Chemotherapy for childhood acute lymphoblastic leukemia (ALL) is associated with alterations in brain activation during attention and executive-function tasks, researchers report. Between 20% and 40% of long-term survivors of childhood ALL have a neurocognitive impairment, including deficits in attention

Dr. Kevin R. Krull and colleagues from St. Jude Children's Research Hospital, in Memphis, Tennessee, recently reported that higher plasma concentrations of methotrexate are associated with executive dysfunction, a thicker cortex and higher brain activity in the frontal regions, but the causes of neurocognitive deficits in ALL survivors remain unclear.

In the current study, the team evaluated the results of neurocognitive testing and functional MRI from 165 childhood ALL survivors, who had chemotherapy but not prophylactic cranial irradiation, five or more years after their diagnosis.

Compared with population norms, survivors had significantly higher rates of impairment on number-letter switching, verbal fluency, digit span backward and forward, block design, grooved pegboard, coding, letter sequencing and Rey copy, the researchers report in the Journal of the National Cancer Institute, online May 21.

Higher methotrexate exposure

Survivors with impaired executive function and processing speed had higher methotrexate exposure, compared with survivors without impairment. Brain activation patterns varied across brain regions, with reduced activation in some areas, suggesting compromised task involvement, and increased activation in other areas, suggesting compensatory task involvement.

Younger age at diagnosis and higher methotrexate exposure were associated with lower brain activation in regions known to be involved in response inhibition, shifting of attention, language, executive functions, and decision-related processes.

Increased activation in regions involved in alerting and decreased activation in regions involved in sustained attention was associated with higher methotrexate exposure, which suggests that some regions ramp up their activity to compensate for reduced activity in damaged or inefficient brain regions.

The researchers note several limitations, including the limited sample size, the lack of a typically developing control group, use of different MRI scanners and the lack of functional MRI data before diagnosis or during therapy with which to compare these findings.

"Despite limitations," they conclude, "this study shows that attention and executive function-related brain activation is associated with important clinical risk factors for neurocognitive deficits in long-term survivors of ALL treated with chemotherapy only."

"The pattern of behavioral and imaging responses provides evidence for altered engagement of neural systems to maintain task performance despite therapy-induced brain injury. Thus, functional imaging may help to clarify the pathophysiology of neurocognitive deficits often seen in ALL survivors and to select patients for remedial intervention based on neural phenotypes."

Dr. Amanda Hutchinson of the University of South Australia Adelaide, who recently reviewed cancer-related cognitive impairment in children, told Reuters Health by email, "Current treatment protocols improve survival and reduce toxicity but are still associated with cognitive impairment and compensatory activation of brain regions later in life."

"Although not the focus of this study, survivors of ALL may need support and intervention in order to overcome cognitive effects of exposure to chemotherapy," said Dr. Hutchinson.

"It is important that research continues to explore the brain activation underlying task performance, as ALL survivors may be using compensatory strategies to achieve task performance equivalent to their peers," Dr. Hutchinson said.

"That is, equivalent performance on a task does not necessarily mean that treatment has not caused damage to the brain. Rather, survivors may be working harder or differently to compensate for inefficient processing or damaged brain regions associated with contemporary chemotherapy treatment," Dr. Hutchinson added.