Sleep issues contribute to cognitive problems in childhood cancer survivors

This is the first study to show that childhood cancer survivors are particularly vulnerable to impaired memory, emotional control, organization and related neurocognitive skills due to fatigue and sleep problems. The link was independent of the survivor's age, sex or cancer treatment.

"While no one functions quite as well when sleep deprived or fatigued, most adults get by. But that is not always the case for survivors, who might already be at greater risk for neurocognitive problems as a result of their cancer treatment," said Kevin Krull, Ph.D., the study's corresponding author and an associate member of the St. Jude Department of Epidemiology and Cancer Control. St. Jude investigators led the study, results of which appear in the April 11 online edition of the journal Cancer.

The impact of sleep difficulties and fatigue on neurocognitive functioning, including the ability to think quickly, was comparable to side effects associated with high-dose cranial irradiation therapy, Krull said.

"Rates of sleep disturbance were not substantially higher among cancer survivors, but cancer survivors who are already at risk for cognitive problems have a three- to four-fold increase of those problems when they are sleep deprived or fatigued," Krull said. This study compared cancer survivors to healthy siblings. Impaired cognitive functioning was defined as scoring in the bottom 10 percent on validated tests that measure thinking and reasoning abilities.

"These problems can profoundly impact a survivor's life," said Krull. Cognitive problems make it less likely survivors will hold a job, live independently, marry or form other social connections. Despite years of work to overcome such treatment side effects, therapies are few and improvements modest. "The results from this study give us two more avenues to pursue and perhaps enhance the benefits of current therapies, including memory training," he said. At St. Jude, work has already begun.

Krull said the findings suggest survivors might benefit from periodic screenings for fatigue and sleep disturbances. The results might be useful for helping adult cancer survivors, who also battle fatigue, sleep difficulties and neurocognitive problems.

The work involved 1,426 survivors and 384 healthy siblings enrolled in the CCSS. The patients were found to have brain and central nervous system tumors, leukemia and lymphoma between 1970 and 1986 when they were age 20 or younger. Participants in this study completed several tests proven to reliably measure memory, organization, task efficiency and emotional regulation. All are indicators of neurocognitive functioning. The participants also completed questionnaires to measure fatigue, sleep quality, daytime sleepiness and vitality.

The CCSS is a collaboration that currently includes 30 U.S. and Canadian institutions. Funded by the National Cancer Institute, it is headquartered at St. Jude. The study's focus is long-term childhood cancer survivors and the goal is to help design therapies that maximize benefit and minimize risk.

Advances in childhood cancer treatment mean about 80 percent of patients today will become long-term survivors. But therapies also leave survivors at risk for a variety of problems. Particularly vulnerable for neurocognitive problems are those who were younger than age 6 when their cancer was found or those whose treatment included high-dose cranial irradiation, steroids or certain chemotherapy agents known as anti-metabolites.

Those risk factors cannot fully explain the neurocognitive variability seen among survivors. Designing more effective therapies requires better understanding of that variability. "There are likely multiple causes, which will require more individualized treatment approaches," Krull said.

More than 20 percent of survivors in this study had neurocognitive problems. Those at a two-fold higher risk of memory problems included survivors treated with high-dose cranial irradiation as well as those who scored highest on measures of daytime sleepiness and decreased vitality. Research found survivors with low vitality scores were three times more likely to have problems controlling their emotions. Fatigue and poor sleep quality were also linked to an increased risk of neurocognitive problems.

Anti-depressant medication was also associated with factors that contribute to cognitive functioning, including a 70 percent increased risk of memory problems and a 56 percent risk of reduced task efficiency. Krull said the link was independent of depression and needs further study.

There is good news. Exercise has helped patients battling chronic fatigue syndrome and other disorders counter the effects of fatigue. Krull said work is already underway at St. Jude to test the impact of exercise and measures to boost cognitive functioning with improved sleep.

Nancy Clanton, Ph.D., of St. Jude, is first author. The other authors are James Klosky, Chenghong Li, Neelam Jain, Deo Kumar Srivastava and Leslie Robison, all of St. Jude; Daniel Mulrooney, University of Minnesota; Lonnie Zeltzer, University of California, Los Angeles; and Marilyn Stovall, University of Texas, M.D. Anderson Cancer Center.

This work was supported in part by the National Cancer Institute and ALSAC.