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.

Cognitive Trajectories in Older Patients with Cancer Undergoing Radiotherapy—A Prospective Observational Study

“…It is possible that the severity of other conditions among our patients masked a potential impact of gender. In line with previous reports, comorbidity, medications, depression, and fatigue were significantly associated with cognitive function in unadjusted models [ 3 , 4 , 6 , 7 ]. As these associations disappeared in the adjusted model, it might be an indication that the association between MoCA and these factors is weaker than between MoCA and age, education, and the number of physical impairments.…”

“…These factors were previous cancer treatment (categorized as endocrine therapy, other systemic therapy (including chemotherapy), cancer surgery, and/or RT), RT treatment intent (curative or palliative, reflecting disease stage, brain cancer, or brain metastases), and fatigue (patient-reported on the QLQ-C30), in addition to a number of physical impairments (continuous 0–5 ADL, IADL, falls, mobility, and nutritional status). The model was adjusted for factors known to influence cognitive function, i.e., age, gender, educational level (categorized as completed compulsory (≤10 years), secondary (11–13 years), or college or university (≥14 years) education), comorbidity (CCI scored 0–26), medications (number of daily mediations), and depression (GDS ≥ 5) [ 3 , 4 , 6 , 7 , 38 ]. Only one patient had been diagnosed with dementia according to CCI.…”

“…Among patients with cancer ≥65 years, approximately 3.8–7% have dementia [ 1 ], and cognitive impairment is reported in 36% of patients over 70 years with advanced cancer [ 2 ]. Over the last decade, there has been an increasing awareness of a condition referred to as cancer-related cognitive impairment (CRCI) [ 3 , 4 , 5 , 6 , 7 ]. CRCI is characterized by a patient-reported and objectively measured cognitive decline presenting in relation to cancer and/or its treatment [ 4 ].…”

“…There are indications that endocrine therapy can contribute to CRCI in patients with breast and prostate cancer and that immunotherapy and antiangiogenics can have a negative impact [ 3 , 7 ]. Except for research on patients with childhood cancer and tumors involving CNS [ 15 ], little is known about how radiotherapy (RT) affects cognitive abilities [ 6 , 7 ].…”

Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice

“…We focussed on frailty as a primary outcome because premature frailty is a well-documented, clinically important problem of long-term cancer survivors ( Ness et al, 2013 ) as well as a strong predictor of multimorbidity and mortality in humans ( Kojima et al, 2018 ) and mice ( Whitehead et al, 2014 ). Sarcopaenia, metabolic disease, and, especially, cognitive decline ( Országhová et al, 2021 ) are major complications in long-term tumour survivors, therefore we included phenotype assays in these domains combined with tissue-specific ex vivo analyses primarily in hippocampus, muscle, and liver. We show here that (i) irradiation-induced lifelong premature ageing can be rescued by a one-off post-irradiation senolytic intervention, (ii) senolytics are still partially efficient in reducing progression after establishment of a premature ageing phenotype, (iii) a relatively short metformin intervention is similarly effective in rescuing premature ageing, and (iv) metformin at therapeutic concentrations acts as a senostatic neither via inhibition of complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production in senescent cells.…”