More children than ever before are surviving cancer for decades after their original diagnosis. However, survivors can experience long-term health effects from treatment, with the Canadian Cancer Society saying that two-thirds of children will develop one or more of these chronic or long-term conditions. In many ways, researchers and health professionals are playing catch-up trying to figure out what aspect of a childhood cancer experience may be responsible for these late health effects. This is particularly tricky with regards to psychological and neurological effects of treatment and for many chemotherapies, it is still unclear what impact these might have on the developing brain.
I had acute lymphoblastic leukemia (ALL) at the age of seven, and have been lucky so far in being able to do everything I have wanted to do academically and physically. However, after talking to survivors to conduct research for a recent TED talk I gave on cancer survivorship, I came across a wide range of experiences regarding long-term effects of childhood cancer. Some people feel that the experience does not affect them cognitively on a day-to-day basis (myself included) and some have formally recognized disabilities such as learning difficulties, more common in children who receive radiotherapy to the brain. However, many survivors with cognitive issues simply aren’t sure whether these issues are related to their early experiences with childhood cancer.
I talked to Dr Ellen van der Plas, Assistant Professor in the Department of Psychiatry at the University of Iowa Hospital and Clinics (formerly at SickKids, Toronto) for further insight. The number of researchers focusing on long-term effects of treatment is now growing steadily, but it has not always been this way.
“The focus was entirely on survival, at any cost. The approach was somewhat that saving lives comes first and then we worry about everything else afterwards,” said van der Plas.
Dr van der Plas specializes in looking at the neurocognitive effects of childhood leukemia treatment. She published a research paper in September last year showing that childhood ALL survivors are more likely to have difficulties with memory and inhibition or voluntary restraint of motor actions than children who have not had leukemia. A lot of adult cancer survivors report changes in their mental health and neurological functioning during/after treatment, commonly referred to as ‘chemo brain,’ but van der Plas says this may not be applicable to children.
“Adults with cancer can remember their lives before cancer, they recognize their brain is operating differently to how it was before. Chemo brain does not seem to apply to children, they don’t have a reference point. It’s just their normal, just who they are. Childhood cancer patients are exposed to all of these treatments when their brain is still growing, which makes a crucial difference when comparing the impacts on children and adults.”
The brain of a 30-year-old is not so drastically different from that of a 40-year-old in developmental terms, however the same cannot be said comparing a 1-year-old and an 11-year-old. Therefore, predicting the impact of individual cancer treatments or indeed the trauma of the whole experience on the developing brain, at the wide range of ages a child gets cancer is infinitely complex.
“At the moment, we are unsure how any trauma related to the experience of having cancer as a child affects the growing brain. Especially children diagnosed as toddlers may not remember much, whereas others do, especially if they are a bit older,” said van der Plas.
It can also be difficult to definitively tell whether differences in neurological functioning are simply due to natural variation between different children or due to the cancer and/or treatments. For example, in comparison to the rest of the population, survivors of childhood leukemia are more likely to have attention deficit hyperactivity disorder (ADHD). ADHD is typically diagnosed around the age of 7 years old, which is often after many childhood cancer diagnoses. While it is challenging to definitively determine if exposure to cancer treatment or the experience of childhood cancer itself, contributes to ADHD symptoms, it is clear that ADHD is far more common among childhood cancer survivors than in those who have not had childhood cancer.
To complicate matters further, a child with ‘typical’ ADHD may have a different disorder than a childhood cancer survivor with ADHD-like symptoms. “We don’t know yet whether ADHD in leukemia survivors is the same as in non-survivors, so studying these people is crucial for determining supportive care,” said van der Plas.
With a cocktail of chemotherapy agents used to treat most childhood cancers, along with radiotherapy and surgery in some cases, how can research try to figure out which of these might be responsible for long-term neurological side effects? It is already fairly-well accepted that surgery and radiotherapy can cause neurological problems in children with brain cancer, but what about chemotherapy? Children with leukemia are a major focus of van der Plas’s work and with 25% of childhood cancer diagnoses being leukemia and around 90% of children now surviving long-term, more work into understanding the impact of treatment is vital.
Scientists have been making improvements for decades to try to refine treatments and minimize side effects. Children with leukemia used to get radiation to the cranium and spine to prevent relapse by targeting leukemia cells ‘hiding’ in the central nervous system. That has now almost universally been replaced with intrathecal methotrexate, a transition that did not reduce survival, but did reduce side effects. However, scientists are now increasingly learning that methotrexate comes with its own range of long- and short-term side effects.
Indeed, although van der Plas cannot definitively say whether methotrexate is the cause of the neurocognitive late effects described in her 2017 paper, scientists suspect that it might well be implicated. This is for many possible reasons, a major one simply being that methotrexate is injected intrathecally, so comes into close contact with brain and spinal nervous tissue. Secondly, my own work suggests that methotrexate may interfere with the production of a protein called myelin, vital for the proper functioning of the brain and central nervous system.
This replacement of cranial radiation with methotrexate is relatively old news, the switch having occurred in the 1990’s in most treatment centres and scientists continue to make improvements to minimize side-effects. The increased use and affordability of genetic analysis of tumors is making prescribing the correct amount of treatment increasingly more commonplace and new treatments such as CAR-T cells may come with less long-term side effects, but require a lot more evaluation before they can even be considered to be a possible replacement for conventional treatments.
However pressing it is to do more research into the side effects of current treatments, it must be stressed that until better alternatives are available, patients need these treatments to survive. The ultimate goal is for childhood cancer survivors to live exactly how they would have before the cancer, but we have a long way to go before this can be achieved.
In the meantime, survivors who feel that they may have any health issues related to their treatment should seek help. Having a conversation with their family doctor is a good starting point. The family doctor could provide a referral to a clinical (neuro) psychologist who can help figure out how to manage any cognitive and learning problems.
Dr Vicky Forster is a postdoctoral cancer research scientist with interests in pediatric cancers and the long- and short-term side effects of treatment. She’s also a 23-year survivor of childhood leukaemia and an advocate for childhood cancer survivorship and patient involvement in research. She currently works at The Hospital for Sick Children (SickKids) on rare pediatric brain tumours. She is passionate about science communication and keeping the whole pediatric oncology community up to date with her research progress.