Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors

Abstract

Background: Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy.

Design: This review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on 'cognition', 'cancer', 'antineoplastic agents' or 'chemotherapy'. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI.

Results: Evidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens.

Conclusions: CRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer.

Keywords: managementof cognitive impairment; animal model; cancer patients; cancer treatments; cancer-related cognitive impairment; neuro-imaging.

Figure 1

Schema outlining the complexity of cancer-related cognitive impairment. In cancer patients and survivors, the effect of chemotherapy on cognitive functions has been shown to impact different brain areas involved in attention, processing speed, memory, and executive functions. Recently, newly developed therapies involving targeted therapy, hormone therapy, and immunotherapy also appear to affect cognitive functions. The cancer treatments were associated with changes in brain volume, metabolic, or network modifications potentially related to direct neuronal toxicity and inflammation and genetic polymorphism combined with the aging process, patients’ emotional status, co-morbidities, or lifestyle. Cancer patients can be affected in multiple aspects, highlighting the urgency of initiating specific onco-neuro-psychological patient care. APOE, Apolipoprotein E; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; Cho, choline; COMT, catechol-O-methyltransferase; IL1-R1, interleukin-1-receptor1; Myo-I, Myo-inositol; NAA, N-acetylaspartate; pNF-H, phosphorylated neurofilament subunit H; TNF-α, tumour necrosis factor-alpha; sTNF-RII, tumour necrosis factor-receptor type II.

Figure 2

Brain regions that show changes in brain morphology, perfusion and/or activation after chemotherapy as reported by longitudinal studies issued from Li & Caeyenberghs, 2018 [11]. Changes in morphology [voxel-based morphometry (VBM) of grey matter or diffusion tensor imaging of white matter] are indicated in red. Changes in perfusion [arterial spin labelling (ASL)] are indicated in green. Changes in brain activation (fMRI) are indicated in blue. Several brain regions reveal overlap between modalities: magenta for overlap between brain morphology and activation, cyan for overlap between activation and perfusion, yellow for overlap between morphology and perfusion, orange for overlap between the three modalities. White matter regions are not included in the figure, nor was the cerebellum. However, two fMRI studies have revealed changes in the right cerebellum (lobule 4–5 and Crus- 2). The longitudinal studies are including cancer types, sample sizes, and chemotherapeutic agents: morphological changes—VBM: [10] 22 TC+, 43 TC−, 25 HC; bleomycin, etoposide, and cisplatin; [91] 8 BC+, 6 BC−; doxorubicin and cyclophosphamide/fluorouracil, epirubicin, cyclophosphamide, with or without docetaxel. In two patients, trastuzumab was also administered; [92] 14 GC+, 11 HC; capecitabine, oxaliplatin; [93] 19 BC+, 19 HC; fluorouracil, epirubicin, cyclophosphamide, docetaxel/cyclophosphamide, docetaxel/cyclophosphamide, doxorubicin; [94] 16 BC+, 12 BC−, 15 HC; doxorubicin/cyclophosphamide/paclitaxel, docetaxel/cyclophosphamide, docetaxel/carboplatin, docetaxel/doxorubicin/cyclophosphamide, docetaxel/cisplatin, paclitaxel. DTI: [95] 22 TC+, 43 TC−, 25 HC; bleomycin, etoposide, and cisplatin; [96] 34 BC+, 16 BC−, 19 HC; fluorouracil, epirubicin, and cyclophosphamide with or without paclitaxel; [97] 26 BC+, 23 BC−, 30 NC; doxorubicin, cyclophosphamide with or without docetaxel or paclitaxel, fluorouracil, epirubicin, cyclophophamide. Changes in perfusion: [98] 31 BC+, 34 HC; doxorubicin, cyclophosphamide, docetaxel; [99] 27 BC+, 26 BC−, 26 HC; doxorubicin, cyclophosphamide, paclitaxel/docetaxel, cyclophosphamide//docetaxel, doxorubicin, cyclophosphamide/docetaxel, cisplatin/doxorubicin, cyclophosphamide/paclitaxel. Changes in activation: [100] 18 BC+, 12 HC; doxorubicin, cyclophosphamide with or without docetaxel. One patient also received trastuzumab; [101] 18 BC+, 16 BC−, 18 HC; fluorouracil, epirubicin, cyclophophamide, with or without paclitaxel; [92] 14 GC+, 11 HC; capecitabine, oxaliplatin; [102] 21 BC+, 21 HC, fluororacil, epirubicin, cyclophosphamide, docetaxel/cyclophosphamide, docetaxel/cyclophosphamide, doxorubicin; [103] 16 BC+, 12 BC−, 15 HC; doxorubicin/cyclophosphamide/paclitaxel/docetaxel/doxorubicin, cyclophosphamide/doxorubicin/cyclophosphamide [20] 28 BC+, 24 BC−, 31 HC; doxorubicin, cyclophosphamide with or without docetaxel or paclitaxel/fluorouracil, epirubicin, cyclophophamide. BC, breast cancer; TC, testicular cancer; GC, gastric cancer; HC, healthy controls. Reprinted from [11], Copyright (2019), with permission from Elsevier.