Late-onset Cognitive Impairment and Modifiable Risk Factors in Adult Childhood Cancer Survivors
Authors: Phillips Nicholas S. , Stratton Kayla L. , Williams AnnaLynn M. , Ahles Tim , Ness Kirsten K. , Cohen Harvey Jay , Edelstein Kim , Yasui Yutaka , Oeffinger Kevin , Chow Eric J. , Howell Rebecca M. , Robison Leslie L. , Armstrong Gregory T. , Leisenring Wendy M. , Krull Kevin R. 
Published: May 2023

Importance

Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood.

Objective

To determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments.

Design, Setting, and Participants

Participants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was available. This study examined the prevalence of new-onset neurocognitive impairment between baseline (23.4 years after diagnosis) and follow-up (35.0 years after diagnosis). The analysis was performed from January 2021 to May 2022.

Exposures

Cancer treatment exposures were abstracted from medical records. Chronic health conditions were graded using Common Terminology Criteria for Adverse Events version 4.03.

Main Outcomes and Measures

The primary outcome was new-onset (present at follow-up, but not present at baseline) neurocognitive impairment (defined as a score in the worst 10% of the sibling cohort). Impairment was assessed using the Childhood Cancer Survivor Study Neurocognitive questionnaire. Relative risks (RRs) and 95% CIs were used to estimate associations of neurocognitive impairment with treatment and health behaviors and conditions using generalized linear models.

Results

The cohort comprised 2375 survivors (mean [SD] age at evaluation, 31.8 [7.5] years; 1298 women [54.6%]) of childhood cancer, including acute lymphoblastic leukemia (ALL; 1316 participants), central nervous system (CNS) tumors (488 participants), and Hodgkin lymphoma (HL; 571 participants). A total of 232 siblings (mean [SD] age at evaluation, 34.2 [8.4] years; 134 women [57.8%]) were included. Compared with siblings, a higher proportion of survivors with no impairment in memory at baseline had new-onset memory impairment at follow-up: siblings proportion, 7.8% (95% CI, 4.3%-11.4%); ALL survivors treated with chemotherapy only, 14.0% (95% CI, 10.7%-17.4%); ALL survivors treated with cranial radiation (CRT), 25.8% (95% CI, 22.6%-29.0%); CNS tumor survivors, 34.7% (95% CI, 30.0%-39.5%); and HL survivors, 16.6% (95% CI, 13.4%-19.8%). New-onset memory impairment was associated with CRT in CNS tumor survivors (RR, 1.97; 95% CI, 1.33-2.90) and alkylator chemotherapy greater than or equal to 8000 mg/m2 in ALL survivors treated without CRT (RR, 2.80; 95% CI, 1.28-6.12). Neurologic conditions mediated the impact of CRT on new-onset memory impairment in CNS survivors. Smoking, low educational attainment, and low physical activity were associated with elevated risk for new-onset memory impairment.

Conclusions and Relevance

These findings suggest that adult survivors of childhood cancer are at elevated risk for late-onset memory impairment related to modifiable risk factors identified early in survivorship.