experienced for a very, very long time. For example, I have a patient who was diagnosed with leukemia at age 2 years. She was successfully treated with chemotherapy. Now she is 8 years old and cancer-free, but unfortunately, she still experiences adverse effects. She will often still complain about pinching, stinging pain in her feet and in her legs during the night. She often also experiences motor impairments in the form of impaired walking and running or difficulty buttoning up her shirt.
Another late effect we see in pediatric cancer survivors is cognitive impairment, which causes these children to struggle to keep up with their peers at school. This also increases their chances of developing anxiety and depression later in life.
Healio: How is your research working to address these issues?
Starobova: We have found that the chemotherapy drug vincristine, which is used very frequently to treat leukemia in children, changes the function of the immune system. It reprograms immune cells to release substances in the proximity of nerves that activate those nerves and cause this type of pain. We have also tested a drug called anakinra (Kineret, Sobi Inc.), which inhibits the signaling of those substances that are released by those immune cells. This basically prevents this pain from even happening.
With this research, I am trying to understand how chemotherapy activates the immune system and how to design treatments to effectively prevent chemotherapy-induced adverse effects. Kineret is already approved for use in the clinic to treat rheumatoid arthritis in children. The beauty here is that we are repurposing a drug that is already used in the clinic, which can save us time in testing and clinical studies. I’m currently trying to find out the optimal time to administer this drug. Does it need to be administered before chemotherapy to prevent the pain from happening? Or is it enough to administer when the patient starts feeling pain? We are also figuring out appropriate dosing. In addition, we are looking more into the mechanism of how the drug activates immune cells, and seeking and developing collaborations with other clinicians who are interested in this area of study.
Healio: You are currently conducting preclinical studies. Will you ultimately study this in children?
Starobova: That is our goal. Before we start testing this in clinical studies, we need to make sure that adding the drug to the chemotherapy regimen is safe. Once we have the safety data, we can move on to clinical studies. Again, we are faced with the issue of the big difference between children and adults. Conventionally, we do preclinical testing in adult mice. So, the question is, how are these results in adult animals transferrable to children? We are working with our collaborators from Telethon Kids Institute (Australia) on developing juvenile models to mimic the developmental state of children.
References:
- American Cancer Society. Key statistics for Childhood Cancers. Available at: www.cancer.org/cancer/cancer-in-children/key-statistics.html. Accessed Oct. 7, 2022.
- Healio Interview.
For more information:
Hana Starobova, PhD, can be reached at University of Queensland, Brisbane QLD 4072, Australia; email: h.starobova@imb.uq.edu.au.
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