As many as one in five survivors of childhood cancer may have sleep problems that can impair cognitive performance in such areas as memory, performance of tasks, and emotional control, according to a report from the Childhood Cancer Survivor Study, led by a team of researchers at St. Jude Children's Research Hospital.
Fatigue and poor sleep quality were found to be closely linked to an increased risk of neurocognitive problems, especially in survivors taking antidepressants and those already vulnerable to cognitive and memory difficulties, according to the study, published in the June 1 issue of Cancer (2011;117:2559-2568).
While the rates of sleep disturbance were not substantially higher among survivors, those already at risk for cognitive problems had a three- to four-fold increase in poor memory and task performance when sleep deprived or fatigued. The impact of sleep difficulties and fatigue on neurocognitive functioning was comparable to cognitive side effects commonly associated with high-dose cranial irradiation therapy.
“This is the first major study to demonstrate that childhood cancer survivors are especially vulnerable to memory, emotional control, organizational, and associated neurocognitive skills due to fatigue and sleep problems,” said senior author Kevin R. Krull, PhD, Associate Member of the Department of Epidemiology and Cancer Control. The association was independent of survivors' age, sex, or type of cancer treatment received, he noted.
The Childhood Cancer Survivor Study (CCSS), funded by the National Cancer Institute, was launched in 1993. The current review involved 1,426 survivors and 384 healthy siblings, including patients treated for brain or central nervous system tumors, leukemia, or lymphoma when they were 20 years of age or younger.
Participants completed several validated tests to evaluate memory, organization, task efficiency, and emotional regulation—all indicators of neurocognitive functioning, as well as answering questionnaires within a three-year period, designed to measure fatigue, sleep quality, daytime sleepiness, and overall vitality. Results were then compared with those of their healthy siblings.
More than 20% of the survivors had neurocognitive problems, with a two-fold greater risk of memory problems among those with sleep problems, daytime sleepiness, and decreased vitality. Patients taking antidepressants were especially prone to cognitive problems, the study found, with a 70% higher risk of memory difficulties and a 56% greater risk of reduced task efficiency.
Moreover, survivors younger than age six when diagnosed, and those treated with high-dose cranial irradiation or anti-metabolites, had comparably elevated rates of neurocognitive problems. Moreover, low vitality scores were associated with three times greater likelihood of problems with emotional control, especially in women.
“This study highlights the importance of considering interventions to help improve sleep and/or physical fitness in childhood cancer survivors as opposed to only pharmacological options to treat sleep disorders or improve attention and overall cognitive functionality,” Dr. Krull said.
Under the Radar?
Until now, the connection between sleep problems, chronic fatigue, and cognitive or memory problems in childhood cancer survivors has been largely under-recognized, he said.
“What we have discovered is that the difference is much more dramatic when cognitive problems and sleep difficulties are compared between survivors and healthy siblings. Forty to fifty percent of survivors reported difficulty falling asleep, but this may be under-reported to their primary physicians, so it is up to doctors to question survivors about any sleep problems, general fatigue, and cognitive difficulties they might be experiencing.”
Many childhood cancer survivors may also experience chronic low-grade inflammation that can cause fatigue and related cognitive problems, but this connection needs to be further explored, he added.
“There are multiple potential causes of chronic fatigue and cognitive difficulties in childhood surviviors, so more individualized treatment approaches are necessary.”
The researchers are now in the early stages of a new study looking at biomarkers in chronic fatigue, notably those associated with such chronic inflammation, which can be detected with available blood tests. The study will take four to five years and will also include an intervention component, Dr. Krull said in a telephone interview.
Neurocognitive problems are relatively common in cancer patients, but the association between them and sleep disturbances and fatigue has not been well documented, according to Carolyn Weaver, RN, a clinical nurse specialist and patient education coordinator at Fox Chase Cancer Center.
“It's a complicated issue, but cancer survivors are living longer than ever before, so it is important to understand what factors are involved in this important quality-of-life issue,” said Ms. Weaver, a member of OT's Editorial Board.
“Cognitive deficits can be a significant barrier to pediatric cancer survivors' ability to further their education and career, to socialize normally, and to become independent.”
She agreed that awareness of sleep problems and fatigue in childhood cancer survivors is under-recognized. “Hopefully the results of this study will encourage more providers to assess survivors for sleep symptoms and educate them about measures that can help.”
Patients are often reluctant to mention sleep or cognitive problems to providers, especially to their oncologist, she added.
“This is a very timely study, and a big step, but other potential influences behind these deficits also need to be identified. We need to zero-in on all potential causes and identify the most effective solutions.”
Also asked for her opinion, Linda A. Jacobs, PhD, Clinical Associate Professor at the University of Pennsylvania Abramson Cancer Center, said, “Our perspective is a little different—In the young adults we see, cognitive impairment is one of the biggest issues, but I wouldn't say that fatigue is as significant factor as the study implies.”
She noted that by far, most cognitive issues seem to be related, at least in part, to the type of therapy survivors received—whole-body or cranial radiation. Even so, much mild cognitive impairment is difficult to explain.
Dr. Jacobs, who directs the LIVE-STRONG Survivorship Center of Excellence, the Living Well After Cancer Program at the Abramson Cancer Center, said that many potential confounders can affect cognition in these patients, and that linking deficits to sleep problems alone might be too simplistic.
“A host of other things must be considered,” she said. “Remember, these survivors may have other problems that can affect performance and quality of life, such as depression, anxiety, relationship issues, difficulties with independence, and [post-traumatic stress disorder]-like symptoms in addition to fatigue that may be secondary to the treatment they received.”
She said a more comprehensive look at the research literature on cognitive difficulties in survivors is needed, and comparison of potential causes in survivors and in the general population.
“A significant amount of data is examined in this study; however, it is very difficult to draw any conclusions from comparisons with the siblings they chose to examine, given the design of the study and considering the timeframes from which they drew their subjects.”
Differences in ages, socioeconomic status, and the type of work these survivors are engaged in, levels of depression and anxiety, and other psychiatric comorbidities, are just a few of the other considerations that must be considered, she said. Many of these survivors may also be taking antidepressants and anti-anxiety medications as well as drugs to treat attention deficit hyperactivity disorder, all of which can affect sleep or cause fatigue and explain some mild cognitive problems.”