Chronic Health Conditions and Neurocognitive Function in Aging Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Abstract

Background: Neurocognitive impairment in survivors of childhood cancer may be associated with direct neurotoxicity, as well as indirect effects of systemic health complications. We evaluated associations among treatment exposures, chronic health conditions, and neurocognitive outcomes in adult survivors of childhood cancer.

Methods: Participants included 5507 adult survivors of childhood cancer (47.1% male; mean [SD] age = 31.8 [7.6] years at evaluation; 23.1 [4.5] years postdiagnosis) in the Childhood Cancer Survivor Study who completed a self-report measure of neurocognitive function. Cardiac, pulmonary, and endocrine chronic health conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Structural equation modeling was used to examine a priori hypothesized causal pathways among cancer treatment, subsequent chronic health conditions, and neurocognitive outcomes. Multivariable models were used to estimate relative risk for associations of treatments and chronic conditions on neurocognitive function. All statistical tests were two-sided.

Results: One-third of survivors with a grade 2 or higher chronic condition reported impairments in task efficiency and memory. In addition to direct effects of cranial radiation, path analyses and multivariable models demonstrated direct effects of cardiopulmonary (β = 0.10, P = .002; relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.12 to 1.44) and endocrine (β = 0.07, P = .04; RR = 1.14, 95% CI = 1.02 to 1.28) conditions on impaired task efficiency. We identified similar effects of cardiopulmonary condition on memory (P = .01) and emotional regulation (P = .01). Thoracic radiation was associated with impaired task efficiency (P = .01) and emotional regulation (P = .01) through endocrine morbidity.

Conclusions: Non-neurotoxic exposures, such as thoracic radiation, can adversely impact survivors' neurocognitive function through chronic conditions. Management of chronic diseases may mitigate neurocognitive outcomes among aging survivors of childhood cancer.

Figure 1.

Consort diagram. Selection of study participants from the Childhood Cancer Survivor Study (CCSS). *Overall numbers do not add up because there are survivors who met more than one exclusion criterion.

Figure 2.

Pathways of cancer therapy on neurocognitive outcomes. Final path models are presented for each neurocognitive measure. All models are adjusted for sex, time since diagnosis, and age at diagnosis. Model fit indices are represented by comparative fit index, Tucker Lewis Index, and root mean square error of approximation. A) The path model for task efficiency. The impact of cranial radiotherapy (RT) on task efficiency is modified by sex (P = .002) and age at diagnosis (P < .001). The impact of anthracyclines on task efficiency is modified by time since diagnosis (P = .03). The impact of thoracic RT on endocrine disease is modified by age at diagnosis (P = .001). The impact of cranial RT on endocrine disease is modified by sex (P = .01), time since diagnosis (P < .001), and age at diagnosis (P < .001). B) Figure 2B shows the path model for memory. The impact of thoracic RT on endocrine disease is modified by age at diagnosis (P = .001). The impact of cranial RT on endocrine disease is modified by sex (P = .003), time since diagnosis (P < .001), and age at diagnosis (P < .001). C) The path model for organization. The impact of thoracic RT on endocrine disease is modified by age at diagnosis (P = .001). The impact of cranial RT on endocrine disease is modified by sex (P = .002), time since diagnosis (P < .001), and age at diagnosis (P < .001). D) The path model for emotional regulation. The impact of anthracyclines on emotional regulation is modified by time since diagnosis (P = .002). The impact of thoracic RT on endocrine disease is modified by age at diagnosis (P = .001). The impact of cranial RT on endocrine disease is modified by sex (P = .004), time since diagnosis (P < .001), and age at diagnosis (P < .001). P values are derived from a probit model with a robust weighted least squares estimator (WLSMV). All P values are two-sided. CFI = comparative fit index; IV = intravenous; RMSEA = root mean square error of approximation; RT = radiation therapy; TLI = Tucker Lewis Index.