an overview of chemotherapy-related cognitive dysfunction ... · following initial treatment,...

An Overview of Chemotherapy-Related Cognitive Dysfunction, or ‘Chemobrain’Published on Cancer Network (http://www.cancernetwork.com)

An Overview of Chemotherapy-Related Cognitive Dysfunction,or ‘Chemobrain’Review Article [1] | September 15, 2014 | Oncology Journal [2], Breast Cancer [3], Palliative andSupportive Care [4]By Halle C. F. Moore, MD [5]

This review will focus largely on the effects of systemic cytotoxic treatment on cognitive function,reflecting what has been most extensively studied in the literature.

Introduction

Chemotherapy-associated cognitive dysfunction, often referred to as “chemobrain,” includessubjectively reported and objectively measured problems with cognition following chemotherapy.The American Cancer Society estimates there will be close to 14.5 million cancer survivors in theUnited States by 2015.[1] Increasingly, individuals with cancer are experiencing long-term survivalfollowing initial treatment, leading to an ever greater need to understand, manage, and preventlasting adverse effects of cancer treatment. Reflecting this need, the American Society of ClinicalOncology has recently issued a set of new Survivorship Guidelines addressing fatigue, mooddisorders, and peripheral neuropathy. Currently there are no clear guidelines for the clinicalassessment and management of chemobrain.

The recognition that a variety of factors other than chemotherapy may contribute to cognitivedecline in cancer patients has led to use of the broader term, “cancer treatment–related cognitiveimpairment.” This review, however, will focus largely on the effects of systemic cytotoxic treatmenton cognitive function, reflecting what has been most extensively studied in the literature. It shouldalso be noted that much of the research on this topic has been conducted in breast cancer patients,as they represent the largest group of long-term cancer survivors who have had frequent exposureto chemotherapy. This review does not address cognitive effects of central nervous system (CNS)malignancies or CNS-directed treatments.In a sampling of participants in the National Health and Nutrition Examination Survey, individualswith and without a history of cancer were surveyed about whether they felt they were limited bydifficulty with memory or periods of confusion. Approximately 14% of cancer survivors reportedmemory problems, compared with 8% of participants without a prior cancer diagnosis, representingan approximately 40% increase in the likelihood of cancer survivors reporting cognitive concerns.[2]Similarly, studies assessing cognitive function with objective cognitive tests have suggested a higherlikelihood of impairment among individuals who have received chemotherapy. In one study of breastcancer survivors who had, on average, completed treatment with adjuvant cyclophosphamide,methotrexane, and fluorouracil (CMF) chemotherapy more than 20 years prior to enrollment,cognitive deficits were observed compared with a control group who underwent the sameneuropsychological tests as part of a population-based assessment.[3]

Factors Other Than Chemotherapy That Have an Impact on CognitiveFunction

Studies that only address cognitive performance in a cross-sectional manner after patients havecompleted chemotherapy do not account for other effects of the cancer diagnosis and treatment orpossible baseline differences between patients who get cancer and those who do not. To get aroundthese limitations, investigators have begun to conduct studies that perform baseline cognitiveassessments and include, in addition to healthy control groups, control groups of patients withcancer types similar to those under investigation but treated without systemic therapy. In somestudies, formal testing of cancer patients after initial diagnosis and surgery but prior to any systemictherapy has demonstrated higher-than-expected baseline rates of cognitive dysfunction. Amongbreast cancer patients who had completed surgery but had not yet initiated planned chemotherapy,cognitive dysfunction rates upwards of 20% have been reported in several studies.[4-6] In a study of

of 10

http://www.cancernetwork.com/review-article

http://www.cancernetwork.com/oncology-journal

http://www.cancernetwork.com/breast-cancer

http://www.cancernetwork.com/palliative-and-supportive-care

http://www.cancernetwork.com/palliative-and-supportive-care

http://www.cancernetwork.com/authors/halle-c-f-moore-md


colon cancer patients evaluated prior to adjuvant chemotherapy, 37% demonstrated cognitiveimpairment prior to systemic treatment,[7] and among testicular cancer patients evaluated aftersurgery but prior to chemotherapy, the incidence of cognitive impairment was 46%.[8] Amongstudies looking at specific cognitive domains affected in newly diagnosed cancer patients,abnormalities have been seen in psychomotor function, verbal learning and ability, executivefunction, language, visual-spatial skill, and memory.[4-6,8,9]There is evidence that surgery and anesthesia contribute to cognitive impairment, particularly inolder patients, those with cardiovascular disease, and patients who undergo more extensive surgicalprocedures or have post-surgery complications. In general, postoperative cognitive dysfunction,believed to be due in part to inflammatory and immune responses to surgery, appears to resolvewithin days to months.[10]It is unclear to what extent baseline cognitive impairment is related to anxiety and depression.Certainly learning of a cancer diagnosis can affect mood, which may in turn affect sleep and otherphysiologic functions. In a small study of breast cancer patients who were to receive eitherchemotherapy or radiation treatment, pretreatment worry was associated with alterations in brainfunction measured by functional magnetic resonance imaging (MRI), and with subjective andobjective measures of cognitive function in both treatment groups, with the prechemotherapy groupreporting significantly more worry.[11] However, in several studies of women undergoing adjuvant orneoadjuvant chemotherapy for breast cancer, the authors reported that anxiety, distress, or poorquality of life correlated with self-perceived cognitive concerns but not with neuropsychological testresults.[6,9,12] In another study of breast cancer patients, cognitive impairment observed prior tosystemic treatment was associated with certain comorbidities but not with anxiety, depression, ortype of surgery.[13]In addition to any modest effects on baseline test performance, mood may influence cognitivefunction assessment during or after chemotherapy treatment. However, these effects seem to bepredominantly in subjective rather than objective performance. In a multicenter study of 101 breastcancer patients undergoing chemotherapy, negative affectivity and depression correlated withself-reported cognitive dysfunction.[14] In another study of 53 breast cancer survivors at least 2years out from diagnosis, subjective cognitive complaints were associated with measures of fatigueand psychological distress but not with objective performance on cognitive testing.[15] Similarly, asdiscussed above, in a study of 40 women receiving adjuvant or neoadjuvant chemotherapy forbreast cancer, the authors found anxiety, depression, and poor quality of life correlated withself-perceived cognitive concerns but not with neuropsychological test results.[12]Endocrine factors may influence objective neuropsychological testing performance afterchemotherapy; however, results have been mixed. In a longitudinal study of breast cancer patientsundergoing chemotherapy for early-stage breast cancer, treatment-induced menopause wasassociated with some decline in cognitive performance following chemotherapy.[16] In anotherlongitudinal study of cognitive effects of chemotherapy for breast cancer, use of adjuvant endocrinetherapy was associated with worse performance on measures of processing speed and verbalmemory.[17] In a prospective study of women receiving adjuvant chemotherapy for breast cancer,fatigue and menopausal symptoms correlated with quality-of-life scores but not with cognitiveimpairment as determined by a High-Sensitivity Cognitive Screen.[18]

Assessment of Cognitive Function

Correlations between subjective reports of cognitive impairment and results of neuropsychologicaltesting have been inconsistent, making it challenging to assess for the presence of cognitivedysfunction. Several studies have found that patients reporting subjective cognitive impairmentduring or following chemotherapy do not show a decline in neuropsychological testingperformance.[15,16,19,20] Other studies that did demonstrate apparent effects of chemotherapy onneuropsychological cognitive testing also found no correlation between those results and patients’subjective concerns.[3,12,21] Additional studies have demonstrated selective relationships betweenpatient-reported cognitive concerns and neuropsychological test results. For example, three studiesin breast cancer patients showed self-perceived cognitive dysfunction was correlated withimpairment of memory but not with other formally tested cognitive domains.[22-24]While there is a growing body of literature on neuroimaging and electroencephalogram changes asindicative of “chemobrain,” these tests currently have no role in the clinical diagnosis ofchemotherapy-associated cognitive dysfunction. According to a publication by the InternationalCognition and Cancer Task Force, “objective [neuropsychological] tests remain the gold standard for

of 10


measuring cognitive function” in the evaluation of cognitive effects of cancer therapies.[25] This taskforce provided recommendations regarding specific tests that should be included in clinical trialsassessing cancer treatment–related cognitive dysfunction. The Hopkins Verbal LearningTest–Revised, the Trail Making Test, and the Controlled Oral Word Association of the MultilingualAphasia Examination were recommended as reliable and sensitive tests that measure learning andmemory, processing speed, and executive function. Because patient reports of cognitive functionhave not been validated as a reliable way to assess cognitive dysfunction, such subjective measureswere believed to be less useful for research purposes.[25]Patient-reported measures of cognitive impairment are, however, extremely important in clinicalpractice and are more likely to impact quality of life than deficits uncovered by standardizedcognitive testing. Objective neurocognitive assessments may not be as sensitive aspatient-perceived changes or may not be testing the specific domains affected in an individualpatient. Currently, there are no specific diagnostic criteria for chemotherapy-related cognitiveimpairment. Similar to assessing fatigue and depression, the patient-reported measures are key inclinical care, and there is currently a need for standardized patient-reported measures of cognitivefunction for use in daily practice.

Neuropsychological impairment attributable to chemotherapy.

Studies that employ standardized neuropsychological testing and include an untreated control groupand/or baseline assessments provide information about the cognitive effects that can be attributedlargely to chemotherapy treatment. There is strong evidence that chemotherapy can causeshort-term impairment in cognitive function. Longer-term studies have had mixed findings.Cross-sectional studies that have compared individuals treated with chemotherapy to healthy controlpopulations at various time points have suggested that some chemotherapy regimens lead toimpaired cognitive function. Moderate to severe cognitive impairment based on the High-SensitivityCognitive Screen was observed in 16% of patients receiving various adjuvant or neoadjuvantchemotherapy regimens for breast cancer, compared with 4% in a healthy control group. In thisstudy, differences between patients and controls appeared to be greater in the cognitive domains oflanguage, attention, concentration, and self-regulation than in the domains of memory andvisual-motor performance.[18] In a study of the effects of chemotherapy for non-Hodgkin lymphoma(NHL) on cognitive function, 30 lymphoma patients and 10 healthy controls were assessed within 3months of completing first-line chemotherapy with a regimen of either rituximab, cyclophosphamide,doxorubicin, vincristine, and prednisone (R-CHOP) or bendamustine plus rituximab. Chemotherapypatients receiving bendamustine with rituximab had lower performance scores on objective cognitivetesting than controls and R-CHOP–treated patients, whose scores were similar to those of populationnorms.[26] In a cohort of women between 3 and 10 years post completion of doxorubicin andcyclophosphamide chemotherapy with or without a taxane, breast cancer survivors performed worseon memory testing but otherwise demonstrated a similar performance on neuropsychologicaltesting[23] compared with healthy controls matched for age and education. In a study of long-termbreast cancer survivors who had received adjuvant CMF chemotherapy over 20 years earlier onaverage, impairment in verbal memory, processing speed, executive function, and psychomotorspeed was observed compared with healthy controls.[3]Cross-sectional studies using control populations of cancer patients who did not receivechemotherapy may be a better way to assess any effects of chemotherapy on cognitive functioncompared with using a healthy control population. One such study compared women who hadcompleted surgery and radiation for breast cancer with those who had completed surgery, radiation,and chemotherapy. Cognitive assessments performed at about 6 months after treatment completiondemonstrated no significant differences between the two groups in episodic memory, attention,complex cognition, motor performance, or language.[27] A study that evaluated breast cancersurvivors who were at least 2 years out from chemotherapy demonstrated impairment in severalcognitive domains compared with survivors who had local therapy without chemotherapy; notably,however, cognitive performance among the chemotherapy recipients was similar to that of a healthycontrol population.[15] In a relatively long-term follow-up study of breast cancer survivors,neuropsychological assessments were done at various time intervals in women treated withfluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy with or without high-dosecyclophosphamide, thiotepa, and carboplatin; CMF chemotherapy; or no chemotherapy. Patientswere initially assessed at an average of 2 years after completion of treatment, with repeatassessment approximately 4 years after treatment completion. At the initial 2-year assessment, anincreased incidence of cognitive impairment was observed in all chemotherapy-treated groups

of 10


compared with the control group. The incidence of cognitive impairment was greatest with high-dosechemotherapy, at about 32%, followed by a 20% incidence of cognitive impairment in the CMF groupand 17% in the FEC group, compared with 6% in breast cancer patients who did not receivechemotherapy. At the time of the follow-up assessment approximately 2 years later (ie, 4 years postcompletion of chemotherapy), differences in the rate of cognitive impairment were no longersignificant between the groups.[28] In another study, which looked at longer-term effects ofchemotherapy in breast cancer and lymphoma survivors who were free of disease at least 5 yearsout from diagnosis, individuals who received chemotherapy were compared with those who receivedlocal therapy without chemotherapy. In that study, cognitive scores were lower in the chemotherapygroup, particularly in the cognitive domains of verbal memory and psychomotor functioning.[29]Studies in which baseline assessments are obtained prior to any chemotherapy treatment allowpatients to serve as their own controls for assessing cognitive changes. Several of these studiesperformed in breast cancer patients[30,16,20] and one in colon cancer patients[31] receivingadjuvant chemotherapy demonstrated no significant change between pre- and post-treatmentcognitive assessments. The majority of longitudinal studies, however, have demonstrated pre- topost-treatment decline in at least some cognitive domains acutely following chemotherapy. Specificcognitive domains that have been observed to be adversely affected by chemotherapy in theshort-term include executive function,[5,14] motor function,[6,9,32] learning and memory,[5-7,32]processing speed,[5,33] attention,[6,32] and visuospatial skills.[6] In a meta-analysis of 17 cognitivefunction studies in breast cancer survivors treated with standard-dose chemotherapy, in whichbaseline testing or a control population was used for comparison, chemotherapy treatment wasassociated with deficits in verbal and visuospatial abilities, but the magnitude of the effect wassmall. Differences were not observed in attention, information processing, motor speed, verbalmemory, or visual memory.[34]Relatively few longitudinal studies have formally assessed cognitive function at more than a yearfollowing completion of chemotherapy treatment. In a study of 85 women receiving chemotherapyfor early-stage breast cancer, control groups were also included and consisted of 49 healthy womenand 43 women with newly diagnosed breast cancer who were not receiving chemotherapy. Subjectsunderwent neuropsychological testing at baseline, at 6 months or at completion of chemotherapy,and at 18 months. No significant differences in cognitive performance between the three groupswere observed over time when controlled for age and intelligence.[16] Another longitudinal study ofearly-stage breast cancer patients that also included a chemotherapy group, a control group ofbreast cancer patients not receiving chemotherapy, and a healthy control group, assessedprocessing speed and other cognitive measures at baseline and at 1, 6, and 18 months aftertreatment. All three groups actually demonstrated improvement in processing speed over time,although the chemotherapy-exposed group did not begin to improve until the secondpost-chemotherapy time point, suggesting that chemotherapy may have counteracted the learningeffect that likely accounted for the improvements in the other two groups. In addition, older patientsand patients with low reading scores who received chemotherapy experienced a decline inprocessing speed scores at the first post-treatment assessment. By 18 months after treatment,however, chemotherapy-treated patients had improvement compared to baseline in all of thecognitive domains assessed.[33] A study that used a High-Sensitivity Cognitive Screen to assesscognitive function in patients undergoing adjuvant chemotherapy for breast cancer compared with ahealthy control group found a 16% incidence of moderate to severe cognitive dysfunction in thechemotherapy group compared with 5% in the controls. Assessments 1 and 2 years laterdemonstrated that these rates had improved, coming down to 4.4% and 3.8%, respectively, in thechemotherapy group and to 3.6% and 0 %, respectively, in the control group. Because the initialtesting was done near the end of chemotherapy, it is impossible to know what the baselinedifferences were between the treatment and control groups.[35] All three of these studies providereassuring evidence that the acute measurable cognitive impairment associated with chemotherapydiminishes significantly with time.

Correlative Tests Suggesting CNS Effects of Chemotherapy

Correlative studies demonstrating CNS changes associated with chemotherapy provide furtherevidence of the effects of this treatment modality on the central nervous system. Structural MRIstudies have demonstrated a reduction in gray matter density in breast cancer patients exposed tochemotherapy; this appears to improve over time after recovery from chemotherapy.[23,36] Whitematter changes have also been observed in association with chemotherapy in a study using the MRI

of 10


technique of diffusion tensor imaging.[32] In addition, functional MRI studies have demonstrated thatpatients with prior chemotherapy exposure have a reduced activation of certain brain regions duringperformance of a cognitive task, compared with baseline results[37] or healthy controls.[23] Inanother study of functional MRI, a subset of patients were more likely to have an increase in brainactivation during a working memory task following chemotherapy compared with baseline and thosechanges correlated with improvement in processing speed scores on neurocognitive testing.[38]Electroencephalography (EEG) has also been investigated as a correlate of chemotherapy-relatedcognitive dysfunction. EEG recordings in patients undergoing chemotherapy for NHL did not differsignificantly from results in an untreated healthy control population.[26] In a study of 26 breastcancer survivors previously treated with CMF chemotherapy and compared with 23 survivors who didnot receive chemotherapy, participants performed information-processing tasks while undergoingconcurrent EEG monitoring. Differences in EEG amplitudes of event-related potentials, which relateto intensity of neural structure activation, and latencies, which relate to timing of activation, wereobserved between survivors who had received chemotherapy and those who had not. While thefindings suggest a potential role for EEG as a noninvasive means of evaluating CNS effects ofchemotherapy treatment, the changes did not actually correlate with cognitive complaints or formalevaluations of information-processing abilities.[21] In a separate pilot study, patients with breastcancer underwent EEG monitoring and neuropsychological testing before, during, and after recoveryfrom chemotherapy, and age-matched healthy controls were evaluated at the same time points. EEGchanges demonstrating increased activity occurred only in patients during chemotherapy andcorrelated with cognitive complaints but not with objective measures of cognitive function.[20]

Cognitive Compensation

A concept that may explain some of the discrepancies observed between correlative tests,subjective cognitive complaints, and formal neuropsychological testing results is that of cognitivecompensation. Individuals with adequate cognitive reserve may have the ability to overcome anydetrimental effects of chemotherapy with an increase in activity in some parts of the brain. Thisincreased effort to perform cognitive tasks may be reflected in more perceived cognitive concerns. Inthe above-described pilot study evaluating EEG as a correlate of cognitive effects of chemotherapy,the alterations in brain activity observed on EEG were heightened following mental and physicaltasks in patients undergoing chemotherapy treatment only, perhaps reflecting an increase in effortto maintain the good performance that was observed on objective measures of cognitivefunction.[20] In a study using functional MRI as a correlate of cognitive function in womenexperiencing chemotherapy-induced amenorrhea, compared with postmenopausal women receivingchemotherapy as well as premenopausal and postmenopausal controls, all subjects underwentneurocognitive testing and functional MRI during a memory task, to enable the investigators toassess patterns of brain activation. Postmenopausal women receiving chemotherapy exhibited somedecline in verbal and visual memory 1 month after chemotherapy treatment, while the women whoexperienced amenorrhea with chemotherapy demonstrated some improvement in these areas. Thelatter group also exhibited an increased magnitude of neural activity on the functional MRI studies,suggesting this younger group was able to compensate for the effects of chemotherapy with achange in neural activity. Although the healthy pre- and postmenopausal controls also demonstratedsome improvement in cognitive testing scores over time, presumably due to practice effects,heightened neural activity was not observed in this group.[38]It is likely that patients with more cognitive reserve would have a greater ability to compensate foradverse cognitive effects of chemotherapy. In a study of breast cancer patients evaluated prior toreceiving chemotherapy, objective cognitive impairment was associated with diabetes,cardiovascular comorbidity, older age, nonwhite race, and lower education.[13] Supporting the ideathat age and reduced cognitive reserve prior to treatment may influence susceptibility totreatment-associated cognitive dysfunction is a longitudinal study of 123 breast cancer patients and45 healthy controls in which chemotherapy use was not strongly associated with worsening objectivemeasures of cognitive function following treatment, except in older patients and in those with lowerbaseline cognitive reserve as measured by a Wide Range Achievement Test 3 reading score.[33]Similarly, patient-reported memory problems have been associated with lower levels of educationand income; such problems have also been associated with poorer general health.[2]

Interventions for Chemotherapy-Associated Cognitive impairment

If, indeed, reduced cognitive reserve is contributing to poor cognitive performance, it is rational to

of 10


recommend that patients attempt to modify other factors that may affect cognitive function. Sincesubjective reports of cognitive dysfunction have been associated with anxiety, depression, fatigue,and sleep disturbance, it is sensible to first address these potential confounding issues in patientswho have cognitive concerns after chemotherapy. It is also important to address whether the patientis taking other medications that may affect cognitive function or contribute to delirium. Similarly,aerobic exercise has potential beneficial effects on cognition, as exercise increases blood flow to thebrain.[39] Precise mechanisms underlying the effects of chemotherapy on cognitive function arepoorly understood and are likely multifactorial. Specific interventions studied for the treatment ofchemotherapy-associated cognitive dysfunction have largely consisted of treatments known to beeffective for fatigue or for other types of cognitive impairment.Modafinil, a neural stimulant approved for treatment of narcolepsy, has been evaluated for cancertreatment–associated cognitive dysfunction. In studies evaluating this drug for treatment of cancertherapy–associated fatigue, results of secondary effects on cognitive function have been variableand inconclusive.[40] Methylphenidate, a more broadly acting neural stimulant, has been evaluatedfor its ability to preserve cognitive function during chemotherapy for breast cancer. In a smallrandomized study in breast cancer patients, however, no significant benefit on cognitive function,sleep quality, fatigue, or anxiety/depression was observed with d-methylphenidate vs placebo.[41] Inanother randomized placebo-controlled trial, Ginkgo biloba (EGb 761 extract, 60 mg bid)administered concurrently with chemotherapy was associated with no differences in subjective orobjective measures of cognitive function compared with a control group.[42]Biofeedback and cognitive-behavioral therapy have also been investigated for reducingchemotherapy-associated cognitive dysfunction. In a feasibility study of 23 women with self-reportedcognitive impairment 6 months to 5 years following chemotherapy for breast cancer, EEGbiofeedback was evaluated for reducing cognitive dysfunction. Patient-reported measures ofcognitive function, sleep quality, fatigue, and anxiety/depression were below population norms atbaseline and improved to within the normal population range following 20 sessions of neurofeedbacktraining over a period of 10 weeks.[43] In a pilot study of breast cancer survivors with self-reportedcognitive concerns, cognitive-behavioral therapy demonstrated promising improvement inself-reported and objectively measured cognitive function, and in patient quality of life.[44] Anotherrandomized study in a similar population suggested improvements in quality of life and verbalmemory performance with cognitive-behavioral therapy, but significant improvement in self-reportedcognitive complaints was not seen.[45]

Summary

Currently, there is no standard approach to the management or prevention of chemotherapytreatment–related cognitive dysfunction. Research has been limited by small sample size in studies,lack of a standard means of assessing cognitive function, and challenges in identification of the mostappropriate control groups. A variety of factors may contribute to the phenomenon described as“chemobrain” and may include the cancer itself, comorbid medical issues, normal aging, fatigue,anxiety, depression, sleep problems, surgery, and endocrine treatments. Depending on the level of apatient’s cognitive reserve, cognitive performance on neuropsychological testing may or may not bepreserved in individuals with subjective complaints of cognitive impairment after chemotherapy.Influences on cognitive function at different time points and the cognitive domains that arepotentially affected are outlined in the Table.Cross-sectional studies evaluating the cognitive function of chemotherapy-treated patients at asingle time point fail to take into account factors other than chemotherapy that may be contributingto a patient’s cognitive impairment. Studies using pre-chemotherapy assessments demonstrate afairly high prevalence of baseline cognitive dysfunction and allow for assessment of change overtime. The practice effect of repeat testing, as well as considerations such as age, comorbidity, andcognitive reserve may all influence the trajectory of cognitive changes over time, highlighting theimportance of including a control population which ideally consists of cancer patients who did notreceive chemotherapy as well as an age-matched healthy control population. Whileneuropsychological testing is valuable in the research setting, its role in evaluating individual patientconcerns is less clear, particularly as patient-reported complaints frequently do not correlate withobjective test results.Interactions between patient- reported cognitive concerns and objective neuropsychological testresults are complex, but there is strong evidence that chemotherapy may result in both subjectiveand objective cognitive dysfunction in the short-term. Memory, attention, psychomotor function,

of 10


processing speed, and executive function appear to be commonly affected.[39,25] There is alsoevidence that subsets of patients experience long-term cognitive effects after chemotherapytreatment; however, these effects generally appear to be modest in severity, and for the majority ofsurvivors, cognitive impairment will diminish over time. For patients with neurocognitive concerns,while pharmacologic therapies remain unproven in this setting, both cognitive rehabilitation withneurofeedback training and cognitive behavioral training show a potential for benefit. Also,acknowledgement by physicians that cognitive change may, indeed, be a consequence ofchemotherapy treatment, and reassurance that improvement over time is anticipated, can bevaluable for patients who may be concerned about the effects they are experiencing.Financial Disclosure: The author has no significant financial interest or other relationship with themanufacturers of any products or providers of any service mentioned in this article.

Table: Influences on Cognitive Function DomainsOver Time in Patients ...

References: 1. American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2014-2015. Atlanta:American Cancer Society; 2014. Available from: http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-042801.pdf.Accessed August 11, 2014.

2. Jean-Pierre P, Winters PC, Ahles TA, et al. Prevalence of self-reported memory problems in adultcancer survivors: a national cross-section study. J Oncol Pract. 2011;8:30-4.

3. Koppelmans V, Breteler MMB, Boogerd W, et al. Neuropsychological performance in survivors ofbreast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol. 2012;30:1080-6.

4. Ahles TA, Saykin AJ, McDonald BC, et al. Cognitive function in breast cancer patients prior toadjuvant treatment. Breast Cancer Res Treat. 2008;110:143-52.

5. Wefel JS, Saleeba AK, Buzdar A, Meyers CA. Acute and late onset cognitive dysfunction associatedwith chemotherapy in women with breast cancer. Cancer. 2010;116:3348-56.

6. Jansen CE, Cooper BA, Dodd MJ, Miaskowski CA. A prospective longitudinal study ofchemotherapy-induced cognitive changes in breast cancer patients. Support Care Cancer.2011;19:1647-56.

7. Cruzado JA, Lopez-Santiago S, Martinez-Marin V, et al. Longitudinal study of cognitive dysfunctionsinduced by adjuvant chemotherapy in colon cancer patients. Support Care Cancer. 2014;22:1815-23.

8. Wefel JS, Vidrine DJ, Veramonti TL, et al. Cognitive impairment in men with testicular cancer priorto adjuvant therapy. Cancer. 2010;117:190-6.

9. Tager FA, McKinley PS, Schnabel FR, et al. The cognitive effects of chemotherapy inpost-menopausal breast cancer patients: a controlled longitudinal study. Breast Cancer Res Treat.

of 10

http://www.cancernetwork.com/sites/default/files/figures_diagrams/1409mooreTable.gif

http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-042801.pdf


2010;123:25-34.

10. Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int. 2014;111:119-25.

11. Berman MG, Askren MK, Jung M, et al. Pretreatment worry and neurocognitive responses inwomen with breast cancer. Health Psychology. 2014;33:222-31.

12. Biglia N, Bounous VE, Malabaila A, et al. Objective and self-reported cognitive dysfunction inbreast cancer women treated with chemotherapy: a prospective study. Eur J Cancer Care. 21:485-492, 2012.

13. Mandelblatt JS, Stern RA, Luta G, et al. Cognitive impairment in older patients with breast cancerbefore systemic therapy: Is there an interaction between cancer and comorbidity? J Clin Oncol.2014;32:1909-18.

14. Hermelink K, Kuchenhoff H, Untch M, et al. Two different sides of ‘chemobrain’: determinantsand nondeterminants of self-perceived cognitive dysfunction in a prospective, randomized,multicenter study. Psycho-Oncology. 2010;19:1321-8.

15. Castellon SA, Ganz PA, Bower JE, et al. Neurocognitive performance in breast cancer survivorsexposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol. 2004;26:955-69.

16. Jenkins V, Shilling V, Deutsch G, et al. A 3-year prospective study of the effects of adjuvanttreatments on cognition in women with early stage breast cancer. Brit J Cancer. 2006;94:828-34.

17. Collins B, Mackenzie J, Stewart A, et al. Cognitive effects of chemotherapy in post-menopausalbreast cancer patients 1 year after treatment. Psycho-Oncology. 2009;18:134-43.

18. Tchen N, Juffs HG, Downie FP, et al. Cognitive function, fatigue, and menopausal symptoms inwomen receiving adjuvant chemotherapy for breast cancer. J Clin Oncol. 2003;21:4175-83.

19. Biglia N, Moggio G, Peano E, et al. Effects of surgical and adjuvant therapies for breast cancer onsexuality, cognitive functions, and body weight. J Sex Med. 2010;7:1891-1900.

20. Moore HCF, Parsons MW, Yue GH, et al. Electroencephalogram power changes as a correlate ofchemotherapy-associated fatigue and cognitive dysfunction. Support Care Cancer. 2014;22:2127-31.

21. Kreukels BPC, Schagen SB, Ridderinkhof KR, et al. Electrophysiologic correlates of informationprocessing in breast-cancer patients treated with adjuvant chemotherapy. Breast Cancer Res Treat.2005;94:53-61.

22. Ganz PA, Kwan L, Castellon SA, et al. Cognitive complaints after breast cancer treatments:examining the relationship with neuropsychological test performance. J Natl Cancer Inst.2013;105:791-801.

23. Conroy SK, McDonald BC, Smith, DJ, et al. Alterations in brain structure and function in breastcancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage. BreastCancer Res Treat. 2013;137:493-501.

24. Downie FP, Mar Fan HG, Houede-Tchen N, et al. Cognitive function, fatigue, and menopausalsymptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patientinterview after formal assessment. Psycho-Oncology. 2006;15:921-30.

25. Wefel JS, Vardy J, Ahles T, Schagen SB. International Cognition and Cancer Task Forcerecommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol.2011;12:703-8.

26. Zimmer P, Mierau A, Bloch W, et al. Post-chemotherapy cognitive impairment in patients withB-cell non-Hodgkin lymphoma: a first comprehensive approach to determine cognitive impairments

of 10


after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone orrituximab and bendamustine. Leuk Lymphoma. 2014 Jun 5:1-6. [Epub ahead of print]

27. Donovan KA, Small BJ, Andrykowski MA, et al. Cognitive functioning after adjuvant chemotherapyand/or radiotherapy for early-stage breast carcinoma. Cancer. 2005;104:2499-507.

28. Schagen SB, Muller MJ, Boogerd W, et al. Late effects of adjuvant chemotherapy on cognitivefunction: a follow-up study in breast cancer patients. Ann Oncol. 2002;13:1387-97.

29. Ahles TA, Saykin AJ, Furstenberg CT, et al. Neuropsychologic impact of standard-dose systemicchemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol. 2002;20:485-93.

30. Debess J, Riis JO, Engebjerg MC, Ewertz M. Cognitive function after adjuvant treatment for earlybreast cancer: a population-based longitudinal study. Breast Cancer Res Treat. 2010;121:91-100.

31. Andreis F, Ferri M, Mazzocchi M, et al. Lack of a chemobrain effect for adjuvant FOLFOXchemotherapy in colon cancer patients. A pilot study. Support Care Cancer. 2013;21:583-90.

32. Deprez S, Amant F, Smeets A, et al. Longitudinal assessment of chemotherapy-inducedstructural changes in cerebral white matter and its correlation with impaired cognitive functioning. JClin Oncol. 2012;30:274-81.

33. Ahles TA, Saykin AJ, McDonald BC, et al. Longitudinal assessment of cognitive changesassociated with adjuvant treatment for breast cancer: impact of age on cognitive reserve. J ClinOncol. 2010;28:4434-40.

34. Jim HSL, Phillips KM, Chait S, et al. Meta-analysis of cognitive functioning in breast cancersurvivors previously treated with standard-dose chemotherapy. J Clin Oncol. 2012;30:3578-87.

35. Mar Fan HG, Houede-Tchen N, Yi QL, et al. Fatigue, menopausal symptoms, and cognitivefunction in women after adjuvant chemotherapy for breast cancer: 1- and 2-year follow-up of aprospective controlled study. J Clin Oncol. 2005;23:8025-32.

36. McDonald BC, Conroy SK, Ahles TA, et al. Gray matter reduction associated with systemicchemotherapy for breast cancer: a prospective MRI study. Breast Cancer Res Treat.2010;123:819-28.

37. McDonald BC, Conroy, SK, Ahles TA, et al. Alterations in brain activation during working memoryprocessing associated with breast cancer and treatment: a prospective functional magneticresonance imaging study. J Clin Oncol. 2012;30:2500-8.

38. Conroy SK, McDonald BC, Ahles TA, et al. Chemotherapy-induced amenorrhea: a prospectivestudy of brain activation changes in neurocognitive correlates. Brain Imaging Behav.2013;7:491-500.

39. Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings andpotential interventions. Palliat Support Care. 2007;5:272-80.

40. Davis J, Ahlberg FM, Berk M, et al. Emerging pharmacotherapy for cancer patients with cognitivedysfunction. BMC Neurol. 2013;13:153.

41. Mar Fan HG, Clemons M, Xu W, et al. A randomised, placebo-controlled, double-blind trial of theeffects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvantchemotherapy for breast cancer. Support Care Cancer. 2008;16:577-83.

42. Barton, DL, Burger K, Novotny PJ, et al. The use of Ginkgo biloba for the prevention ofchemotherapy-related cognitive dysfunction in women receiving adjuvant treatment for breastcancer, N00C9. Support Care Cancer. 2013;21:1185-92.

of 10


43. Alvarez J, Fremonta LM, Granoff DL, Lundy A. The effect of EEG biofeedback on reducingpostcancer cognitive impairment. Integr Cancer Ther. 2013;12:475-87.

44. Ferguson RJ, Ahles TA, Saykin AJ, et al. Cognitive-behavioral management ofchemotherapy-related cognitive change. Psychooncology. 2007;16:772-7.

45. Ferguson RJ, McDonald BC, Rocque MA, et al. Development of CBT for chemotherapy-relatedcognitive change: results of a waitlist control trial. Psychooncology. 2012;12:176-86. Source URL: http://www.cancernetwork.com/oncology-journal/overview-chemotherapy-related-cognitive-dysfunction-or-chemobrain

Links:[1] http://www.cancernetwork.com/review-article[2] http://www.cancernetwork.com/oncology-journal[3] http://www.cancernetwork.com/breast-cancer[4] http://www.cancernetwork.com/palliative-and-supportive-care[5] http://www.cancernetwork.com/authors/halle-c-f-moore-md

of 10

http://www.cancernetwork.com/oncology-journal/overview-chemotherapy-related-cognitive-dysfunction-or-chemobrain

http://www.cancernetwork.com/oncology-journal/overview-chemotherapy-related-cognitive-dysfunction-or-chemobrain

an overview of chemotherapy-related cognitive dysfunction ... · following initial treatment,...

Documents