Cognitive effects of cancer and its treatments at the intersection of aging: what do we know; what do we need to know?

Abstract

There is a fairly consistent, albeit non-universal body of research documenting cognitive declines after cancer and its treatments. While few of these studies have included subjects aged 65 years and older, it is logical to expect that older patients are at risk of cognitive decline. Here, we use breast cancer as an exemplar disease for inquiry into the intersection of aging and cognitive effects of cancer and its therapies. There are a striking number of common underlying potential biological risks and pathways for the development of cancer, cancer-related cognitive declines, and aging processes, including the development of a frail phenotype. Candidate shared pathways include changes in hormonal milieu, inflammation, oxidative stress, DNA damage and compromised DNA repair, genetic susceptibility, decreased brain blood flow or disruption of the blood-brain barrier, direct neurotoxicity, decreased telomere length, and cell senescence. There also are similar structure and functional changes seen in brain imaging studies of cancer patients and those seen with "normal" aging and Alzheimer's disease. Disentangling the role of these overlapping processes is difficult since they require aged animal models and large samples of older human subjects. From what we do know, frailty and its low cognitive reserve seem to be a clinically useful marker of risk for cognitive decline after cancer and its treatments. This and other results from this review suggest the value of geriatric assessments to identify older patients at the highest risk of cognitive decline. Further research is needed to understand the interactions between aging, genetic predisposition, lifestyle factors, and frailty phenotypes to best identify the subgroups of older patients at greatest risk for decline and to develop behavioral and pharmacological interventions targeting this group. We recommend that basic science and population trials be developed specifically for older hosts with intermediate endpoints of relevance to this group, including cognitive function and trajectories of frailty. Clinicians and their older patients can advance the field by active encouragement of and participation in research designed to improve the care and outcomes of the growing population of older cancer patients.

Figure 1

Change in Processing Speed by Treatment, Age group, and Cognitive Reserve Among Breast Cancer Patients Pre- to post-treatment change in processing speed by treatment, age groups, and level of cognitive reserve (assessed by the Wide Range Achievement Test (WRAT)-Reading). Reprinted with permission from Ahles et al 2012, Journal of Clinical Oncology

Figure 2

Impact of Change in Brain Resources and Frailty Levels on Cognitive Performance by Age The same change in brain resources can have a minimal effect on cognitive performance in a young adult (a), a moderate effect in an older adult with high cognitive reserve (b) and a greater effect on an older adult with low cognitive reserve (c). Likewise, the same change in frailty level will have differential effects on the individual as a function of overall system reserve. Adapted and reprinted with permission from Ahles et al, Psychooncology 2012

Figure 3

Postulated Common Underlying Aging Processes Associated with Frailty, Cancer and Cancer Systemic Therapy and their Impact on Cognitive Outcomes

Figure 4

Trajectories of Cognitive Decline Based on Theories of Aging and Frailty Phenotype Adapted from Ahles et al, 2012 Journal of Clinical Oncology