Edited by: R. Thomas Jagoe, McGill University, Canada
Reviewed by: Charlotte K. Callaghan, Trinity College Dublin, Ireland; Loredana Bergandi, University of Turin, Italy
*Correspondence: Hélène Castel
This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology
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There have been improvements in the efficacy of cancer treatments, and also in the management of side effects and patient care over the last decade. However, cancer treatments, most often chemotherapy, may induce side effects on the bone marrow, heart, cardiac, or digestive system and often cause nausea, alopecia, or even cognitive impairments Ahles (
To identify and characterize subgroups of patients at risk of cognitive impairment induced by cancer and its treatment, and to adapt patient treatment, it is essential to discover biological factors mediating cognitive problems and/or risk factors, such as genetic polymorphisms, inflammatory indicators, or blood biomarkers (Kesler et al.,
The objective of this review was to establish a summary of original articles published since 2005, including all biological predictive factors of cognitive changes in cancer patients, particularly after cancer treatment. Moreover, we discuss the limitations of these studies, concerning their different types, methods, results, and interpretation.
Articles were retrieved from PubMed using the following key words:
- MeSH terms: “cognition disorders,” “neurotoxicity syndromes,” “biological markers,” “prognosis,” “biological factors” - PubMed terms: “predictive factors,” “cancer,” “chemobrain,” “chemofog,” “cognitive dysfunction,” “cognitive impairments”
This review was guided by the PRISMA statement and used a search strategy focused on three components: “cognition disorders,” “predictive factors”/”biological markers,” and “neoplasms,” searched in PubMed (with MeSH and PubMed terms). Original studies since 2005 were included, regardless of type (i.e., cross-sectional and longitudinal, randomized, and non-randomized, single center and multicenter). Selection was not based on cancer type; mainly acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), breast, lung, prostate, and differentiated thyroid carcinoma were included; however, brain tumors and cancers involving brain metastasis were excluded, because of their mass effects and potential consequences of surgery/resection on the brain, which are likely to directly impact cognitive function (Table
Breast | Leuprolide | GnRH agonist: reduce estrogen levels by continuous (and not pulsate) infusion of a GnRH action mimic |
Tamoxifen | Adjuvant hormonal treatment: blockage of estrogenic receptors (ER) in early and advanced ER-positive breast cancers | |
Exemestane | orally active aromatase |
|
Anti-aromatases | Competition with aromatase which blocks estrogen synthesis (not indicated in cited publications) | |
Doxorubicin | Antibiotic intercalating DNA agent, inhibitor of Topoisomerase II, and oxygen free radical producer leading to toxicity | |
Cyclophosphamide | Bifunctional inhibitor of DNA transcription and replication leading to mitotic cell apoptosis | |
Docetaxel | Cytotoxic properties |
|
5-FU | Inhibition of thymidylate synthase (inhibition of DNA synthesis) | |
Vincristine | Stop tubulin polymerization and block cell during metaphase | |
Methotrexate | Inhibition of folic acid (cytotoxic effect) through inhibition of mitochondrial metabolism | |
ALL |
Methotrexate | Inhibition of folic acid (cytotoxic effect) through inhibition of mitochondrial metabolism |
Cytarabine | Block DNA synthesis during cell division | |
mRCC |
Sunitinib | Inhibition of tyrosine kinase receptors involved in tumor growth |
Sorafenib | Kinase inhibitor which leads decrease of tumor cell proliferation | |
VEGFR inhibitors | Angiogenesis inhibitor (stop tumor growth) | |
Radiotherapy | Tumor cell apoptosis by DNA deterioration |
The first exclusion criterion, evaluated by reading abstracts, was the absence of at least one of the three domains, i.e., “cognition disorders,” “predictive factors,”/“biological markers,” and “neoplasms.” Between 2005 and 2015, 65 studies at least partly covered the topic under investigation. Other exclusion criteria, determined by reading entire papers, concerned studies of brain tumors or cranial radiotherapy, or the absence of clear data on cognition and/or biomarker levels. Of the initially selected 65 studies, 23 were finally included in the analysis (Figure
Cheung et al., |
Multi-center prospective cohort | 50.5 ± 8.4 | Breast ( |
Chemotherapy (anthracycline) | IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ, TNF-α | Sensitive multiplex immunoassay (Venipuncture) |
- Processing speed - Response speed - Memory - Attention (battery of tests) - + Self-report functioning |
➢ T1: Before chemotherapy ➢ T2: 6 weeks ➢ T3: 12 weeks after initiation of chemotherapy |
- Response speed performance (2.2% of patients) - Memory (13.2%) - Attention (7.3%) - Processing speed (2.2%) - Response speed (4.2%) + Self-perceived cognitive disturbances (29.3%) |
↗ IL-1β: Poorer response speed performance ↗ IL-4: better response speed and less cognitive complaints ↗ IL-6: more severe cognitive complaints |
Ganz et al., |
Prospective, cross-sectional at basal line, longitudinal and observational cohort | 51.3 ± 7.8 | Breast (patient-received CT |
Radiotherapy Chemotherapy (FEC |
IL-6, IL-1, TNF-α RII, CRP | Sensitivity ELISA tests (Venipuncture) |
- Psychomotor - Executive functions - Verbal learning and memory - Visual learning and memory - Visuo-spatial and motor speed (battery of tests) - Cognitive complaints |
➢ T1: before therapy ➢ T2: 6 months later ➢ T3: 12 months later |
Memory complaints |
↗ TNF-RII: memory complaints |
Ishikawa et al., |
Cross-sectional, case-control | 63 (23–83) | Solid malignancies (various types: advanced, inoperable or recurrent) (Patients: |
Chemotherapy | IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, VEGF | Multiplex cytokine array system (Venipuncture) | Cognitive complaints (2 items of the EORTC QLQ-C30) |
➢ After chemotherapy |
Not specified | IL-6 and VEGF: negative correlation with subjective cognitive functioning |
Janelsins et al., |
Stratified, randomized, double-blinded, and longitudinal | 52.2 ± 10.2 | Breast (AC/CAF |
Chemotherapy (AC/CAF or CMF) | IL-6, IL-8, MCP-1 | Colorimetric ELISA kits (Venipuncture) |
- Heavy-headed - Thoughts muddled - Difficulty thinking - Concentration and forgetful - Self-report functioning |
➢ Prior to on-study chemotherapy cycle 2 ➢ After 2 consecutive chemotherapy cycles |
All subjective domains (12-44% of patients) |
- AC/CAF: No significant correlation between IL-6 or IL-8 and cognitive complaints. Significant correlation between MCP-1 and forgetfulness, difficulties with concentration and thinking. - CMF: No significant correlation |
Kesler et al., |
Cross-sectional, case-control | 54.6 ± 6.5 | Breast (Case: |
Chemotherapy Number of regimens | IL-6, TNF-αs | Sandwich immunoassay (ELISA) (Venipuncture) |
- Verbal memory - Learning - Global intelligence (battery of tests) - + Cognitive complaints |
➢ Mean 4.8 ± 3.4 years off-therapy |
Verbal memory (objective and subjective) |
-↗ IL-6, ↗ TNF-α levels: ↗ Memory difficulties. In the breast cancer group, ↘ left hippocampal volume associated with ↗ TNF-α and ↘ IL-6, with a significant interaction between these two cytokines |
Meyers et al., |
Longitudinal | 60.2 (21–84) | Acute Myelogenous Leukemia (AML) or Myelodysplastic syndrome (MDS) ( |
Chemotherapy: lipodaunocin plus Cytoxan or topotecan, plus or minus thalidomide | IL-1, IL-1RA, IL-6, IL-8, TNF-α, (+ Hb) | Standard enzyme-linked immunoabsorbant assays |
- Attention, - Graphomotor speed - Verbal fluency - Visual-motor scanning speed - Executive functions - Fine motor dexterity - Memory (battery of tests) |
➢ Before treatment ➢ and after 1 month of therapy |
- Memory - Verbal fluency - Cognitive processing speed - Executive function and fine motor dexterity |
↗ IL-6 level: ↘ executive function ↗ IL-8 level: ↗ memory performance |
Mulder et al., |
Cross-sectional, case-control | 60 (38-81) (+ TKI) | Metastatic renal cell cancer (mRCC) or Gastrointestinal stromal tumor (GIST) (VEGFR TKI group: |
VEGFR TKI |
Testosterone, sex hormone binding globuline, estradiol, albumin, vitamin B12, thyroid function, CRP, ESR |
Specific ELISA (Venipuncture) |
- Learning and memory - Attention and concentration - Executive functions (battery of tests) - + Self-report functioning |
➢ Sunitinib or sorafenib for at least 8 weeks |
- Learning and memory, and executive functions:Both patient groups significantly worse than healthy - Cognitive complaints > VEGFR TKI patients vs. healthy |
- ↗ levels of ESR: ↘ scores learning, memory, attention, concentration and executive function - CRP and neutrophils: ↘ scores learning and memory (VEGFR TKI group). - Correlation between markers of systemic inflammation and worse cognitive performances - No correlation between serum IL-8 and cognitive functioning, or between free testosterone or estradiol and neuropsychological tests |
Shibayama et al., |
Cross-sectional | 47 ± 52 (+RT) 46.6 ± 6.2 (-RT) | Breast (Exposition to adjuvant RT with 25 CT: |
Adjuvant regional RT | Plasma IL-6 | Chemiluminescent enzyme immunoassay (Venipuncture) |
- Attention/ concentration - Immediate verbal and visual memory - Delayed recall (battery of tests) |
➢ 1 year after the initial therapy |
- Delayed recall and immediate verbal memory in radiotherapy group |
↘ delayed recall mediated by ↗ plasma IL-6 level |
The main cytokines analyzed in the reviewed studies were the pro-inflammatory triad, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin 1β (IL-1β). As IL-6 is an early mediator of inflammation and a key component of the acute phase response, it can also moderate inflammation by dampening TNF-α and IL-1β responses. Currently, the exact mechanisms involved in the inflammatory response during cancer therapy are not fully understood. Nevertheless, in cancer patients, circulating levels of cytokines were often increased and could be significant determinants of the alteration of particular cognitive functions after chemotherapy (Meyers et al.,
Besides IL-6, which was described as marker of both cancer-associated and cancer treatment-induced inflammation, studies of other cytokines were less frequently reported. A longitudinal cross-sectional study, including baseline measurements, demonstrated changes in a number of pro-inflammatory cytokines; however, only levels of TNF receptor type-II (TNF-RII) were significantly higher in plasma from chemotherapy-treated patients compared with those who did not receive chemotherapy, with no differences observed in IL-1ra, IL-6, or C-reactive protein (CRP; Ganz et al.,
In addition to cancer-related increases in circulating cytokine levels, data reported by Janelsins et al. (
Circulating cytokines associated with cognitive impairment in cancer patients during the course of treatment, or in survivors after the end of treatment, represented the most measurable and measured factors, and studies converged to suggest that chemotherapy could dysregulate cytokine levels, which may interfere with brain functioning, leading to cognitive impairment (Ahles and Saykin,
Although this hypothesis raises interesting therapeutic options, other studies did not show any significant correlation between plasma cytokine levels and cognitive impairment with or without chemotherapy (Pomykala et al.,
Since tumors can expand through development of angiogenic features and via release of angiogenetic factors, including vascular endothelial growth factor (VEGF), recently introduced targeted therapies include inhibitors of tyrosine kinase VEGF receptor (VEGFR TKI) and drugs targeting VEGF itself. As VEGF is also involved in neurogenesis and brain vascularization, it might be supposed that levels of VEGF could be linked to cognitive impairments (Table
Fan et al., |
Non-randomized sub-study | 53 to 50 | Breast (Patients received hEPO: |
Chemotherapy as adjuvant or neoadjuvant treatment | Hb | Blood tests |
- Global efficiency (MMSE) - Verbal memory - + Self-report functioning |
➢ After chemotherapy |
No significant difference between groups |
- No association between Hb and cognitive functioning. - Protective effect of hEPO against delayed cognitive dysfunction not shown |
Iconomou et al., |
Prospective, single-center, non-randomized | 58.9 ± 9.9 | Solid malignancy ( |
Chemotherapy | Anemia, Hb hEPO | Hb levels (Venipuncture) |
- Global efficiency: - Orientation - Recording - Attention - Calculation - Recall - Language - Copying (MMSE) |
➢ T1 = baseline ➢ Study completion-T2 = week 12 |
No clinically significant alterations during hEPO treatment | Change of Hb not related with change of objective or subjective cognitive performance |
Mancuso et al., |
Prospective, observational | 76.6 ± 4.8 | Lung ( |
Chemotherapy | Anemia, Hb | Haemoglobin level |
- Global efficiency - Orientation - Recording - Attention - Calculation - Recall - Language and copying (MMSE) |
➢ Before chemotherapy (baseline) ➢ after each CT cycle |
Not specified |
↗ Hb: positive correlation with MMSE value |
Massa et al., |
Longitudinal | 71.4 (68–75) | Solid malignancy: Lung, oral cavity, ovary, breast, endometrial colon, stomach (Cancer patients with anemia related to cancer chemotherapy: |
Chemotherapy + rHuEPO | Hb level | Blood tests |
- Global efficiency |
➢ Prior to start chemotherapy ➢ After 4, 8 and 12 weeks of treatment |
Better cognitive functions |
↗ Hb levels: ↗ cognitive functioning assessed by MMSE after 4, 8 and 12 weeks of rHuEPO treatment |
Natori et al., |
Cross-sectional | 45.5 to 50 | Breast (pNF-H positive: |
Chemotherapy Many regimens | pNF-H level | ELISA (Venipuncture) |
- Nonverbal - Intellectual capacity - Premorbid intellectual quotient (battery of tests) - + Self-report functioning |
➢ Naïve ➢ Different cycles of chemotherapy 1, 3 or 7 cycles, ➢ Completed chemotherapy for at least 24 months |
No difference among the patient groups |
- ↗ serum pNF-H level but no association with cognitive deficits |
Tan et al., |
Longitudinal | 71 (59–89) | Prostate ( |
Leuprolide | Plasma Aβ40 and Aβ42 |
ELISA |
- Global efficiency - ± verbal episodic memory |
➢ Before the first leuprolide injection (baseline), ➢ At 2, 4 and 12 months |
Better memory performance (practice effect) | No association between Plasma Aβ40 and Aβ42 levels and cognitive efficiency or memory functions |
Several studies investigating the contribution of chemotherapy-induced anemia to cognitive impairment in cancer patients suggested that changes in Hb were linked to the development of cognitive impairment during chemotherapy. This was stressed in the elderly cancer population studied by Mancuso et al. (
Other systemic biological markers were also highlighted. A relationship between androgen receptors and amyloid precursors has been described (Takayama et al.,
Another candidate plasma marker for cognitive dysfunction following therapy-induced brain damage is axonal phosphorylated neurofilament subunit H (pNF-H), levels of which are increased in the blood of patients who have had acute brain ischemic stroke compared with controls, and are associated with the severity of the stroke (Singh et al.,
Andreano et al., |
Longitudinal, Case-control | 41.9 (27–49) | Breast (Case: |
Lupron (Leuprolide) | Cortisol, estradiol, progesterone, glucocorticoids | Salivary ELISA for cortisol, estradiol and progesterone + physiological stressor |
- Working memory - Verbal paired associate memory - Narrative recall (level of emotional arousal was considered) (battery of tests) |
➢ After treatment for cases ➢ during the mid-luteal phase of menstrual cycles for controls |
Narrative recall: delayed recall for emotional material |
-↘ ovarian hormone levels - No difference of salivary cortisol level after stress -↘ glucocorticoid responsiveness: absence of enhancement of memory consolidation for emotional material in cases |
Jenkins et al., |
Prospective, longitudinal, case-control | 67.5 ± 4.7 | Prostate (Case: |
Leuprolide | Free and bound testosterone, β-estradiol, sex hormone-binding globulin | Serum, Not specified |
- Auditory/verbal memory - Visual memory, - Working memory and attention, - Processing speed - Vigilance - Intelligence |
➢ Before drug treatment (Baseline T1) ➢ at 3 months before radiotherapy (T2) ➢ 9 months later (T3) |
- Verbal - Visual spatial - Processing speed |
↘ bioavailable testosterone, but no correlation with cognitive performance |
Moon et al., |
, Cross-sectional, case-control | 70.9 ± 5.0 | Differentiated Thyroid Carcinoma (Case: |
TSH-suppressive therapy | Free T4 and TSH levels | RIA (Venipuncture) |
- Verbal fluency - language - global cognitive function - memory - visuospatial function - attention - executive function |
➢ After at least 5 years of TSH-suppressive treatment |
° No difference between patient and control groups |
↗ T4 level: ↗ global cognitive and visuospatial functions |
Endocrine function, specifically gonadal and stress hormones, may also contribute to cognitive difficulties during cancer treatment. To date, the results of research into hormonal factors remain inconclusive, and studies are often related to patients receiving hormonal therapy. For example, significant reductions in free testosterone and β-estradiol levels were detected in prostate cancer patients after 3 months exposure to leuprolide, and some changes in spatial memory also were observed during treatment; however, there was no association between the changes in hormonal factors and those in cognition (Jenkins et al.,
Kamdar et al., |
Prospective cohort | 4.4 ± 3.9 −12.1 ± 11.3 | ALL ( |
Methotrexate chemotherapy | 6 Genotype polymorphisms (folate pathway: MTHFR |
Genotyping essay by PCR (Venipuncture) |
- Attention - Processing speed - Verbal fluency - Visuo-spatial motor speed (battery of tests) |
Years after end of therapy: 5.3± 4.4 | Global cognitive functioning: 44.3% of patients | Combined effect of multiple folate pathway polymorphisms (MS and MTHFR): ↗cognitive disturbance probability (attention and processing speed) |
Krull et al., |
Cohort | 7.0 ± 3.11 | ALL ( |
Chemotherapy (without prophylactic cranial irradiation) | Many genetic polymorphisms | Genotyping by PCR (Venipuncture) |
- General intelligence - Processing speed - Working memory - Sustained attention - + cognitive complaints (assessed by parents) |
2 years completion of consolidation therapy | Sustained attention and attention difficulties reported by parents | MS (/ MAOA ↗ Cognitive disturbance probability (attentiveness and response speed) |
Small et al., |
Cross-sectional, Case-control | 56.93 ± 9.01 (RT) 51.22 ± 8.63 (CT) | Breast (RT: |
Chemotherapy and radiotherapy | COMT |
DNA collection by saliva and genotyping |
- Overall cognition - Episodic memory - Attention - Complex cognition - Verbal fluency - Motor speed (battery of tests) |
6 months after end of treatments |
° COMT-Val+ carriers performed worse than COMT-Met homozygote carriers: Attention, verbal fluency and motor speed |
COMT-Val homozygote: ↗ Cognitive disturbances probability |
There is relative heterogeneity among cancer patients regarding (i) the various domains of cognition that can be affected, including working memory, executive functions, verbal memory, and processing speed; and (ii) the proportion of patients exhibiting long-term cognitive deficits, independent of fatigue or emotional disturbances. This has prompted medical researchers to investigate potential predisposing factors for the development of cognitive impairment during cancer and its treatment. Indeed, immune status, cancer diagnosis in the elderly, and/or a number of key genetic polymorphisms can predispose to cognitive changes (Ahles and Saykin,
The key role of neurotransmitters as potential predisposing markers, is stressed by the other polymorphism commonly reported as linked to cognitive impairments, the Val158 Met encoding single-nucleotide polymorphism in catechol-O-methyltransferase (COMT), which catalyzes the metabolic breakdown of catecholamines through the methylation of dopamine and noradrenaline (Ahles and Saykin,
Other genetic polymorphisms also appear to be implicated in cognitive changes, such as those regulating folate pathways. Kamdar et al. (
When attempting to identify direct biological factors associated with cognitive alterations in cancer patients, variations in levels detected in cerebrospinal fluid (CSF) would be expected to provide better information about causal links with, or consequences of, treatment. Relationships between alterations in phospholipids, SM, and lysophosphatidylcholine (LPC) concentrations, as markers of white matter integrity, and some domains of cognitive function, were identified in children with ALL before and during long periods of chemotherapy (methotrexate administration over a period of years; Krull et al.,
Krull et al., |
Longitudinal | 7.0 ± 3.11 | ALL ( |
ChemotherapyMethotrexate | CSF phospholipids (PE |
Extraction and separation by chromatography (lumbar punctures) |
- General cognitive abilities - Processing speed - Working memory - Visual-motor integration - Academic functions (battery of tests) |
➢After completion of induction therapy (initial assessment) ➢Consolidation period:- one year after the initial assessment, - 2 years after - 3 years after |
- Motor speed - Verbal and visual working memory - Motor speed |
- Association between early variations in SM and motor speed and in LPC and verbal working memory; - Association between later elevation in SM with decline in visual working memory |
Moore et al., |
Longitudinal | 7.83 ± 2.87 | ALL ( |
Chemotherapy Methotrexate | CSF monounsaturated and saturated fatty acids: (palmitic, stearic, palmitoleic and oleic acids) | Gas chromatography |
- General intelligence - Visual-motor skills - Academic abilities (battery of tests) |
➢At diagnosis, prior treatments (fatty acids) ➢achieved remission (baseline) ➢1 year later (cognitive abilities) |
- Global intelligence - Academic math abilities - Visual motor skills declines |
-↗ ratio stearic/oleic acids: negative correlation with global intelligence and academic math abilities -↗ ratio palmitic/palmitoleic acids: negative correlation with global intelligence |
Protas et al., |
Longitudinal | 7.59 (range 2–16) | ALL ( |
Chemotherapy Number of regimens | CSF Tau protein | ELISA |
- Intelligence quotient (verbal performance) (battery of tests) |
➢At diagnosis ➢after induction treatment ➢during consolidation ➢before maintenance therapy |
Not specified | Tau protein level (at the initiation of maintenance therapy) negatively correlated with verbal abilities |
CSF analysis can also provide inform about the microtubule-associated protein tau, whose CSF levels have already been associated with neurotoxicity and neurodegenerative pathologies. There is a significant increase in tau protein after induction and during consolidation, compared with at the time of diagnosis, in ALL patients. The level of tau measured before maintenance therapy was negatively correlated with verbal abilities (Protas et al.,
Overall, studies of patients with ALL receiving methotrexate-containing chemotherapy regimens for long periods demonstrate robust links between cognitive domains, such as working memory or verbal abilities, and modified CSF components, such as fatty acids, phospholipids, and even tau protein, which plays an important role in Alzheimer's disease (Table
It is important to consider clinical, physiopathological, and psychological factors in addition to biological markers, in relation to cognitive impairment of patients with cancer. In particular, to evaluate the contribution of co-morbidities and associated treatments, is essential to understand patient history and knowledge of these factors can help to predict cognitive impairments and determine the significance of changes in circulating factors in cancer patients during treatment. In support of this idea, in a study aiming to identify predictors of cognitive performance in breast cancer patients, treatment for hypertension was identified as having a significant negative impact on verbal fluency and working memory performance, and treatment for diabetes mellitus, was found to detrimentally affect executive functioning and reaction speed (Schilder et al.,
Several limitations should be noted in the studies analyzed in this report. There is an absence of meta-analyses, and the majority of available studies were prospective cross-sectional trials, mostly composed of small samples, and consequently had relatively low statistical power. Also, the studies included are not strictly comparable, because of the different methods used. Biological measurement methods are the main limit, and thus the variability in assessed cognitive domains and tests analyzed should also be considered in evaluation of this review. Indeed, some studies use global efficiency analyses, such as MMSE, whereas others applied batteries of tests, which are more sensitive for objective measurement of cognitive impairments. It should also be noted that practice effects can modify test results, particularly in longitudinal studies repeatedly using the same tests on patients after short periods of time. Finally, the large diversity of chemotherapy regimens used, inconsistent sampling points, and various cognitive assessment methods remain the major obstacles to identification of clear correlations between circulating biological factors levels and performance in specific domains of cognition. In addition, brain imaging could be an interesting approach to correlation of brain activity and biological markers in patients exhibiting no obvious cognitive impairment (Ferguson et al.,
A number of potential predictive markers have been identified that require validation in large series. Indeed, initial studies of factors, such as selected cytokines, stress hormones, CSF proteins, lipids, or Hb levels, have provided interesting information about changes in biomarkers that evolve during the course of the treatment of cancer patients, and also about genetic polymorphisms predisposing to cognitive deficits. Additional longitudinal studies, and investigation of other factors, previously identified in different pathological situations as associated with fatigue or aging, should facilitate better characterization of risk of cognitive impairment in cancer.
The question addressed in this study is among the priorities in cancer patient care and the ability to use biological risk factors to predict, better understand, and help to prevent cognitive issues, or adjust treatments for specific populations of patients identified as at risk, would be of major benefit. Such markers would also likely facilitate identification of biological mechanisms underlying neurotoxicity, and could open new avenues for testing and evaluation of therapeutic strategies designed to prevent cognitive dysfunction during cancer treatment, leading to improved quality of life, autonomy, and return to work rates of cancer survivors.
HC and AD selected, read and analyzed articles. ML, MT, and MD built tables and analyzed cognitive domains evaluated in each study. HC and FJ supervised, organized and wrote the manuscript.
Academic French governemental organization: Inserm and Normandie University, Anti-cancer center: Baclesse center, Caen, France
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Inserm, the Baclesse Center, the Normandie Rouen and Caen Université, and the Cancéropôle Nord-Ouest that aided the efforts of the authors.
Cyclophosphamide/cyclophosphamide plus fluorouracil
Acute lymphoblastic leukemia
Apolipoprotein E
amyloid-β peptides 40 and 42
Cyclophosphamide, methotrexate, and fluorouracil
Catechol-O-methyltransferase
C-reactive protein
Cerebrospinal fluid
Chemotherapy
Deoxyribonucleic acid
Doxorubicin
Enzyme-linked immunosorbent assay
Erythropoietin
Gonadotropin-releasing hormone
Hemoglobin
Interleukin
Interferon γ
Lysophosphatidylcholine
Monocyte chemoattractant protein 1
Mini-mental State Examination
5,10-methylenetetrahydrofolate
Metastatic renal cell cancer
Phosphorylated neurofilament subunit H
Sphingomyelin
Tumor necrosis factor-alpha
Tumor necrosis factor-receptor type II
Vascular endothelial growth factor
Tyrosine kinase VEGF receptor
Radiotherapy.