Pediatric patients with acute lymphoblastic leukemia (ALL) treated with methotrexate, a chemotherapy drug, can experience challenges with mental flexibility and organization compared with expectations from the general population. These affected cognitive processes can be important for behaviors such as multitasking and task changing.1

This study, published in the Journal of Clinical Oncology, used neurocognitive testing, functional MRI, and structural MRI in 218 long-term survivors who were at least 5 years from diagnosis and at least 8 years old.

Results revealed that higher plasma levels of methotrexate during ALL treatment correlated with anatomical and functional changes in the brain in regions important for mental flexibility, planning, reasoning, and additional skills pertinent to executive function. Increased activity in the frontal lobe of the brain suggests survivors’ brains might be compensating for impaired cognitive function.

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“With 5-year survival rates for pediatric ALL approaching 95%, researchers are focused on better understanding and reducing the neurotoxicity patients still experience during and sometimes long after treatment,” said Kevin Krull, PhD, a member of the St. Jude Children’s Research Hospital Department of Epidemiology and Cancer Control, Memphis, Tennessee, and first author of this study.

“It remains a relatively common problem even in the contemporary treatment era of chemotherapy only. This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors. This information is essential for designing effective intervention to address the risk.”

Methotrexate, unlike many other chemotherapy drugs, can cross the blood brain barrier into the brain and central nervous system. To overcome potential differences among patients in the metabolism of methotrexate, researchers measured plasma levels of methotrexate during treatment rather than estimate concentrations from the dose administered.

Though intelligence was within normal limits (mean, 98; standard deviation, 14), measures of executive function, processing speed, and memory were less than population means (P < .02).

Higher methotrexate concentration in the plasma was associated with worse executive function (P < .02) and higher functional MRI activity. Prefrontal brain regions showed thicker cortices, which suggests disrupted neuronal pruning, and white matter structural changes were associated with these findings. Neurocognitive impairment was also associated with these findings.

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Krull said.

“While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”


1. Krull KR, Cheung YT, Liu W, et al. Chemotherapy pharmacodynamics and neuroimaging and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia [oublished online June 6, 2016]. J Clin Oncol. doi:10.1200/JCO.2015.65.4574.