An Update on Cancer- and ChemotherapyRelated Cognitive Dysfunction: Current Status

Michelle C. Janelsins,a Sadhna Kohli,b Supriya G. Mohile,c Kenneth Usuki,a Tim A. Ahles,d and Gary R. Morrowa,e
The purpose of this review is to summarize the current literature on the effects of cancer treatment–related cognitive difficulties, with a focus on the effects of chemotherapy. Numerous patients have cognitive difficulties during and after cancer treatments and, for some, these effects last years after treatment. We do not yet fully understand which factors increase susceptibility to cognitive difficulties during treatment and which cause persistent problems. We review possible contributors, including genetic and biological factors. Mostly we focus is on cognitive effects of adjuvant chemotherapy for breast cancer; however, cognitive effects of chemotherapy on the elderly and brain tumor patients are also discussed. Semin Oncol 38:431-438 © 2011 Elsevier Inc. All rights reserved.

p to 75% of cancer patients experience cognitive impairment (eg, problems with memory, executive functioning, and attention) during or after treatment of their cancer. For many (up to 35%), this persists for months or years following treatment.1– 6 With more than 11 million cancer survivors in the United States,7 up to 3.9 million individuals may be living with long-lasting cognitive difficulties from cancer and cancer treatments. This is an important area of concern, because these effects could influence adherence to treatments and lead to long-term impairment. Cognitive deficits that occur from cancer or its treatment vary and may be subtle or dramatic, temporary or permanent, and stable or progressive.8 We highlight


recent work in cancer- and chemotherapy-related cognitive difficulties and explore possible mechanisms.

Some cognitive problems in those who receive chemotherapy are more severe than in those who only receive locoregional therapy (eg, radiation, surgery).9,10 Cognitive problems with chemotherapy can negatively impact activities of daily living such as (1) work performance,5 (2) access to medical and other health services, and (3) caring for and socially interacting with family members.11 Systematic research to understand cognitive difficulties with chemotherapy was first reported during the mid 1990s to early 2000s2– 4,12; early studies often did not include pretreatment assessment data and/or were cross-sectional in design. The lack of pretreatment data was most likely due to difficulty obtaining such information from newly diagnosed patients. Studies over the past decade have incorporated pretreatment assessments of cognitive function. The importance of a pretreatment baseline was evidenced in a study5 of the effects of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy on cognitive function in breast cancer. This was one of the first prospective, longitudinal studies to assess cognitive function with pretreatment and post-treatment cognitive measures. There were no overall mean differences in cognitive function between patients and controls (normative data). Within-subject analyses showed that 61% had cognitive declines in learning, attention, and processing speed. If the pretreatment assessment had been 431


of Radiation Oncology, University of Rochester Medical Center, Rochester, NY. bDepartment of Oncology, Mayo Clinic, Rochester, MN. cDepartment of Medicine, University of Rochester Medical Center, Rochester, NY. dDepartment of Psychiatry and Behavioral Sciences, Memorial SloanKettering Cancer Center, New York, NY. eDepartment of Psychiatry, University of Rochester Medical Center, Rochester, NY. The authors do not have any financial disclosures or conflicts of interest. Partially supported by NCI R25CA10618. Address correspondence to Michelle C. Janelsins, PhD, Research Assistant Professor, University of Rochester Medical Center, James P. Wilmot Cancer Center, Department of Radiation Oncology, Rochester, NY 14642. E-mail: 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2011.03.014

Seminars in Oncology, Vol 38, No 3, June 2011, pp 431-438

the cause may not be apparent. Figure 1. and to understand those that contribute to long-lasting impairment. executive function. 12% to 82% of patients had cognitive difficulties in the domains of executive function.432 M.5 Another recent study revealed that 23% of women being treated for breast cancer had difficulty before chemotherapy. For example. Most studies of chemotherapy-related cognitive difficulties have focused on breast cancer. in one study 33% of patients had cognitive difficulties in verbal learning and memory prior to chemotherapy. Not all studies revealed significant changes in all domains. These include computerized tomography (CT). not only to document the extent of the cognitive changes via neuropsychological testing but also to probe changes in brain volume.22 For example.and/or treatment-related cognitive difficulties. single-photon emission-computed tomography (SPECT). and possible mechanisms of action.C. 46% would not have had detectable cognitive impairments (because their post-treatment assessment scores were normal). Assessment of various biological factors (eg. those exposed to chemotherapy had the greatest deficits. Approximately 10 additional longitudinal studies have investigated cancer. genetic markers. Bolded topics are discussed within this review. Longitudinal studies are needed in other disease groups to understand whether cognitive difficulties are more or less severe in these conditions. in a crosssectional study. psychomotor speed. metabolic status. and Metabolism Subtle cognitive changes pose unique challenges to detection and management. depression) or to other factors (eg.13–23 In all. and attention appear most frequent. Although we currently have no treatments for cognitive difficulties in cancer patients. More work is needed in well-powered long-term observational studies to understand the course and severity of cognitive difficulties. Additionally. MRI has particular value MECHANISMS We are far from understanding the underlying molecular mechanisms that contribute to cognitive difficulties. nisms have been proposed (Figure 1). depression. This is extremely important since cognitive dysfunction can be subtle. Brain Volume. These studies used a variety of cognitive assessments and control groups.21 Several studies have shown cognitive deficits in cancer patients before chemotherapy. memory. the decline may nevertheless represent a clinically significant difference. Documenting these changes is possible with neuroimaging techniques. Multiple factors can contribute to cognitive difficulties in cancer patients. Various biological and psychological mecha- . subtle cognitive changes may be confounded by other problems commonly associated with cancer and its treatment. and the inflammatory response to cancer treatments. and stress. and brain imaging) may help identify high-risk groups for cognitive difficulties or those at highest risk for persistent long-term effects. and a healthy control group. inflammatory markers. Some also can be psychological factors such as anxiety.5. those not exposed. and CNS activity following treatment. and fatigue. also may cause cognitive difficulties. many studies had small numbers and were not powered to test multiple cognitive domains. no large prospective study in lymphoma has been conducted to confirm these results.3 breast and lymphoma patients showed long-term problems.22 These could be related to psychological variables related to cancer diagnosis (eg. objective neuropsychological measures. Activity. identifying biological markers related to cognitive function would enable us to understand possible mechanisms and eventually develop successful interventions. anxiety. and most investigated patients on various treatment regimens. and magnetic resonance imaging (MRI). anxiety. If a patient scores well on a cognitive test before chemotherapy and less well after treatment (but that score is still within the normal range). To develop prophylactic interventions. First. One recent study compared patients exposed to chemotherapy. Possible contributors to cognitive difficulties in cancer patients. those in memory. and attention. positron emission tomography (PET). which increase vulnerability to development of cognitive difficulties.10. stress. many treatment studies assessed the effects of chemotherapy and used standard neuropsychological assessments. Second. however. and the impairments not evaluable with standard. Janlesins et al unavailable. More research is needed to explicitly understand factors that lead to cognitive difficulties before and during treatment. like depression. cognitive reserve). we must understand the mechanisms behind the effects of treatment on cognition. The latter two are particularly powerful because they allow one to assess metabolic activity (PET via radiolabeling and MRI via various spectroscopic techniques). Physiological factors. such as the patient’s genetic make-up and hormone levels. processing speed. We need to use every tool at our disposal.

these reductions were not seen in patients not exposed to chemotherapy or in healthy controls. Large-scale observational studies that correlate changes in cytokines and chemokines with those in cognitive function should help clarify the association between inflammation and cognitive function in cancer patients on different chemotherapy regimens.45 Cancer survivors with at least one E4 allele scored significantly lower in the visual memory and spatial ability domains.32 Two studies examined the association between apolipoprotein E (APOE) and catechol-o-methyltransferase (COMT) genotypes and cognitive function in cancer survivors. inflammation. These include highresolution anatomical images. as well as conventional neuropsychological testing. whereas higher levels of IL-8 were associated with better memory performance in patients with acute myelogenous leukemia and myelodysplastic syndrome prior to treatment. and distribution of lipids. Diffusion MRI allows measurements of the diffusivity of water in the brain. MRI can be repeated on the same individual to assess short. Several genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) in genes in multiple signaling pathways (ie. which allow accurate measurement of therapy-induced changes in gray and white matter volumes. and poor outcomes in stroke and traumatic brain injury. Elevated peripheral levels of pro-inflammatory cytokines may be related to cognitive problems. interleukin [IL]-1 ) in those treated . Functional MRI measures areas of brain activation during stimuli such as a motor task or neuropsychological assessment. Alzheimer’s disease. DNA repair. Genetic Contributors Only a subgroup of breast cancer survivors may experience long-term changes in cognitive ability. dopamine.33 In breast cancer patients receiving paclitaxel.43 Apolipoprotein E (ApoE) is a complex glycolipoprotein that facilitates uptake. and other immune factors on cognitive function in cancer is needed.or long-term longitudinal changes. Neuroimaging techniques have matured and are readily available in most clinical settings. Evidence for this hypothesis may be the lack of correlation between self-report and performance on neuropsychological testing. Neuroimaging studies would also determine whether patients use compensatory mechanisms to enhance performance on neuropsychological testing even though they are aware that their function is worse than before treatment.39 – 41 Therefore.37 The investigators are currently assessing cytokine levels in relationship to cognitive function (via neuropsychological and computerized tests) in an ongoing observational study of cognitive function in colorectal cancer. transport. cyclophosphamide.38 Further clarification of the role of cytokines.44 The human E4 allele has been associated with a variety of disorders with prominent cognitive dysfunction. Preliminary work24 showed reductions in gray matter volume of frontal and temporal brain regions over the course of chemotherapy with partial recovery after treatment. future studies of the effects of cancer therapies on cognition should include neuroimaging. Thus. chemokines.26 for Hodgkin’s disease.Cancer and chemotherapy-related cognitive dysfunction 433 because of the range of techniques available to probe brain anatomy and physiology. and methotrexate. but particularly the combination of MRI techniques. because it does not use ionizing radiation. These data temporally coincide with functional changes in neurocognitive assessment.25 Preliminary imaging work has demonstrated by functional MRI that a patient diagnosed with breast cancer receiving chemotherapy had to “work harder” to complete a cognitive task than her twin sister who did not have cancer. levels of IL-6 increased 3 days after treatment compared to pretreatment but not in those who received a combination of fluorouracil.36 Another study found a trend between cytokine levels and cognitive performance in breast cancer.35 Increased levels of IL-6 have been associated with poorer executive function. oxidative stress) perhaps related to cognitive decline in normal aging. will prove useful in elucidating the structural.42. The application of any of the neuroimaging techniques.34 Significant changes in markers of endothelial and platelet activation were found in breast cancer on anthracycline-based treatment. genetic variation related to cognitive function may be associated with increased risk for long-term cognitive changes. Finally. Although similar studies can be done with PET. to test hypotheses about the fundamental processes involved in the cognitive dysfunction following therapy.32 Chemotherapy has been associated with increased levels of pro-inflammatory cytokines (eg. they are limited by dose exposure guidelines and may not be possible at frequent intervals. with a trend to score lower in executive function compared to survivors who did not carry an E4 allele. metabolic. It appears to play an important role in neuronal repair and plasticity after injury. These include otherwise normal patients with memory complaints. and functional consequences of cancer and cancer therapies. Alzheimer’s disease and other syndromes with cognitive decline. Spectroscopic MRI provides information about the biochemical processes in the brain. further supporting the hypothesis that inflammation occurs as a result of chemotherapy.27–31 there is little information about the relationship of inflammatory responses to cognitive function in cancer.42 Cytokines and Other Inflammation Markers Although increased inflammatory markers are associated with cognitive difficulties in numerous neurodegenerative diseases and cognitive disorders.

45 Breast cancer survivors who were COMT-Val carriers and exposed to chemotherapy performed more poorly on tests of attention than healthy controls who were also carriers. In one longitudinal prospective study of older patients with breast cancer. this could be related to menopausal status.63 Other studies demonstrated no significant change in Mini-Mental Status Exam (MMSE) scores after chemotherapy or hormonal therapy over a short time period. Cognitively impaired persons receive less definitive cancer care than others. comorbidity. prospective. The cognitive effects of hormonal therapy with androgen deprivation therapy (ADT) in men with prostate cancer have conflicting results due to small sample size.43 These studies support the hypothesis that genetic factors increase vulnerability to cognitive changes with cancer treatments.14 Thirty-nine percent scored 2 standard deviations below normative data at 6 months compared to their baseline neuropsychological test scores. following complaints of memory changes and impaired concentration.14 Exploratory analyses of longitudinal CGA results demonstrated no changes in functional status.64.54 –56 Cognitive disorders in older patients present prior to cancer treatment are often underdiagnosed without screening. For example. or depression post-menopausal status is associated with alterations in cytokines such as IL-648 and cognitive difficulties in learning and memory.50 Breast cancer patients who received chemotherapy and tamoxifen have greater difficulty than those who received chemotherapy alone.53 Cognitive disorders such as dementia limit life expectancy and can affect whether patients should receive adjuvant therapy. increasing interest in epigenetics (changes in gene activity without any in DNA structure) and cognitive function may lead to examination of chemotherapy-induced epigenetic changes associated with cancer-treatment related cognitive impairment. and those associated chemotherapy-induced cognitive change such as DNA damage/repair (eg.C. long-term studies are necessary to definitively assess the impact of breast cancer treatment on the cognitive function of older patients. with less availability of a neurotransmitter critical for cognitive function. short observation time.32 Finally. The literature on hormonal balance and cognition suggests that menopausal status and endocrine therapy can also influence cognitive function in cancer. or perhaps a heteroge- . Janlesins et al The COMT Val158Met SNP has been associated with dopamine levels in the prefrontal cortex. 51% of 45 evaluable patients perceived a decline in cognitive function after 6 months of chemotherapy. COMT-Val carriers perform more poorly on tests of attention and executive function compared to COMT-Met carriers.57 Cognitive impairment is associated with an increased risk for progression to dementia.47 The differential diagnosis of the type and extent of impairment is important in treatment planning and prognosis. with progression rates of 10% to 15% per year compared with 1% to 2. Examination of other neural repair/ plasticity genes and neurotransmitter activity genes. 28 older women with breast cancer scheduled for adjuvant chemotherapy underwent neuropsychological testing and a comprehensive geriatric assessment (CGA) before therapy and 6 months after completion.25 Another cross-sectional study assessing tamoxifen in premenopausal breast cancer patients compared to healthy controls found greater difficulty in visual and verbal memory and processing speed.61.49 Case studies in cancer reveal that cognitive difficulties can vary among patients who received the same course of chemotherapy. the transition from pre.67 More large.5% in the cognitively intact.58 – 60 One fifth of geriatric cancer patients screen positively for cognitive disorders in an academic setting. compared to healthy controls). Prevalence approaches 50% in community-living populations older than 80 years. Six percent to 10% of people age 65 years suffer from dementia. COMT-Val carriers metabolize dopamine more rapidly. recombination 11 homolog A46) or blood-brain barrier damage may reveal important associations with post-treatment cognitive function.66 At the same time. Hormonal Therapy TREATMENT-RELATED COGNITIVE IMPAIRMENT IN ELDERLY CANCER PATIENTS Impaired cognitive function is a common complaint among older patients presenting for medical treatment. The data are still limited regarding the impact of cancer treatment on an older person’s cognition. exemestane.434 M.51 One prospective study found deterioration in verbal memory and executive function in post-menopausal patients taking tamoxifen for 1 year (but not in those taking the aromatase inhibitor.52 Larger studies are needed to confirm these results and to address the combined effects of chemotherapy and endocrine therapy on cognitive function in cancer.65 In one longitudinal study. Menopausal Status and Hormonal Therapies Most evidence for cognitive difficulties in cancer patients and survivors is attributed to chemotherapy. Cognitive disorders interfere with medication compliance and consent to treatment and increase caregiver burden.62 Chemotherapy Investigators have prospectively studied the impact of cancer treatment on cognitive function in older patients with breast cancer. one population-based study suggests that women with breast cancer who receive chemotherapy have a higher likelihood of dementia after long-term follow-up.

Future work in animal models will provide more mechanistic insight and allow testing of interventions for cognitive impairment.68 Several studies have evaluated ADT on the cognition of men with prostate cancer but few have described the baseline prevalence of cognitive impairment. while people with average or better scores at baseline displayed improvements in visuospatial planning and timed tests of phonemic fluency. Toxicity from brain tumor therapy may range from focal neurological deficits to generalized neurological syndromes. these tools have not yet demonstrated the ability to detect treatment-induced changes in cognition. This was despite the fact that doxorubicin was not detected in the brains of these mice.Cancer and chemotherapy-related cognitive dysfunction 435 neous effect of ADT.).5 standard deviations below the mean on 2 neuropsychological measures at baseline. Supplement to American Society of Clinical Oncology. animal models may inform hypotheses relating to the clinical condition. induction of oxidative stress and mitochondrial dysfunction.76 Since patients with brain tumors live longer.85 These studies suggest that chemotherapy causes neurotoxicity within the brain and that inflammation may be a mediator of cognitive difficulties by reducing neural transmission. Clinical suspicion of dementia is not as sensitive as available screening tools. ages 49 to 75. A more detailed neuropsychological evaluation is needed to accomplish this goal. Morrow GR.74 MiniCog. Janelsins M.63 further understand the effects that chemotherapy and other treatments have on intact brain structures and cognitive function. Cognitive function in breast cancer patients . The purpose of screening is to assess cognitive capacity and stratify risk.80 – 83 Mice exposed to doxorubicin had increased cortical and hippocampal levels of tumor necrosis factor-alpha (TNF.77– 80 likely due to reductions in adult neurogenesis. Blessed Dementia Rating Scale. ANIMAL STUDIES Animal models are especially important to the cancer and cognition field. We have reviewed various topics relevant to the cognition and cancer field and highlighted important areas for future research.73 MMSE. This suggests that some may have cognitive impairment prior to treatment.69 They found improvements in visual and semantic memory. Roscoe JA.72 A cognitive assessment tool (eg.and chemotherapy-related cognitive impairment is an important clinical problem that negatively impacts quality of life for many individuals during treatment and post-treatment. 71 years). metabolic dysregulation. While not significantly different. TREATMENT-RELATED COGNITIVE IMPAIRMENT IN BRAIN TUMOR PATIENTS In addition to the neurological complications brain tumors themselves impose. These frequently include fatigue and cognitive impairment. 2.70 They also noted that the community control group performed significantly better than the prostate cancer group at baseline. assuming that study in a human is even technologically possible. While parallel findings between animal and human experiments do not establish equivalence. Animal studies have found that chemotherapy agents can negatively affect memory behavior in mice. This again suggests that a subset have cognitive impairment before treatment that may impact overall results. hyperactivation of microglia. In another study of 32 patients (median age. Bunston T. It is not easy to assess molecular changes in the human brain. which may impact overall results. SUMMARY Cancer.71 Within exploratory analyses. abnormal scores should trigger a comprehensive work-up with cognitive specialists. Abdolell M. cerebrovascular disorders). and increased neural cell death. Cognitive functioning in breast cancer patients during and following chemotherapy [abstract]. including decreased executive function. the range on the MMSE of the treatment group at baseline was 21–29. addressing a research question in an animal model is usually much less expensive than the same research question in a human study. These patients may experience a broad array of both acute and late toxicities. Understanding the factors that lead to cognitive impairments from chemotherapy and other cancer treatments will allow us to better understand how to educate patients about these difficulties and ultimately how to treat them. it is important to REFERENCES 1. One study examined the cognitive function of 25 men.84. 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