Long-Term Cognitive Dysfunction in Cancer Survivors

Abstract

Cancer-related cognitive impairment (CRCI) is a frequent side effect experienced by an increasing number of cancer survivors with a significant impact on their quality of life. Different definitions and means of evaluation have been used in available literature; hence the exact incidence of CRCI remains unknown. CRCI can be described as cognitive symptoms reported by cancer patients in self-reported questionnaires or as cognitive changes evaluated by formal neuropsychological tests. Nevertheless, association between cognitive symptoms and objectively assessed cognitive changes is relatively weak or absent. Studies have focused especially on breast cancer patients, but CRCI has been reported in multiple types of cancer, including colorectal, lung, ovarian, prostate, testicular cancer and hematological malignancies. While CRCI has been associated with various treatment modalities, including radiotherapy, chemotherapy, hormone therapy and novel systemic therapies, it has been also detected prior to cancer treatment. Therefore, the effects of cancer itself with or without the psychological distress may be involved in the pathogenesis of CRCI as a result of altered coping mechanisms after cancer diagnosis. The development of CRCI is probably multifactorial and the exact mechanisms are currently not completely understood. Possible risk factors include administered treatment, genetic predisposition, age and psychological factors such as anxiety, depression or fatigue. Multiple mechanisms are suggested to be responsible for CRCI, including direct neurotoxic injury of systemic treatment and radiation while other indirect contributing mechanisms are hypothesized. Chronic neuroinflammation mediated by active innate immune system, DNA-damage or endothelial dysfunction is hypothesized to be a central mechanism of CRCI pathogenesis. There is increasing evidence of potential plasma (e.g., damage associated molecular patterns, inflammatory components, circulating microRNAs, exosomes, short-chain fatty acids, and others), cerebrospinal fluid and radiological biomarkers of cognitive dysfunction in cancer patients. Discovery of biomarkers of cognitive impairment is crucial for early identification of cancer patients at increased risk for the development of CRCI or development of treatment strategies to lower the burden of CRCI on long-term quality of life. This review summarizes current literature on CRCI with a focus on long-term effects of different cancer treatments, possible risk factors, mechanisms and promising biomarkers.

Keywords: biomarkers; cancer survivors; cancer treatment; cancer-related cognitive impairment; pathogenesis; risk factors.

FIGURE 1

Illustration summarizing risk factors and mechanisms of cancer-related cognitive impairment (CRCI), resulting in self-reported and objectively assessed cognitive dysfunction.

FIGURE 2

Hypothetical model of proposed immune-related mechanism of cancer treatment induced cognitive impairment in cancer survivors [adopted from Ciernikova et al. (2021)]. Abbreviations DAMPs = damage-associated molecular patterns; HMGB 1 = high-mobility group box 1; IL-1a/b = interleukin 1a and 1b; IL6 = interleukin 6; LPS = intestinal microbiota associated lipopolysaccharide; SCFAs = short-chain fatty acids produced by intestinal microbiota; TNFa = tumor necrosis factor-alpha.

FIGURE 3

Biomarkers of cognitive dysfunction in cancer patients can be divided into several categories: genetic biomarkers, plasma biomarkers, biomarkers of cerebrospinal fluid and radiological (neuroimaging) biomarkers.; Abbreviations: APOE-E4 = apolipoprotein E4; BDNF = brain-derived neurotrophic factor; COMT = catechol-O-methyltransferase; SCFAs = short-chain fatty acids.