PALLIATIVE MEDICINE (A JATOI, SECTION EDITOR)

Clearing the Air: A Review of Our Current Understandingof “Chemo Fog”

Erin O’Farrell & Joyce MacKenzie & Barbara Collins

Published online: 13 March 2013# Springer Science+Business Media New York 2013

Abstract An increasing number of cancer survivors has led toa greater interest in the long-term side effects of cancer treat-ments and their impact on quality of life. In particular, cognitiveimpairments have been frequently reported by cancer survivorsas an adverse effect which they attribute to the neurotoxicity ofchemotherapy and have dubbed “chemobrain” or “chemo fog.”Research within the past 15–20 years has explored the manyfactors thought to contribute to cancer-related cognitive declinein an attempt to determine a potential cause. In spite of manyconfounding factors, there is growing evidence that the neuro-toxicity of chemotherapy does contribute to cognitive changes.This review examines the evolution of “chemo fog” researchwith a look at methodological issues, the status of our currentunderstanding, and suggestions for future research.

Keywords Chemo fog . Chemobrain .

Chemotherapy-related cognitive impairment . Cognitivefunction . Adjuvant chemotherapy

Introduction

Advances in cancer treatments have led to increased survivalrates and a growing number of individuals who are living withthe long-term side effects of cancer therapies. Cognitive de-cline is one of the most frequently reported adverse effectsamong cancer survivors [1]. Patients generally attribute thesecognitive disturbances to toxic effects of chemotherapy, as

implied by their use of terms such as “chemo fog” and“chemobrain.” However, in the early years of the adjuvantchemotherapy era, such symptoms were generally dismissedby the medical community as psychological rather than neu-rological. Although it was recognized that many chemothera-peutic agents could be acutely neurotoxic when delivereddirectly to the central nervous system, it was believed thatmost of these agents could not penetrate the blood–brainbarrier and thus were unlikely to cause neurotoxicity whenadministered systemically in the adjuvant setting.

Most studies of the cognitive effects of adjuvant systemicchemotherapy have been conducted primarily in breast cancer(BC) patients. These studies began to appear in the literature inthe latter half of the 1990s [2, 3], shortly following theestablishment of adjuvant chemotherapy as the new standardof care for treatment of most breast tumors. The study ofchemotherapy-related cognitive impairment (CRCI) has large-ly focused on patients with BC for several reasons, primarilyits high prevalence and generally good prognosis, such thatmany BC survivors expect to resume active, cognitively de-manding lives following treatment. These early efforts weregenerally small, local, retrospective, cross-sectional studiesand, although they were important in validating the cognitivecomplaints of cancer patients and impelling the research en-deavor, uncontrolled confounding factors prevented isolation ofthe specific effects of chemotherapy on cognition.

One of the most troublesome confounding factors was thisissue of psychological distress—cancer patients, particularlythose patients requiring chemotherapy, are at elevated risk ofanxiety and depression, both of which can undermine cognitivefunction. Other confounding factors include fatigue and effectsof anesthetic and surgery. One particularly important confound-er is the effect of medications and treatments given in conjunc-tion with cytostatic drugs that may, in and of themselves, affectcognition. Among these are palliative medications designed tomitigate the side effects of chemotherapy, including anti-

E. O’Farrell :B. CollinsSchool of Psychology, University of Ottawa, Ottawa, ON, Canada

J. MacKenzie : B. Collins (*)The Ottawa Hospital – Civic Campus, 1053 Carling Ave,Room A628,Ottawa, ON K1Y 4E9, Canadae-mail: bcollins@ottawahospital.on.ca

Curr Oncol Rep (2013) 15:260–269DOI 10.1007/s11912-013-0307-7

nauseants, anti-emetics, and anti-inflammatories, as well asother adjuvant treatments. In some two thirds of BC patients,their tumors express estrogen and/or progesterone receptorsand grow in the presence of these hormones [4]. An importantadjunctive treatment for these tumors is long-term (5 years ormore) anti-estrogen therapy (with or without cytostatic drugs).It is well established that estrogen acts in the brain to influencecognition [5, 6], and there is growing evidence to suggest thatthe hormonal therapies, which work either by blocking estro-gen receptors or by preventing estrogen synthesis, have adetrimental effect on cognitive functioning [7–17].

Careful attention to study design and methodology is re-quired to address these many confounding factors. Therefore,key researchers in this field formed the International Cognitionand Cancer Task Force (ICCTF) [18] in 2006 to establishguidelines for harmonizing study methodologies, thereby pro-moting more comparable findings among studies [19•]. As aresult, we are now able to provide at least partial answers tosome of the most frequently asked questions concerning CRCI.This article will review current methodological issues andrecommendations and the status of our knowledge with regardto these frequently asked questions.

Methodological Considerations

Cross-Sectional Versus Longitudinal Designs

One of the major limitations to the early studies on CRCI wasthat they were retrospective and cross-sectional in design andthus could not distinguish chemotherapy-induced cognitivechanges from pretreatment cognitive disturbances related tohost or disease factors. These studies were prey to bothoverestimation and underestimation of CRCI. Overestimationwas a particular risk in studies that used a healthy controlgroup because, as later prospective studies demonstrated, upto 35 % of BC patients showed pretreatment cognitive impair-ment which would have been misattributed to chemotherapyin these cross-sectional designs [20–22]. On the other hand,cross-sectional designs failed to detect pretreatment-to-posttreatment cognitive decline in up to 46 % of individualswho, because of high premorbid function, still scored withinthe normal range on posttreatment cognitive testing [22]. Inmost cases, the ICCTF recommends prospective longitudinalstudies [19•].

Control Groups

An important methodological consideration is the nature of thecontrol group used. In retrospective, cross-sectional studies inwhich patients are assessed at a single point in time aftercompleting chemotherapy, a disease control group is essentialto account for a number of factors besides treatment that may

influence cognition, such as constitutional and genetic riskfactors for cancer, psychological distress associated with acancer diagnosis, and biological changes associated with thedisease itself (as noted already, cancer patients are at increasedrisk of cognitive disturbance before any exposure to adjuvanttherapy). A disadvantage to the disease control group is the factthat those patients who are not receiving chemotherapy may bereceiving alternative treatments, such as anti-estrogen therapy,that may, in themselves, affect cognition [7–9, 11–17].

In prospective within-subject designs, repeated measure-ment of the same subject before and after treatment serves tocontrol for stable host and disease factors. One importantdisadvantage of this approach is that practice effects associatedwith repeated testing of an individual can mask subtle adverseeffects of treatment. Investigators attempt to mitigate this byusing parallel alternative forms of tests but practice effectsencompass far more than just content-based savings (e.g.,reduced anxiety, an established strategy) and, thus, it is stillimportant to include a control group to measure and accountfor these effects. In fact, without a control group, it may evenappear that cancer patients’ cognition improves after chemo-therapy [22]. The ICCTF recommends inclusion of both adisease control group and a healthy control group even inprospective longitudinal studies (in the event that the practiceeffect may be different in cancer patients from that in healthyindividuals) [19•]. However, we have empirically addressedthe issue of control groups. We obtained the same results withour longitudinal data whether we used a disease control group,a healthy control group, or published norms (unpublishedobservations).

Approach to Data Analysis

The effect sizes in this field are typically quite modest and,thus, the data analytic techniques used can significantly influ-ence the conclusions drawn from a particular study. One keydifference among studies is whether data are analyzed at theaggregate level (e.g., comparing group means) or at the levelof individual impairment or decline (comparing the frequencyof impairment or decline across groups). In that CRCI affectsonly a subgroup of patients, these subtle effects can be easilyobscured in comparing group means. Several studies havefailed to find group differences in mean cognitive functionbut have found significant differences in the frequency ofcognitive impairment or decline between the chemotherapyand control groups [22, 23]. However, as elegantly demon-strated by Shilling et al. [24] and Schilder et al. [21], the use ofdifferent definitions of impairment (e.g., the extent of negativechange in a given score as well as how many scores showingdecline would constitute impairment) greatly influences esti-mates of risk. The ICCTF generally recommends that, in orderto be considered impaired, the standardized scores on a givenmeasure should be −1.5 or lower and that the number of such

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scores required to consider a given participant cognitivelyimpaired should be determined in accordance with the prob-ability of obtaining such a result by chance given the size ofthe test battery [19•].

When data are analyzed at the aggregate level, longitudinalmodeling techniques are recommended over analysis of vari-ance or t tests, in that they allow for differing numbers andspacing of assessments across respondents and are more ro-bust to violation of assumptions [19•]. Different statisticalapproaches have been taken to evaluate decline at the individ-ual level. The ICCTF recommends approaches that accountfor practice effects, such as the reliable change index withpractice effects model or regression-based change models[19•]. We have argued in favor of the latter because it allowsthe inclusion of important covariates [25]. Differences amongstudies in the choice of covariates used in the analysis mayalso contribute to inconsistency in results. Most studies haveincluded, as a minimum, measures of mood and fatigue, andthis would seem advisable.

Cognitive Measures Used

Another critical issue concerns whether cognition is assessedsubjectively, by means of a self-report questionnaire, or ob-jectively, by means of performance-based neuropsychologicaltesting. In most cases, subjective measures of cognitive im-pairment correlate poorly, if at all, with objective measures,indicating a need to include both [26–30]. Among neuropsy-chological studies, the size and composition of the test batterydiffers widely. The selection of tests can contribute tooverestimation or underestimation of true cognitive impair-ment [24]. Many neuropsychological tests may not be sensi-tive enough to detect the subtle changes associated withchemotherapy or may fail to target the affected cognitivedomains. For example, basic mental status screening testsare probably not sensitive enough for this purpose [31]. Thenumber of neuropsychological measures used may also be acritical determinant of study outcome as the likelihood offinding an impaired score or abnormal decline in a score willgenerally increase in keeping with the size of the test battery[32]. The ICCTF has recommended a core battery of neuro-psychological measures that are well validated, sensitive tothe types of deficits observed in cancer patients, andappropriate for multinational use [19•].

What Do We Know Now?

Is There an Association Between Chemotherapy Exposureand Cognitive Disturbance?

Despite considerable variability in methodology and find-ings, most of the studies done in this area over the past

20 years support the idea that chemotherapy-exposed BCpatients are at increased risk of cognitive dysfunction. Wefeland Schagen [33] recently tabulated results of studiesconducted in BC patients between 1995 and 2012 and foundthat 78 % of cross-sectional studies (n = 23) and 69 % ofprospective longitudinal studies (n = 26) found evidence insupport of CRCI.

Is the Cognitive Disturbance Causedby Chemotherapy-Related Neurotoxicity?

It is now quite clear that many factors contribute to cognitivedisturbances in cancer patients, including anxiety, depression,hormonal fluctuations, fatigue, other treatments, and the dis-ease itself. Recent prospective studies find cognitive dysfunc-tion in a substantial portion of cancer patients even prior tostarting adjuvant therapy [20, 21]. MRI measures of brainstructure and function have also shown pretreatment differ-ences between cancer patients and healthy controls [20,34–36] which cannot be fully accounted for by depression,anxiety, fatigue, or surgical factors, suggesting that they maybe due to the disease itself. In recognition of this, it has beensuggested that terms such as “chemofog” and “chemobrain”be replaced with a more encompassing term such as “cancer-or cancer-therapy- related cognitive change” [37]. At the sametime, there is also mounting evidence that chemotherapyexposure is a significant contributing factor to cognitivesymptoms in cancer survivors.

As recently as 8–10 years ago, a BC patient complainingof cognitive disturbances during chemotherapy was likely tobe prescribed an antidepressant. This belief that cognitivedisturbances were psychogenic was supported by the factthat most studies found poor, if any, correlation betweenpatients’ subjective reports of cognitive disturbance andobjective measures of cognitive performance [26–30]. Sub-jective complaints were found to correlate more stronglywith measures of emotional state, reinforcing this idea thatwhat a patient referred to as chemo fog was a psychologicalreaction to stress. However, recent findings suggest that thepoor correlation between subjective and objective cognitivemeasures may have to do with fundamental differences inmeasurement parameters [29]. It seems likely that patients’self-assessments capture perceived decline from premorbidfunction, whereas, in most cases, the neuropsychologicalscores do not (typically, static scores are used in thesecorrelations). In analyzing our own data, we found that anobjective pretreatment–posttreatment measure of cognitivechange did correlate with subjective reports, whereas a one-time posttreatment objective measure did not (unpublishedobservations). Deprez et al. [38••] also found a significantcorrelation between objective and subjective measures whenusing a cognitive change score. It has also been suggestedthat subjective and objective measures often tap different

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cognitive domains and that this may contribute to their poorcorrelation. In relating subjective complaints to neuropsy-chological test scores, Deprez et al. also focused on specific,relevant, and compatible cognitive domains. Other investi-gators who have taken this more focused approach [7, 39]have also found significant subjective–objective correla-tions. Moreover, although cognitive complaints do tend tocorrelate with emotional functioning, most studies find thatthis cannot fully account for the objective neuropsycholog-ical abnormalities [2, 23, 27, 33, 40••, 41]. Clearly, there ismore to the story than psychological distress.

Increasingly sophisticated clinical studies, supplementedby animal and brain imaging research, are producing objec-tive evidence that chemotherapy is neurotoxic and can con-tribute to cognitive disturbances. An early study by vanDam et al. [3] hinted at this, by suggesting a dose–responserelationship. They compared cognitive function in high-riskBC patients who had been randomly assigned to receivehigh-dose or standard-dose chemotherapy and in early-stageBC patients receiving no systemic adjuvant treatment. Thisstudy, conducted an average of 2 years after completion ofchemotherapy, revealed a significant difference among thegroups in risk of cognitive impairment, with 32 % of thehigh-dose group showing cognitive impairment comparedwith 17 % of the standard-dose group and 9 % of the controlgroup. In a follow-up to that study, these investigators alsoshowed that their high-dose group was significantly morelikely to show late electrophysiological abnormalities [42,43] than the control patients, with the risks in the standard-dose group falling somewhere in between. This group hascorroborated their findings in a prospective randomizedcontrolled study which showed that BC patients receivinghigh-dose therapy were at a significantly elevated risk ofcognitive decline, whereas the standard-dose group was not[44]. Other cross-sectional studies have identified durationof treatment and number of chemotherapy cycles as riskfactors for cognitive disturbance [2, 26, 45]. Magnetic res-onance spectroscopy studies in BC patients have shownwhite matter abnormalities following high-dose chemother-apy that were not detectable following lower-dose inductionchemotherapy [46–48].

We capitalized on this notion of “dose–response” rela-tionship as an approach to establishing causality in our latestprospective longitudinal study [40••]. We assessed BC pa-tients after each cycle of chemotherapy and observed alinear decline in cognitive function even after controllingfor baseline performance, practice effects, and changes inmood and fatigue. We submit that this clear dose–responserelationship strongly suggests that chemotherapy is indeed acause of cognitive disturbance.

Compelling evidence of chemotherapy neurotoxicity alsocomes from animal studies, which allow tighter control ofthe factors that confound clinical research. These studies

have shown persistent performance decrements in animalmodels of learning and memory following exposure to che-motherapeutic agents, as well as decreased neurogenesis andcellular proliferation and increased cellular death withinareas of the brain such as the hippocampus and thesubventricular zone [49, 50].

Further causal evidence for the neurotoxicity of chemo-therapy comes from structural and functional neuroimagingstudies, which show differences in cerebral blood flow[51–53] and in the volume of white and grey matter inchemotherapy-treated BC patients compared with controls[38••, 46–48, 54–59]. A landmark neuroimaging study wasthat of McDonald et al. [60••] as it was the first controlledprospective MRI study in the field. They found significantdecreases in gray matter density in bilateral frontal, tempo-ral, and cerebellar regions as well as the right thalamus inBC patients shortly following completion of chemotherapythat were not evident in either a disease or healthy controlgroup. These changes could not be accounted for in terms ofpostsurgical effects, disease stage, psychiatric symptoms,psychotropic medication, or hormonal treatment status,suggesting that they were due to the effects of chemotherapy.New techniques such as diffusion tensor imaging (DTI) arecontributing to a better understanding of the nature and scopeof the underlying structural changes and suggest that whitematter may be particularly vulnerable to the neurotoxic effectsof chemotherapy and that changes in white matter functionmay persist for years after completion of treatment [55].

Functional MRI (fMRI) and positron emission tomogra-phy (PET) studies have also been conducted in cancerpatients. These studies show patterns of brain activation inresponse to a cognitive challenge and provide a “window onthe working brain.” Abnormalities have been observed in anumber of brain areas in response to a variety of activationtasks. For example, increased activation in the prefrontalcortex and the cerebellum has been observed in patientsduring a working memory task [53]. Increased activation hasbeen interpreted as an indication that the brain is having tocompensate for insult by recruiting a wider neural networkthan would normally be required to support the task. Theseaberrations in neural activation patterns can be observed in theabsence of differences in performance on the cognitive activa-tion tasks and may account for patient complaints of cognitivedecline in the absence of actual performance decrements (i.e.,theymay experience their cognitive processing as less efficientand more tiring). Regional decreases in brain activation havealso been observed, and are construed as evidence that thedamage to the brain has surpassed its capacity to compensate.

Neuroimaging studies in this field are restricted by thesame methodological flaws that characterized the early neu-ropsychological studies, including the failure to conductpretreatment baseline assessment. Studies by our group re-vealed significant pretreatment differences in white and grey

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matter volume (whole brain and regional) between patientsand controls [36], as well as in brain activation patterns onfMRI [34, 35], emphasizing the importance of prospectivelongitudinal designs. We have published one of the first pro-spective longitudinal fMRI studies in BC patients [61], whichshowed abnormal changes in the activation pattern inchemotherapy-treated patients and thus lends further supportto the idea that chemotherapy affects neural function.

Functional imaging studies, although holding great prom-ise, are in their infancy and the significance of the findings isdifficult to interpret. For example, both increases and decreasesin brain activation are construed as evidence of brain dysfunc-tion, and high numbers of comparisons are conducted in smallsamples, raising concerns about inflated type I error rates.Improvement of this situation will require that studies becomemore focused and hypothesis-driven.

The recent study of Deprez et al. [38••] constitutes a sig-nificant advance in the imaging literature and a model forfuture studies. It is one of the first studies to examine relation-ships between changes in neuropsychological and neuroim-aging measures in a well-controlled prospective design.Thirty-five BC patients who received chemotherapy, as wellas a group of cancer patients not treated with chemotherapyand a healthy control group, were repeatedly assessed with acomprehensive neuropsychological battery and DTI. The re-sults showed significant decline in white matter integrity inmultiple tracts involved in cognition, significant decreases onneuropsychological tests of attention and memory, and signif-icant correlations between the neuropsychological and imag-ing results in the chemotherapy group. This cross-validationfrom the neuropsychological and imaging investigations ismuch more compelling than either finding in isolation.

What Is the Frequency/Rate of Occurrence of CRCI?

There is general consensus among researchers that only asubgroup of BC patients develop CRCI; however, the esti-mated rate of impairment ranges from 17 to 78 % [33].Clearly, this variation has to do with the aforementionedmethodological differences. In a recent longitudinal studyconducted by our group that met the recommendations ofthe ICCTF [40••], we found that approximately one third ofpatients showed cognitive decline over the course of theirchemotherapy. This is in close agreement with a previouslongitudinal study conducted by our group [23] and withfigures reported by Jansen et al. [62].

What Cognitive Domains Are Impaired?

All cognitive and psychomotor domains have been impli-cated in one study or another [26, 40••, 63–67]. Disagree-ment among studies as to the most vulnerable cognitivedomains is primarily due to the multifactorial nature of

neuropsychological tests and the relatively arbitrary assign-ment of a given test to a particular cognitive domain. In ourrecent longitudinal study [40••], we assigned tests to cogni-tive domains on empirical grounds by means of principalcomponents analysis. This resulted in four cognitive factorswhich seemed to correspond to processing speed, workingmemory, visual memory, and verbal memory. We obtained alarge effect size for working memory and processing speed,and significant but small effect sizes for the domains ofvisual memory and verbal memory. This fits well withpatients’ self-reports of diminished cognitive efficiencyand difficulties with multitasking. It is also consistent withresults of recent imaging [38••, 54, 56] and animal [49]studies showing that the toxic effects of chemotherapymay affect white matter. Alternatively, working memoryand processing speed scores may have been more sensitivebecause they were time-dependent and because very subtlecognitive deficits may be better captured by speed than byaccuracy of response. For this reason, computerized testingis attracting increasing interest from researchers in this fieldbecause it allows for accurate measurement of response timein milliseconds.

It could well be that chemotherapy-related neurotoxicityresults in a generalized decrease in mental processing speedand capacity rather than focal cognitive deficit and that thismay be manifested in preexisting areas of weakness that willdiffer from one individual to another. This could partlyaccount for why studies are more likely to find significanteffects if impairment is analyzed at the individual levelindependently of a specific cognitive domain.

What Is the Severity and Duration of CRCI?

Meta-analyses of BC studies [12, 68, 69, 70•, 71] consis-tently yield small to moderate effect sizes (−0.2 to −0.5range), indicating a subtle negative effect of chemotherapyon cognitive functioning. Anderson-Hanley et al. [72] foundlarger effect sizes (approaching 1.0 in the domains of exec-utive function and verbal memory), but their analysis in-cluded studies of various cancer populations and covered abroader range of disease severity.

Retrospective, cross-sectional studies have found evi-dence of impaired cognitive functioning in BC patients aslong as 21 years after treatment [51, 73], and irregularities inbrain structure and function have also been reported in long-term BC survivors 4–21 years after treatment. Functionaldifferences include altered activation patterns on fMRI [51]and PET [53] and lower amplitude and increased latency ofthe P3 component in electrophysiological studies [42,74–76]. Structural studies using various MRI techniques(voxel-based morphometry, spectroscopy, DTI) show reduc-tions in brain volume [55, 59], axonal injury, and decreasedwhite matter integrity [55]

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More recent prospective longitudinal studies with mid-range to long-range follow-up (9 months to 4 years) gener-ally find that CRCI remits after termination of chemothera-py [26, 63, 77, 78]. However, there appears to be a smallsubgroup showing more intractable cognitive dysfunction[78], and one recent prospective longitudinal study [79]indicated the occurrence of new, delayed cognitive declinein 29 % of patients following treatment completion (wequestion if this might be partly due to postchemotherapycommencement of hormonal therapy). Recent epidemiolog-ical studies have looked at whether or not chemotherapyexposure is a risk factor for the later development of de-mentia. Heflin et al. [80] found that, among 486 monozy-gotic geriatric twin pairs discordant for cancer, long-termcancer survivors were twice as likely to be diagnosed withdementia as their unaffected sibling. In very large cohorts ofelderly BC survivors, Heck et al. [81] found a significantlyhigher risk of dementia in women treated with chemothera-py than in those patients not exposed to chemotherapy,whereas Baxter et al. [82] reported that past chemotherapywas not associated with a greater risk of developingdementia and Du et al. [83] found that dementia risk wassignificantly lower in patients who had received chemo-therapy in the past. We simply do not know yet whether ornot chemotherapy exposure increases the risk of dementialater in life.

What Is the Impact of CRCI in Everyday Life?

In an online survey conducted in 2010 by the CanadianBreast Cancer Network to determine the economic impactof BC, it was determined that chemotherapy had importanteconomic implications for survivors. Among some 450 re-spondents—women with a BC diagnosis in the previous5 years—8 % reported that “chemobrain” was a significantbarrier to returning to work. Those women who had re-ceived chemotherapy had the greatest reduction in house-hold income, had taken more time off work (as had theirfamily members), were more likely to have had to quit theirjobs, and had a greater perception that the financial burdenimposed by their illness would impact their long-termhealth. Chemotherapy exposure also emerged as a signifi-cant predictor of work changes after cancer in a population-based study with a more heterogeneous cancer population[84]. Smaller cohort studies of BC patients that includedneuropsychological testing have reported an association be-tween cognitive functioning and work-related outcomes(perceived ability to work and actual likelihood of returnto work) [22, 85]. Reid-Arndt et al. [86] reported an associ-ation between executive functioning deficits and decreasedproductivity, community involvement, and social role func-tioning in BC patients 1 month after chemotherapy. In sum,evidence is beginning to accrue that, although CRCI may be

subtle, it has important functional implications and canadversely affect quality of life for cancer survivors.

What Are the Risk Factors for CRCI?

In their recent prospective longitudinal study, Ahles et al.[63] found that older age and lower cognitive reserve wererisk factors for short-term treatment-related reductions inprocessing speed, and that additional treatment with hor-monal therapy was a risk factor for more persistent declinein verbal ability. The results of our initial study were com-patible with this, likewise indicating that lower educationallevel (considered an index of cognitive reserve) was a riskfactor for short-term decline [23] and that patients who wenton to receive hormonal therapy after chemotherapy weremore likely to show persistent decline at the 1-year follow-up [77]. Wefel et al. [79] found that the delayed declineobserved in almost one third of their participants was relatedto baseline performance, further hinting at neural reserve asa risk factor for long-term deficits. At the same time, otherstudies have failed to find any correlation between CRCIand age or cognitive reserve (at least as reflected in educa-tion) [33]. There may also be genetic risk factors for CRCI.Ahles et al. [87] found that, among long-term survivors ofBC and lymphoma treated with chemotherapy, those whocarried an ε4 allele of the apolipoprotein E gene (which is agenetic risk factor for other cognitive disorders, includingAlzheimer’s disease) scored lower on cognitive tests thanthose without an ε4 allele. However, to our knowledge,these results have not been replicated. Higher dose of che-motherapy, whether we are talking about dose intensity [3]or cumulative dose [2, 40••] is a well-established risk factor.Most prospective studies find no association between cog-nitive and menopausal status, although Jenkins et al. [88]reported that BC patients who experienced a chemotherapy-induced menopause were more likely to show cognitivedecline over the course of treatment than those who didnot. As noted, most studies fail to find a correlation betweencognitive change and psychological factors, such as depres-sion, anxiety, and fatigue [26, 33]. The differential riskassociated with specific chemotherapeutic agents and regi-mens is not well characterized as yet. This awaits largermultisite studies with sufficient sample sizes to provideadequate power for this type of subgroup analysis.

Conclusions and Future Directions

Although complaints of “chemo fog” have existed since theinstitution of systemic adjuvant chemotherapy, it is only inthe last 15–20 years, with increasing use of adjuvant che-motherapy and a growing cohort of cancer survivors with afocus on quality of life, that we have seen serious systematic

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study of this problem. It has proved to be a rather elusivephenomenon—it seems that only a subgroup of patients areaffected and the cognitive changes are generally subtle. As aresult, methodological variations from study to study cangreatly influence whether or not cognitive changes aredetected. Furthermore, there are a host of other factors thatcan influence cognition in cancer patients—anxiety, mooddisturbance, other medications, and biological responses tothe disease itself—and confound the study of CRCI. In spiteof this, with increasing collaboration among researchers andresulting refinement and harmonization of study methods,the “fog” surrounding chemo fog is beginning to clear.

The preponderance of studies shows that cancer patientsare at increased risk of mild cognitive impairment. In manyinstances, abnormalities can be detected even prior to com-mencement of systemic adjuvant treatment, suggesting thatfactors other than chemotherapy contribute to these cogni-tive changes. However, a prospective study that controlledfor practice effects indicated that about one third of BCpatients, the most widely studied population, show signifi-cant cognitive decline over the course of treatment. Al-though many of these women still score within normallimits on neuropsychological testing after chemotherapy,there is now some evidence to suggest that the decline issufficient to affect quality of life (e.g., return to work) forsome individuals. Given the impossibility of doing random-ized controlled trials in this field, the type and duration oftreatment are inextricably confounded with host and diseasecharacteristics, making it very difficult to establish whetherchemotherapy is truly a causative factor. However, datafrom animal studies and from imaging studies, along withevidence of a dose–response relationship between chemo-therapy and cognitive disturbance, strongly indicate thatsystemic chemotherapy can be neurotoxic and that its effectson the central nervous system do contribute to the cognitivechanges. Psychological distress—long thought to be respon-sible for the cognitive changes in cancer patients—does notprove to be significantly related to the neuropsychologicalchanges. Longitudinal studies that extend beyond the end oftreatment suggest that, in most cases, CRCI abates over time[77, 89]. However, both cross-sectional and longitudinalstudies indicate that there may be a small subgroup ofpatients who experience more chronic, perhaps even perma-nent, cognitive changes. The risk factors for this are still notwell understood but may include chemotherapy dose andneural reserve. At this time, there is no evidence to suggestthat chemotherapy exposure increases the risk of developingdementia later in life.

An understanding of the potential cognitive side effectsof cancer treatment is critical to making informed decisionsabout treatment, particularly for patients with a good prog-nosis for whom adjuvant chemotherapy minimally reducesthe risk of disease-free survival. It is, moreover, important

that we screen for CRCI in our patients so that we canprovide education, support, reassurance, and interventionfor those patients who are affected. Future studies shouldaim to provide a better understanding of the relative neuro-toxicity of specific chemotherapeutic agents and regimensused in the adjuvant setting as well as host factors whichplace a given individual at risk of developing cognitive sideeffects, as such information can be used to personalizetreatment recommendations. Further study of the mecha-nisms of neurotoxicity is also a priority for future research,as this will guide the development of neuroprotective andpreventive strategies. Ultimately, we will seek to developnew chemotherapeutic drugs with minimal neurotoxicityand, towards this aim, we should consider routinely includ-ing cognitive testing as a secondary outcome in chemotherapydrug trials.

Conflict of Interest Erin O’Farrell declares no conflict of interest.Joyce MacKenzie declares no conflict of interest.Barbara Collins declares no conflict of interest.

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