Structural brain alterations following adult non-CNS cancers: a systematic review of the neuroimaging literature

Abstract

Background: Cancer and cancer treatments may impact the brain through several pathways leading to cognitive impairment. Neuroimaging evidence has begun to elucidate the neurobiological underpinnings of cancer-related cognitive impairment. The aim of this paper was to systematically review available literature on structural brain alterations following adult non-central nervous system (CNS) cancers and associated treatments. Methods: This review followed PRISMA guidelines and was registered in PROSPERO (ID#107387). Comprehensive searches were conducted in June 2018 using PubMed and Web of Science. Inclusion criteria were English peer-reviewed journal articles of formal, controlled studies that examined structural neuroimaging outcomes in adult non-CNS cancer patients and survivors. Selected articles were assessed for quality and risk of bias using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Thirty-six publications of prospective and cross-sectional studies met inclusion criteria and were included. Structural brain alterations following cancer and its treatment were reported in a majority of the publications as evidenced by reduced global and local gray matter volumes, impaired white matter microstructural integrity, and brain network alterations. Structural alterations were most often evident when cancer-treated groups were compared with healthy controls, and more subtle when compared with cancer controls. Regarding the existence of pretreatment impairments, the evidence was equivocal. There was significant between-study heterogeneity in imaging analytical approaches and use of statistical adjustments. Over half reported associations with cognitive outcomes, though regions and associated cognitive domains were heterogeneous. Conclusions: Structural brain alterations following cancer and cancer treatments were reported in a majority of the reviewed studies. However, the extent of observed alterations depended on the choice of comparison groups. Methodological issues exist that will need to be addressed systematically to ensure the validity of findings. Large-scale prospective studies with extended assessment points are warranted to replicate and build upon initial findings.

Figure 1.

Several pathways are hypothesized to underlie the detrimental impact of cancer and cancer treatments on the brain and cognitive functions. First, cancer and cancer treatments (e.g., chemotherapy) may either directly, or indirectly through various pathophysiological mechanisms including epigenetic changes, DNA damage and oxidative stress, mitochondrial dysfunction, pro-inflammatory cytokine release, and endocrine and circadian disruptions, result in brain alterations and cognitive impairment (A). These mechanisms should be regarded as co-occurring and dependent processes as indicated by the white arrow. Second, cancer and cancer treatments may lead to increased psychological distress (e.g., symptoms of depression and anxiety) and behavioral changes (e.g., sleep disturbances), which may again, either directly or indirectly, impact the brain and cognitive functions (B+C). Third, activated mechanisms and associated brain alterations, as well as cognitive changes, may on their own have a negative impact on psychological and behavioral factors resulting in a negative feedback loop (C). Finally, known genetic and demographic risk factors may moderate these pathways.

Figure 2.

Flowchart of included studies according to PRISMA.

Figure 3.

Number of publications by patient sample size.