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.

STATE OF THE FIELD
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

U

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

SUMMARY OF CLINICAL RESEARCH LITERATURE
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

aDepartment

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: michelle_janelsins@urmc.rochester.edu 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 scores.to 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. A study of outcomes at 1 year found cognitive losses in those undergoing hormonal treatment compared to controls. Furthermore. 45% scored 1. Brezden CB. following 12 months of androgen deprivation. Experiments in animal models can usually be done much more quickly than parallel clinical studies and allow for many more aspects of a research question to be addressed. Unfortunately. Tannock IF. Jean-Pierre P.75 and Short Portable Mental Status Questionnaire) for older cancer patients should screen for baseline impairment and follow effects of therapy on cognitive function. the treatments are often associated with harmful effects on the CNS that can lead to cognitive impairments. This suggested that some had significant cognitive impairment prior to treatment. Phillips KA. 2009:47. resulting both from direct toxic effects on the nervous system and indirect dysfunction (eg. those who scored below expectation at baseline displayed no change in cognition.

Psychooncology. Ferguson RJ. McDonald BC. Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer’s disease. 19. 2002. Smith PF. Cooper BA.22: 48-54. Petersen L. 17.109:1905–13.117:198 –202. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective. Conroy SK. et al. 7. Vismara C. Ahles TA. 2007. Deutsch G. Br J Cancer. 2009. Verma S. 18:2695–701. et al. [Epub ahead of print] 23. Saykin AJ. Furstenberg CT. Quesnel C. 2010 Sep 5. Saykin AJ. Kohli S. and nonamnestic mild cognitive impairment in older persons: a population-based study. Cancer. A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Schagen SB. 26. 5.94:803– 8. 31. Ivers H. Dienst ER. Jenkins V. McNaull BB. 32. J Natl Cancer Inst. randomized. et al. Schindler D. 29. Collins B. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. Roscoe JA. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. 20. Pusztai L. Wefel JS. 2008. Saykin AJ. 6. 2006. Serum cytokine in response to chemo-radiotherapy for Hodgkin’s disease. Breast Cancer Res Treat.4:61– 6. Galimberti D. Mills PJ. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Collins B. Miaskowski CA.110:143–52. Martin-Aragon S. Buzdar AU. Boogerd W. Wieneke MH. et al. The cognitive effects of adjuvant chemotherapy in early stage breast cancer: a prospective study.100:2292–9. Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective. 25. Denburg NL. longitudinal study. 22. Lovati C. 2008. Cognitive impairments associated with breast cancer treatments: results from a longitudinal study. Cancer.25:3866 –70. Tumori. Ahles TA. et al. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. Greendale GA.27:415–34. Yee A. 2001. Nat Rev Cancer. 2007. Muller MJ. Viviani S. 1995. Schagen SB. 2009. Ganz PA. Knopman DS. Reid-Arndt SA.C. Reuben JM. 34. 2007.51:159 – 65. 2006. Ahles TA. 14. receiving adjuvant chemotherapy. et al. Fenoglio C.27: 1763– 8. Villani F. Rosen C. Neurobiol Aging. Shilling V. Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. Cognitive effects of chemotherapy in post-menopausal breast cancer patients 1 year after treatment.25:94 –102. Cancer facts and figures. et al. Psychooncology. et al. inflammation. Bielajew C. 12. McDonald BC. J Psychosoc Oncol.3:54 –9. GA: American Cancer Society. Bermejo P. 2009. Measuring neuropsychological change following breast cancer treatment: an analysis of statistical models. Mellenbergh GJ. Cognitive function in breast cancer patients prior to adjuvant treatment.90: 210 – 8. Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer’s disease. J Natl Cancer Inst. Bonfante V.28:4434 – 40. Benedi J. Inflammation and anti-inflammatory strategies for Alzheimer’s disease . Dodd MJ.7:192–201. 10. Ahles TA. McGuinness B. et al. Saykin AJ.20:485–93. Lux MP. Muller MJ. Support Care Cancer. Candidate mechanisms for chemotherapy-induced cognitive changes. A prospective longitudinal study of chemotherapy-induced cognitive changes in breast cancer patients. Lenzi R. 2008.54:925–31. Curr Opin Invest Drugs. Castellon SA.436 M. Hermelink K. 27. 2009.94:828 –34. Breast Cancer Res Treat. J Clin Exp Neuropsychol. Roberts RO. van Dam FS. 2010. Untch M. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. 2006. Schultz SK. Bower JE. 2010 Oct 10. Inflammation in Parkinson’s disease: an update.98:1742–5. Self-reported cognitive impairments in patients with cancer. 4. Cancer.56:3–14. 9. 2009. Beglinger LJ. 21. 2000. 2004. 30. Meyers CA. Stewart A. Busia A. 2004. J Clin Oncol. Cytokine. 15. Saykin AJ. Villani M. 2008. Metabolic syndrome.26:955– 69. Wefel JS.17:122–30. J Neurooncol. Theriault RL. 35. 8. Stewart A. 2004. Mackenzie J. Hamburger HL. 2010. Parker B. et al. 2010. Tomiak E. Passmore AP. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. Ahles TA. Boogerd W. Savard J. 18. J Clin Exp Neuropsychol. McDonald BC. Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: a pilot prospective longitudinal study. Saykin AJ. Muller MJ. Jansen CE. West JD. McDonald BC. Stewart A. 1998. J Clin Oncol. Bielajew C. J Clin Oncol. 2006. Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. Ancoli-Israel S. Geda YE. 2010. 16. Predictors of . 28. Bielajew C. Mendoza TR.123:819 –28. Ahles TA. Griggs JJ. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. Atlanta. Janlesins et al 3. 33. van Dam FS. et al. J Clin Oncol. Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy.116: 3348-56. 2008. et al. 24. Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study.31:73– 89. Meyers CA. Mackenzie J. 11. multicenter. 13. Gerontology. Abraham L. J Neuropsychiatry Clin Neurosci. Breast Cancer Res Treat. Collins B. Saleeba AK. Hudis C. Davis RN. van Dam FS. Hurria A.116: 113–23. Verma S. Perry MC. longitudinal trial.a mini-review.18:134 – 43. Schagen SB. J Am Geriatr Soc. Yamada TH. Hsieh C.9:478 – 84. J Oncol Practice. 2009. Cognitive and psychological factors associated with early posttreatment functional outcomes in breast cancer survivors.24:11-8. 2007. Ouimet LA. Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy. Psychooncology. Alzheimer Dis Assoc Disord. Immunol Lett. Todd S.

et al. et al. Mohile SG.12:612–9.56:1687–92. Pfohl M. Hunt WC. J Am Geriatr Soc.117:1369 –76. 43. Montgomery GW.256:183–94. 65. 40. Assessment of the older cancer patient. Epigenetics. Vardy JL. Cognitive effects of tamoxifen in pre-menopausal women with breast cancer compared to healthy controls. 2008. 54. 64. 61. Treatment for breast cancer in patients with Alzheimer’s disease. Petersen RC. 46. 52. Aapro M. Joy AA.25:577– 609. 2004. Endocr Rev. Green HJ. Dhillon H. New York.29: 125–32. 2007. Fiocco AJ. Gamboa MC. Catechol-O-methyltransferase (COMT) genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Franco R. et al. Rawson KS. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Morley KI. Bertram L. Quality of life compared during pharmacological treatments and clini- . 2000.54: 1119 –24. Ann Intern Med. A prospective. Behav Genet. Petersen RC. Noll WW. 68. Fisher GG. Neurol Clin. 2004. Klepin H. 58. Plassman BL.2:275– 82. Lindquist K. Memorial-Sloan Kettering Cancer Center.97:1107–14.329:24-7. 2001. 2008. J Intern Med. Pond GR. et al. 49. March 8 –9. Lamont EB. et al. J Am Geriatr Soc. 2003. J Am Geriatr Soc. et al. Goldfarb S. Booth C.96:823–30. Paraska K. 39. Science. Perry RT. 2004. Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient’s perspective. inflammation in response to anthracycline-based chemotherapy for breast cancer. 59. Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. 2006. Lee JS. 2008.22:98 –104. fatigue. Beex LV. Saykin AJ. Zuckerman E. Alzheimer’s disease and mild cognitive impairment. Cognition and Cancer Meeting. Pfeilschifter J.6:364 –71. Rodin MB.53:1897–904. 2007. et al. 2010. Salminen E. and memory study. McAllister TW. McGinnis M. 60. 2006. J Clin Oncol. Trotter T. Heck JE. 48. Small BJ. Saykin A. Mild cognitive impairment as a diagnostic entity. McDonald B. 2003. Goodwin JS. Cognitive function in colorectal cancer patients: interim analysis of a longitudinal prospective study [abstract]. Saykin AJ. NY. Chen H. 2002. Ahles TA. 62. Mohile S.23:90 –119. Prevalence of dementia in the United States: the aging. 50. 2009. McQueen MB. Hurria A.Cancer and chemotherapy-related cognitive dysfunction 437 36.63–77. The genetics of cognitive processes: candidate genes in humans and animals. COMT genotype and cognitive function: an 8-year longitudinal study in white and black elders. Epidemiology. longitudinal study of the functional status and quality of life of older patients with breast cancer receiving adjuvant chemotherapy. Cancer. Fisher GG. Collins JS. et al. 2010.74:1296-302.31:511–31. Huang MH. Changes in proinflammatory cytokine activity after menopause. Br J Cancer. Kelley BJ. 2007. 66. et al.72: 1850 –7. Heck JE. 2003. et al. Walsh E. et al. Hurria A. 2009. et al. Langa KM. Cognitive dysfunction following adjuvant chemotherapy for breast cancer: two case studies. Can older cancer patients tolerate chemotherapy? A prospective pilot study.30:473– 8. Curr Psychiatry Rep. Cytokine levels in patients with colorectal cancer and breast cancer and their relationship to fatigue and cognitive function [abstract]. Korpela J. Neurology. et al. Watson B Jr. Gupta SK. Blacker D. Cancer. J Clin Oncol. Cognitive effects of hormone therapy in men with prostate cancer: a review. Determinants of survival in older cancer patients. 2008. MemorialSloan Kettering Cancer Center. 2010. 63. Albert SM. 2010. Nat Genet. et al.104:788 –93. et al. Portin R. 55. Psychooncology. The seductive allure of behavioral epigenetics.52: 1681–7. Roth AJ. Rosen C. Meyer J. 2005. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. J Clin Oncol. J Am Geriatr Soc.39:17–23. 53. Wight RG. Vardy J. 51. Geriatric assessment in older patients with breast cancer. A comprehensive geriatric intervention detects multiple problems in older breast cancer patients. Gorin SS. 57. 2003. Nelson CJ. 2010. Schilder CM. Patterns of dementia diagnosis in Surveillance. March 8 –9. Estey E. 69. Gorin SS. NY. A practical approach to geriatric assessment in oncology. Headley BC. Langa KM.49:69 –75. diagnosis. Cognition and Cancer Meeting. Panageas KS. Tanzi RE. Cognitive impairment. Extermann M. 2007. et al. Plassman BL. Koditz R.148:427–34. 2007. Neuroepidemiology. Cantor A. Ahles T. Samet JM. Oncol Nurs Forum. 2008. Xu W. Meyer J. 2005. J Cancer Surviv. Crit Rev Oncol Hematol. et al. Mullin K.28:1294-300. 42. et al. and End Results breast cancer survivors who use chemotherapy. 45.89:971– 6. Palmer JL. Genetics of cognitive decline post cancer chemotherapy [abstract]. New York. et al. 44. Ferrell R.113:1097–106. Seynaeve C. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Androgen deprivation and cognition in prostate cancer. 2010. J Natl Compr Cancer Netw. Meyers CA. J Natl Cancer Inst. Cognitive effects of cytotoxic cancer chemotherapy: predisposing risk factors and potential treatments. Albert S. 38. and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Miller G. Neurology. Association of a haplotype for tumor necrosis factor in siblings with lateonset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative.25:1936 – 44. 2000. Cancer.18S:9070. Cancer.14. Hurria A. Albitar M. 2011.7:226 –36. Greendale GA. 70. Patterns of presentation. 2004. Carlson LE. Schatz H. Brain Behav Immun. demographics. 88:1031– 8. Am J Med Genet. Hershman D. Pakenham KI. 41. 67. Hematol Oncol Clin North Am. Breast Cancer Res Treat. et al. 1996. 56. Extermann M.98:343– 8. and treatment in older patients with colon cancer and comorbid dementia. Ahles TA. 47. et al. Prevalence of cognitive impairment without dementia in the United States. Bender CM. 37.

114:797– 811. The Mini-Cog as a screen for dementia: validation in a population-based sample.12: 189 –98.23:325–33. Han R.75: 152-9. Kraszpulski M. eds. IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice.199:527–38. Mayer-Proschel M.28:292–8. Metab Brain Dis. Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory. Bennett G. Sultana R. 77. Walker EA. Dietrich J. 72. 2006. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. TNF-alpha-mediated central nervous system toxicity. Janlesins et al 71.166:796– 807. 2010. et al. Chodosh J. Aluise CD. Pharmacol Biochem Behav. Noble M. 78. et al. The effects of the anti-cancer drugs. J Am Geriatr Soc. 2008. J Psychiatr Res. Mohile SG. Br J Psychiatry. Neurobiol Dis. Neurologic complications of cancer. DeAngelis LM. 75. James I.52:1051–9. 2003. Cognitive dysfunction induced by chronic ad- 79. 80. Abraham J. et al. Han R. Crit Rev Oncol Hematol. . side effects of chemotherapy. Tomlinson BE. 1968. 2008. Lacy M. Chen P.7:12. Walker A. Mustafa S. Cole MP. et al. Adriamycin-induced. Noble M. 74. A practical method for grading the cognitive state of patients for the clinician. Foley JJ. 2006.C. Psychopharmacology (Berl). Cognitive effects of androgen deprivation therapy in an older cohort of men with prostate cancer. “Mini-Mental State”. Yang YM. Physician recognition of cognitive impairment: evaluating the need for improvement. J Am Geriatr Soc.28:323–30. Petitti DB. 2004. 2004. Dietrich J. 85. cal monitoring for non-localized prostate cancer: a randomized controlled trial. McHugh PR. 2010. Cole MP. Berg MJ. 73. Raffa RB. Wigmore PM. Rodin M. Blessed G. Elliott M.23:127–39. on cognitive function in mice. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. Zhang HT. Eur J Neurosci.85:66 –75. Luebke A. methotrexate and 5-fluorouracil. Scanlan JM.93:975–9.5:22. Roth M. Konat GW. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Vardy J. Winocur G. BJU Int. New York: Oxford University Press. Tangpong J. ministration of common cancer chemotherapeutics in rats. Posner JB. Kerr L. Janelsins MC. 2010. 83. Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug Adriamycin: implications for oxidative stress-mediated chemobrain. Folstein MF. Binns MA. 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Yang Y.438 M. Joshi G. Roscoe JA. Mayer-Proschel M. 2006. Borson S. J Biol. et al. 84. 76. Neuroscience. 1975. Cancer Invest. J Biol.51:1451– 4. 2008. Folstein SE. 2009. 81. 82. Ganguli M. Tannock I. 2008.

Sign up to vote on this title
UsefulNot useful