Neurocognitive impairment in childhood cancer survivors stems from both disease, treatment
Survivors of childhood cancer are at risk for neurocognitive decline later in life related to the disease and treatment, a complication that may become more common as cancer treatments improve and more survivors reach adulthood.
Research has shown that apparent neurocognitive impairment is possible after treatment directed to the cranial nervous system, such as exposure to cranial radiation, intrathecal chemotherapy and neurosurgery.
However, neurocognitive impairment also has been seen among children who do not receive such therapies.
In both cases, neurocognitive impairment may not develop immediately after therapy but in later stages of survivorship.
“Neurocognitive and neurodevelopmental late effects are very important issues for a large number of our survivors and can have some very real-world consequences,” Matthew C. Hocking, PhD, pediatric psychologist in the division of oncology at Children's Hospital of Philadelphia, told Healio in an interview. “For example, adolescent and young adult survivors of pediatric brain tumors are at risk for having few friends and lower rates of attending college, holding full-time employment and achieving independent living.”
Hocking added that physicians can improve key aspects of quality of life by reducing the risk for these late effects and addressing them when they first develop.
The prevalence of neurocognitive impairment among cancer survivors varies across diagnoses, treatment and time since treatment, Kevin R. Krull, PhD, faculty member and endowed chair in cancer survivorship in the departments of epidemiology and cancer control and psychology at St. Jude Children’s Research Hospital, told Healio.
At the beginning of long-term survivorship, around 5 years from diagnoses, approximately 30% of survivors of any cancer and approximately 40% of survivors with brain tumors have significant neurocognitive impairment, according to Krull. Additionally, approximately 55% of survivors of any cancer and approximately 70% of survivors of brain tumors show symptoms of neurocognitive impairment during middle adulthood.
“This increase appears to be associated with accelerated aging and accelerated accumulation of chronic health conditions,” she said. “Advances in modern therapy now used at St. Jude Children’s Research Hospital appear to be lowering the prevalence of impairment at the beginning of long-term survivorship to between 25% and 35%, and we hope this lower rate is maintained as these new survivors age into adulthood.”
Hocking added that along with type of cancer and treatment, age at diagnosis and treatment can affect the risk for neurocognitive impairment among survivors, whether immediately after treatment or later in life.
“Certain cancer treatments, specifically cranial radiation therapy and intrathecal chemotherapy, carry higher risk,” he said. “This is especially true for children who are diagnosed and treated at a younger age, because cancer therapies directed at the brain tend to affect future brain development. Given that the two most common childhood cancers — acute lymphoblastic leukemia and brain tumors — involve both of these factors, there are many childhood cancer survivors at risk for neurocognitive late effects. The types and severity of neurocognitive late effects generally depend on how all these factors interact with one another.”
Assessment of neurocognitive impairment or decline among cancer survivors is often completed with the use of comprehensive neuropsychological evaluations.
Hocking said that these evaluations use norm-based, standardized tests to assess different aspects of cognitive functioning, including working memory, processing speed, executive function and attention regulation.
“Historically these evaluations take a full day and are completed by neuropsychologists,” he said. “Because neuropsychologists are short in supply, we haven’t been able to assess everyone who needs it. This is particularly difficult because we often want to have a child evaluated serially over time to monitor for progressive decline and establish appropriate accommodations and services.”
To address some of these challenges, Hocking added that the field is now moving toward briefer assessments, attempting to screen those who are at risk and determine who needs a more comprehensive assessment. Additionally, computerized assessments that do not necessarily require a fully trained neuropsychologist also are becoming more prominent.
“Here at Children’s Hospital of Philadelphia, we have developed a new screening program and are now trying to assess every child who may experience cognitive changes as a result of their cancer,” Hocking said.
Connection to frailty
Annalynn Williams, PhD, recently conducted a study with co-author Krull and colleagues, published in Journal of Clinical Oncology, focused on the connection between frailty and neurocognitive decline among adult survivors of childhood cancer.
Results from the study showed that both frail and prefrail survivors of childhood cancer experienced greater declines in memory, attention and executive function — domains commonly associated with aging and dementia — compared with nonfrail survivors.
Williams, who is from the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, told Healio that these complications are often demonstrated among elderly patients with breast cancer.
“In our study, however, the declines we found were large and among young adult survivors who are experiencing these declines decades earlier than their peers,” Williams said. “Because a significant number of survivors of childhood and adolescent cancer experience frailty, we wanted to understand if these associations existed or are exacerbated in young adult survivors to identify a high-risk group for intervention to preserve neurocognitive function. Frailty and neurocognitive decline may share similar underlying mechanisms and may respond to interventions designed to simultaneously improve physical and neurocognitive functioning.”
The number of different chemotherapeutic agents and radiation that survivors may be exposed to during treatment, whether directly to the cranial nervous system or other regions of the body, can result in systemic and organ-specific damage, Williams explained.
“In addition to frailty, our group has recently demonstrated that chronic health conditions, such as cardiopulmonary conditions, are associated with neurocognitive impairments,” he said. “We hypothesize that the initial insult to their neurocognitive functioning by cancer treatment is exacerbated later in life by conditions such as frailty to bring about neurocognitive decline earlier than if they had never experienced cancer.”
Addressing neurocognitive decline
As physicians continue research into the current and future prevalence of and associations with neurocognitive impairment among survivors, another hurdle is making sure patients receive the care they need, either as preventive measures or interventions.
Hocking noted that, currently, there are not a lot of “great options” for intervention, but those that have been tested and yielded improvements — including in-person cognitive rehabilitation therapies, computerized interventions and physical activity interventions — may not be readily accessible.
“Access is probably the biggest issue in terms of survivors and families making use of these interventions,” Hocking said. “Generally, these interventions are available only at large pediatric medical centers within the context of a research study. This really limits who can access them. Our field has an opportunity to determine the best evidence-based interventions that are effective and then disseminate them to providers in the community — and train them accordingly — so that they can be accessed by those who need them.”
Because of the interplay with other conditions, such as frailty, continued surveillance of this population is key.
“It is also important to engage in recommended surveillance of at-risk health conditions to limit contributions from new chronic health to neurocognitive decline,” Krull said.
Williams and Krull agreed that broad interventions targeting both physical and neurocognitive function designed with survivors of childhood and adolescent cancer in mind are needed.
“In the meantime, counseling survivors to be avoid sedentary behavior and engage in mind-stimulating and social activities is important,” Krull said.
- Hocking MC, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02327.
- Williams AM, et al. J Clin Oncol. 2021;doi:10.1200/JCO.21.00194.
For more information:
Matthew C. Hocking, PhD, can be reached at email@example.com.
Kevin R. Krull, PhD, can be reached at firstname.lastname@example.org.
AnnaLynn M. Williams, PhD, can be reached at email@example.com.