Evolution of neurocognitive function in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only
The purpose of this study was to determine the evolution of neurocognitive problems from therapy completion to long-term follow-up in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.
We evaluated whether attention problems observed at therapy completion evolve into long-term executive dysfunction in 158 survivors treated on a single institution protocol. Treatment data (high-dose intravenous methotrexate exposure [serum concentration] and triple intrathecal chemotherapy injections) were collected. Parent report of behavior and direct cognitive testing of survivors was conducted at end of therapy, and survivors completed neurocognitive testing when > 5 years post-diagnosis.
At the end of chemotherapy, survivors (52% female; mean age 9.2 years) demonstrated higher frequency of impairment in sustained attention (38%) and parent-reported inattention (20%) compared to population expectations (10%). At long-term follow-up, survivors (mean age 13.7 years; 7.6 years post-diagnosis) demonstrated higher impairment in executive function (flexibility 24%, fluency 21%), sustained attention (15%), and processing speed (15%). Sustained attention improved from end of therapy to long-term follow-up (p < 0.001). Higher methotrexate AUC and greater number of intrathecal injections were associated with attention problems (p = 0.009, p = 0.002, respectively) at the end of chemotherapy and executive function (p < 0.001, p = 0.02, respectively) problems at long-term follow-up. Attention problems at the end of therapy were not associated with executive function problems at long-term follow-up (p’s > 0.05). The direct effect of chemotherapy exposure predicted outcomes at both time points.
Conclusions and Implications for Cancer Survivors
Survivors should be monitored for neurocognitive problems well into long-term survivorship, regardless of whether they show attention problems at the end of therapy. Treatment exposures are the best predictor of long-term complications.
KeywordsChildhood acute lymphoblastic leukemia Childhood cancer Chemotherapy Attention, executive function Behavior
We thank Dr. Mary Relling, PharmD, St. Jude Children’s Research Hospital, and her lab that provide pharmacokinetic data, and Pia Banerjee, PhD, Joycelynn Butler, MS, William Lewis, MS, Adrienne Studaway, Med, Adrienne Studaway, Med, Cynthia Jones, MA, and Deborah Stewart, MA, all from Cognitive Neuroscience group, St. Jude Children’s Research Hospital, for providing technical support.
The following authors have made substantial contributions to the intellectual content of the paper, including conception/design (WL, YTC, DS, KRK), acquisition, analysis, or interpretation of data (WL, YTC, HMC, LMJ, DS, VGN, HZ, JGG, IH, LLR, CHP, MMH, KRK), drafting of the manuscript (WL, YTC, KRK), and critical revision of the manuscript for important intellectual content (WL, YTC, HMC, LMJ, DS, VGN, HZ, JGG, IH, LLR, CHP, MMH, KRK). Contributions also include statistical analysis (WL, DS) and obtaining funding (KRK, LLR, MMH). All authors have approved the final version of this manuscript. KRK had full access to all data in the study and had final responsibility for the decision to submit for publication.
This study was funded by NIMH (R01-MH085849 to KR Krull), NCI (U01-CA195547 to MM Hudson/LL Robison), and American Lebanese Syrian Associated Charities.
Compliance with ethical standards
Conflict of interest
All authors have no conflict of interest including financial interests, activities, relationships, and affiliations and sources of funding and support.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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