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Either Called “Chemobrain” or “Chemofog,” the Long-Term Chemotherapy-Induced Cognitive Decline in Cancer Survivors Is Real

Open ArchivePublished:September 14, 2010DOI:https://doi.org/10.1016/j.jpainsymman.2010.04.021

      Abstract

      Context

      In recent years, there is growing evidence in the medical literature to support an association between administration of commonly used chemotherapeutic agents and an increased risk for cognitive impairment.

      Objectives

      We herein critically summarize data relating to the pathophysiological mechanisms by which chemotherapy may induce cognitive impairment in patients surviving from solid tumors. The clinical and epidemiological characteristics and the proposed management strategies to counter chemotherapy-induced cognitive impairment (CICI) also are presented.

      Methods

      References for this review were identified by searches of PubMed from 1995 until December 2009 with related terms.

      Results

      Both the pathogenetic mechanisms and the overall clinical nature of CICI remain vaguely defined. Findings indicate that CICI is a relatively common event that, in most of the cases, remains underdiagnosed, thereby adversely affecting the quality of life of patients with cancer. Effective pharmacological interventions toward the symptomatic or prophylactic management of CICI also are lacking.

      Conclusion

      Either called “chemobrain” or “chemofog,” the long-term CICI in cancer survivors is real. The need for multidisciplinary care interventions toward a timely diagnosis and management of CICI is clearly warranted.

      Key Words

      Introduction

      In recent years, there has been growing evidence in the medical literature to support an increased incidence of cognitive decline in cancer survivors, resulting from chemotherapy. Chemotherapy-induced cognitive impairment (CICI), also called “chemobrain” or “chemofog,” is currently recognized as a relatively common adverse effect of chemotherapeutic agents typically administered to treat various types of solid tumors, mainly breast, lung, prostate, and ovarian cancers.
      • Sioka C.
      • Kyritsis A.P.
      Central and peripheral nervous system toxicity of common chemotherapeutic agents.
      CICI is defined as the impairment of patients’ memory, learning, concentration, reasoning, executive function, attention, and visuospatial skills during and after discontinuation of chemotherapy. In most of the cases, it has a subtle manifestation and induces short-term transient sequelae. However, a number of chemotherapeutic agents given either as monotherapy or in combination regimens commonly exert, in individual cases, sustained, long-term cognitive side effects, thereby further adversely affecting the quality of life (QOL) of patients with solid tumor cancer.
      • Ferguson R.J.
      • Ahles T.A.
      Chemotherapy associated cognitive impairment in patients with cancer and cancer survivors.
      The vulnerability to and overall nature of CICI remains vaguely defined, mainly because of the presence of several interacting pathogenetic mechanisms by which chemotherapy may impact the cognitive ability of cancer survivors. Current knowledge also indicates the implication of various genetic and other confounding factors in the genesis of CICI.
      • Saykin A.J.
      • Ahles T.A.
      • McDonald B.C.
      Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives.
      In addition, limitations in available research studies on the topic significantly contribute to a lack of agreement about the definition and characterization of CICI as a clinical entity.
      • Anderson-Hanley C.
      • Sherman M.L.
      • Riggs R.
      • Agocha V.B.
      • Compas B.E.
      Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature.
      This review critically looks at the biological mechanisms, incidence, risk factors, diagnosis, characteristics, and management of cognitive impairment associated with commonly used chemotherapeutic agents for solid tumors. We also highlight areas of future research to pursue.

      Search Strategy and Selection Criteria

      References for this review were identified by searches of PubMed from 1995 until December 2009 with the terms “chemotherapy and cognitive impairment,” “chemobrain,” “chemofog,” “chemotherapy-induced central neurotoxicity,” “breast cancer and cognitive changes,” “chemotherapy-induced cognitive changes,” and “treatment of chemotherapy-induced cognitive changes.” Articles also were identified through searches of the authors’ own files. Only articles published in English were reviewed.

      Pathogenesis of Chemotherapy-Induced Cognitive Impairment

      The pathogenesis of cognitive impairment in patients with cancer treated with chemotherapy is largely unknown.
      • Ahles T.A.
      • Saykin A.J.
      Candidate mechanisms for chemotherapy-induced cognitive changes.
      Its etiology is likely multifactorial through interacting mechanisms that cause either direct or indirect effects on the central nervous system (CNS) and cognitive ability of patients.
      A genetic predisposition appears to play a significant role in determining and possibly predicting the long-term cognitive decline in cancer patients. It has previously been reported that those cancer survivors specifically having the allele e4 of the apolipoprotein E (APOEe4) are at increased risk to manifest a more significant cognitive deficit compared with patients who have other APOE alleles.
      • Anderson-Hanley C.
      • Sherman M.L.
      • Riggs R.
      • Agocha V.B.
      • Compas B.E.
      Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature.
      • Ahles T.A.
      • Saykin A.J.
      Candidate mechanisms for chemotherapy-induced cognitive changes.
      In any case, the identification of a potent genetic biomarker to predict patients at high risk of developing chemotherapy-induced cognitive changes is still lacking, and, therefore, further study is needed on this very important issue.
      Commonly used chemotherapy agents are unable to cross the blood-brain barrier (BBB) in significant amounts. However, genetic variability in transporters of the BBB can alter its structure, thus allowing small doses of chemotherapy to enter the brain parenchyma. Particularly, patients having alleles associated either with lower-efficiency DNA-repair mechanisms or less-efficient efflux pumps, such as the gene multidrug resistance 1, encoding the protein P-glycoprotein, are considered most vulnerable to manifesting CICI.
      • Hoffmeyer S.
      • Burk O.
      • von Richter O.
      • et al.
      Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
      It previously has been demonstrated that even fairly small doses of chemotherapy are toxic to brain structures related to cognition, inducing cell death and reduced cell division.
      • Vardy J.
      • Wefel J.S.
      • Ahles T.
      • Tannock I.F.
      • Schagen S.B.
      Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop.
      Nevertheless, the effect attributed to drugs unable to cross the intact BBB (e.g., platinum drugs and taxanes) indicates a putative mechanism of action.
      Some commonly used conventional chemotherapy is able to penetrate the BBB, such as 5-fluorouracil. These drugs can cause direct neurotoxic damage to the CNS and, thus, decline of cognitive function in cancer survivors through injury of the microglia, oligodendrocytes, neuronal axons and subsequent demyelination, and alterations in water content and neurotransmitter levels.
      • Vardy J.
      • Wefel J.S.
      • Ahles T.
      • Tannock I.F.
      • Schagen S.B.
      Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop.
      Studies have demonstrated that several cytostatic agents, such as 5-fluorouracil, carmustine, cisplatin, and cytarabine, are toxic for CNS progenitor cells and oligodendrocytes, and that 5-fluorouracil causes delayed myelin damage.
      • Dietrich J.
      • Han R.
      • Yang Y.
      • Mayer-Pröschel M.
      • Noble M.
      CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.
      Toxicity to progenitor cells within the CNS after chemotherapy might be a critical biological mechanism of delayed and long-term neurotoxicity and may offer a compelling explanation for cognitive impairment in cancer survivors.
      • Dietrich J.
      • Han R.
      • Yang Y.
      • Mayer-Pröschel M.
      • Noble M.
      CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.
      Hormonal changes secondary to chemotherapy-induced menopause also can indirectly adversely affect the cognitive function of patients because of the decreased levels in the neuroprotective estrogen hormones. In addition, patients treated with hormonal therapies for prostate and breast cancer may experience cognitive decline because of reduced testosterone and estrogen levels.
      • Ahles T.A.
      • Saykin A.J.
      Candidate mechanisms for chemotherapy-induced cognitive changes.
      The antioxidant and neuroprotective effects of testosterone and estrogens, and the importance of estrogens in maintaining telomere length, are highlighted in several trials,
      • Vardy J.
      • Rourke S.
      • Tannock I.F.
      Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research.
      which suggest that reduced concentrations of these hormones secondary to hormonal therapy can cause CICI even when given as monotherapy without chemotherapy.
      However, further investigations are needed to assess the long-term effects of hormonal therapies on the cognitive ability of cancer survivors, as recent literature also contains conflicting reports. A prior study of 110 patients with breast cancer failed to reveal a significant association between either hormone level or menopausal symptoms, with induction of cognitive dysfunction after administration of adjuvant chemotherapy.
      • Tchen N.
      • Juffs H.G.
      • Downie F.P.
      • et al.
      Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer.
      In any case, accurate conclusions on this topic can only be safely drawn after the completion and publication of large continuing adjuvant trials.
      DNA damage affecting the CNS secondary to increased oxidative stress also has been proposed as another potential mechanism of CICI.
      • Ahles T.A.
      • Saykin A.J.
      Candidate mechanisms for chemotherapy-induced cognitive changes.
      • Blasiak J.
      • Arabski M.
      • Krupa R.
      • et al.
      Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer.
      Oxidative stress is mainly caused by an imbalance between the production of reactive oxygen, which includes free radicals and peroxides. Specifically, free radicals are known to be produced as a result of exposure to exogenous toxins. Alternatively, some free radicals arise normally during endogenous metabolism to neutralize viruses and bacteria.
      • Valko M.
      • Leibfritz D.
      • Moncol J.
      • et al.
      Free radicals and antioxidants in normal physiological functions and human disease.
      Considering that the long-term effects of free radicals are represented by damage on DNA, there are several lines of evidence to support that chemotherapy can cause reduced antioxidant capacity and point mutations in mitochondrial DNA, thus leading to cognitive decline.
      • Ahles T.A.
      • Saykin A.J.
      Candidate mechanisms for chemotherapy-induced cognitive changes.
      • Wardell T.M.
      • Ferguson E.
      • Chinnery P.F.
      • et al.
      Changes in the human mitochondrial genome after treatment of malignant disease.
      Additionally, it has previously been proposed that the increased formation of byproducts of oxidative stress because of chemotherapy induces cumulative damage (blood clotting) to blood vessels in the CNS through mechanisms implicating interference with blood perfusion and flow to the small vessels of the CNS.
      • Barton D.
      • Loprinzi C.
      Novel approaches to preventing chemotherapy-induced cognitive dysfunction in breast cancer: the art of the possible.
      Cancer-related anemia, a very common side effect of cancer and/or chemotherapy, also has been proposed as capable of inducing a variety of debilitating symptoms, including cognitive impairment and worse visual memory and executive function tasks, through decreased cerebral oxygenation, thoroughly adversely affecting the QOL of patients with cancer.
      • Heras P.
      • Argyriou A.A.
      • Papapetropoulos S.
      • et al.
      The impact of weekly dosing of epoetin alfa on the haematological parameters and on the quality of life of anaemic cancer patients.
      However, as highlighted in a recent study in which 77 patients completed a self-administered measure of fatigue and a battery of psychometrician-administered measures of cognitive performance before and during chemotherapy, this effect also may be strictly related to the degree of anemia-related fatigue.
      • Jacobsen P.B.
      • Garland L.L.
      • Booth-Jones M.
      • et al.
      Relationship of hemoglobin levels to fatigue and cognitive functioning among cancer patients receiving chemotherapy.
      Thus far, a number of studies have been conducted on the effect of epoetin-alpha (Ea) on the cognitive function of patients with cancer through normalization of hemoglobin, indicating promising yet inconclusive results.
      • O’Shaughnessy J.A.
      • Vukelja S.J.
      • Holmes F.A.
      • et al.
      Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.
      • Massa E.
      • Madeddu C.
      • Lusso M.R.
      • Gramignano G.
      • Mantovani G.
      Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy.
      In any case, the general pattern that emerges so far indicates that Ea may enhance cognitive performance and also may prevent cognitive deterioration in breast cancer patients during neoadjuvant and adjuvant anthracycline-based chemotherapy.
      • Massa E.
      • Madeddu C.
      • Lusso M.R.
      • Gramignano G.
      • Mantovani G.
      Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy.
      Our experience contradicts this view; in a previous study conducted by our group, anemia was corrected through time with Ea, but there was no significant objective or subjective changes in the cognitive function of patients over a period of 12 weeks.
      • Iconomou G.
      • Koutras A.
      • Karaivazoglou K.
      • et al.
      Effect of epoetin alpha therapy on cognitive function in anaemic patients with solid tumours undergoing chemotherapy.
      Finally, the pathogenesis of CICI also may be partly attributed to immune dysregulation, secondary to either the cancer and/or chemotherapy, with release of inflammatory cytokines that can cross the BBB, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha.
      • Cleeland C.S.
      • Bennett G.J.
      • Dantzer R.
      • et al.
      Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms.
      This effect is mostly seen in patients treated with immunotherapies with IL-2 and interferon-a. These patients have a strong trend to higher cytokine levels being associated with poorer executive function, spatial ability, and reaction time.
      • Meyers C.A.
      Mood and cognitive disorders in cancer patients receiving cytokine therapy.
      However, conventional chemotherapy with taxanes also has been associated with increased levels of IL-6, IL-8, and IL-10.
      • Tsavaris N.
      • Kosmas C.
      • Vadiaka M.
      • Kanelopoulos P.
      • Boulamatsis D.
      Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes.
      A strict correlation between cytokine levels and cognitive ability in cancer survivors has been supported by the preliminary results of two studies presented as meeting abstracts, which observed that the plasma levels of inflammatory cytokines could remain elevated in patients with breast cancer and colorectal cancer compared with healthy controls for a period of two years after the discontinuation of treatment.
      • Booth C.M.
      • Vardy J.
      • Crawley A.
      • et al.
      Cognitive impairment associated with chemotherapy for breast cancer: an exploratory case-control study.
      • Vardy J.
      • Rourke S.
      • Galica J.
      • et al.
      Cytokine levels in patients (pts) with localized colorectal cancer (CRC) after surgery and their relationship to fatigue and cognitive function.
      Taken together, there is lack of robust evidence to accurately define the mechanisms of chemotherapy-associated cognitive changes. As a consequence, the pathogenesis of CICI remains vaguely defined, and therefore, the issue about the elucidation of mechanisms conferring CICI merits further exploration.

      Grading of Chemotherapy-Induced Cognitive Impairment

      To date, most of the studies have used comprehensive neuropsychological (NP) batteries, incorporating up to 16 NP tests, with most taking up to four hours to be executed. Indeed, extensive NP testing is, in most instances, a very time-consuming procedure. It also requires trained personnel (psychometrist, neuropsychologist) to be performed, thus limiting its applicability in the general setting.
      • Vardy J.
      • Rourke S.
      • Tannock I.F.
      Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research.
      Yet, the question that remains to be clarified is whether extensive testing, which is able to detect subtle cognitive changes, is preferable to shorter testing with the risk of not identifying such mild cognitive decline. Guidelines still do not exist; however, the necessity of guidelines was agreed on at the Venice workshop, and a working group was established that should provide recommendations for cognitive domains to be evaluated. In any case, the panel of experts recommended that NP testing should be focused on assessing attention, processing speed, memory, learning, retrieval, language, visuoperception, constructional abilities, motor skills, and executive function.
      • Vardy J.
      • Wefel J.S.
      • Ahles T.
      • Tannock I.F.
      • Schagen S.B.
      Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop.
      The ideal NP battery to accurately assess CICI should establish responsiveness, should assess the full range of cognitive and psychological function, and be designed to allow comparison with demographically corrected normative data. Moreover, it should have minimal practice effect on repeat testing. Toward this view, Taillibert et al.
      • Taillibert S.
      • Voillery D.
      • Bernard-Marty C.
      Chemobrain: is systemic chemotherapy neurotoxic?.
      have proposed a set of specific, easily applied, and repeated tests to accurately detect cognitive changes in cancer survivors. Authors recommend that patients should be assessed using the Wechsler Adult Intelligence Scale, 3rd edition, and the MATTIS Dementia Rating Scale, whereas for a rapid and global evaluation of the executive functions, the frontal assessment battery or the Stroop color word test are suitable.
      • Taillibert S.
      • Voillery D.
      • Bernard-Marty C.
      Chemobrain: is systemic chemotherapy neurotoxic?.
      Apart from the NP batteries, few studies have used either brief summary tests, such as the high sensitivity cognitive screen (HSCS), or computerized tests. The HSCS takes less than 30 minutes to complete, and it has been considered to have a significant practice effect.
      • Tchen N.
      • Juffs H.G.
      • Downie F.P.
      • et al.
      Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer.
      • Fogel B.S.
      The high sensitivity cognitive screen.
      • Brezden C.B.
      • Phillips K.A.
      • Abdolell M.
      • Bunston T.
      • Tannock I.F.
      Cognitive function in breast cancer patients receiving adjuvant chemotherapy.
      However, it does not appear to be a reliable tool for measuring CICI in longitudinal studies. Considering also their limited availability, it remains uncertain thus far whether computerized tests are superior compared with conventional NP tests to provide further information on cognitive status and changes in cancer survivors.
      • Vardy J.
      • Wong K.
      • Yi Q.L.
      • et al.
      Assessing cognitive function in cancer patients.
      It is of note that the use of the short version of the Mini Mental State Examination (MMSE) should be avoided, because it appears to be of low sensitivity to detect subtle changes in cognition. MMSE also lacks validated alternative forms for repeated administration and has no timed component, thus rendering it insensitive to subcortical white matter changes potentially related to chemotherapy.
      • Iconomou G.
      • Mega V.
      • Koutras A.
      • Iconomou A.V.
      • Kalofonos H.P.
      Prospective assessment of emotional distress, cognitive function, and quality of life in patients with cancer treated with chemotherapy.
      Overall, despite the use of different NP batteries and other grading tools, accurate grading of CICI still represents a matter of debate, mainly because of the fact that there are variances in interpreting clinical aspects, thereby leading to poor reliability. Additionally, various impairment and functionality items are used in these NP batteries, which clearly hamper their general interpretability, while limitations result also from intra- and interobserver variation of these tests.
      • Vardy J.
      • Rourke S.
      • Tannock I.F.
      Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research.
      Other problems are the definition of impairment; reference groups (normative data from a healthy population, healthy control groups, cancer control groups that have not received chemotherapy); and corrections for practice effects that cannot altogether be avoided.
      Of note, a recent study applied different methods of analysis to the same data and arrived at impairment rates between 12% and 68.5% in the chemotherapy group and between 4.8% and 64.3% in the healthy control group. This study highlighted the importance and effect of different methodological issues on the accurate evaluation of cognitive decline in cancer survivors and demonstrated the need for a collaborative effort to standardize the methods of evaluating CICI.
      • Shilling V.
      • Jenkins V.
      • Trapala I.S.
      The (mis)classification of chemo-fog—methodological inconsistencies in the investigation of cognitive impairment after chemotherapy.
      In any case, because the need for an easily, widely applied, and effective grading system of assessing CICI is clear, well-designed systematic clinimetric studies are warranted to accurately detect and grade the incidence and severity of CICI.

      Clinical Characteristics of Chemotherapy-Induced Cognitive Impairment

      Typically, the chemotherapy-related cognitive changes are hardly identifiable without thorough NP testing, and usually, various domains of cognition are spotty and subtlely affected. The cognitive tasks that are affected by CICI are summarized in Table 1, whereas the involved brain areas are depicted in Fig. 1. Briefly, the cognitive skills relevant to CICI include memory, executive function, processing speed, and reaction time abilities.
      Table 1Cognitive Skills Affected by Chemotherapy
      Cognitive FunctionDescription
      Working memoryThe ability to actively monitor, temporarily store, and manipulate information or behaviors
      Episodic memoryThe memory of autobiographical events that can be explicitly stated
      Remote memoryThe ability to recall events that happened years ago
      Verbal memoryThe ability to retain linguistic information for a designated time period and typically presented orally
      Visual memoryThe ability to create an eidetic image of past visual experiences
      Executive functionCognitive abilities that control and regulate other abilities and behaviors
      Processing speedThe ability to automatically and fluently perform relatively easy or overlearned cognitive tasks
      Visual-spatial abilityThe ability to generate, retain, retrieve, and transform well-structured visual images
      AttentionThe ability to selectively concentrate on one aspect of the environment, while ignoring other things
      ConcentrationThe ability to concentrate mental powers on an object
      Reaction timeThe ability to react and/or make decisions quickly in response to simple stimuli
      Motor speedThe ability to perform body motor movements (movement of limbs) with precision, coordination, or strength
      CICI can persist for a long time after the discontinuation of chemotherapy. The literature contains reports noting the duration of CICI from 2 to 10 years postchemotherapy.
      • Schagen S.B.
      • van Dam F.S.
      • Muller M.J.
      • et al.
      Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma.
      • Ahles T.A.
      • Saykin A.J.
      • Noll W.W.
      • et al.
      The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy.
      In any case, available data do not accurately define the duration of CICI, and hence, long-term longitudinal studies are warranted to elucidate this important issue.

      Incidence of Chemotherapy-Induced Cognitive Impairment

      Current knowledge shows that cognitive impairment is a common and important toxicity of chemotherapy, which often leads to impact on clinical endpoints and QOL of patients. Summarized clinical data from available studies show that the incidence of long-term CICI can affect a significant proportion of cancer survivors, with an incidence rate ranging from 16% to 75%.
      • Tchen N.
      • Juffs H.G.
      • Downie F.P.
      • et al.
      Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer.
      • Vardy J.
      • Tannock I.
      Cognitive function after chemotherapy in adults with solid tumours.
      Differences in the nature of studies and the methodology applied could account for discrepancies among results. Most of the published studies applied a cross-sectional design, thus, lacking any assessment of cognitive function before chemotherapy initiation, and therefore, the cognitive dysfunction found in the cross-sectional studies may have originated pretherapy. To date, few longitudinal studies have been conducted with conflicting results.
      The first longitudinal study that assessed the cognitive function of 18 patients treated with adjuvant chemotherapy for breast cancer reported that 61% of participants experienced a decline in selected cognitive skills, including verbal and visual memory, executive function, visuospatial ability, and information processing speed, three weeks postchemotherapy.
      • Wefel J.S.
      • Lenzi R.
      • Theriault R.L.
      • Davis R.N.
      • Meyers C.A.
      The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial.
      Likewise, in a recent study, 30 women with breast cancer completed NP testing before the initiation and during chemotherapy with doxorubicin/cyclophosphamide. CICI affected 33% of the participants, with significant decreases in visuospatial skill (P<0.001) and total cognitive scores (P=0.001).
      • Jansen C.E.
      • Dodd M.J.
      • Miaskowski C.A.
      • Dowling G.A.
      • Kramer J.
      Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide.
      Another prospective, multicenter, longitudinal study performed 12 NP tests to assess the cognitive performance in 101 patients with breast cancer after administration of neoadjuvant chemotherapy with epirubicin/paclitaxel/cyclophosphamide, and supplementation with darbepoetin alpha. CICI affected 27% of the patients, and this effect remained unrelated to self-reported cognitive problems, emotional distress, menopause, or darbepoetin alpha administration.
      • Hermelink K.
      • Untch M.
      • Lux M.P.
      • et al.
      Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study.
      A significant cognitive impairment across several NP measures, especially executive function, was noted in seven out of 28 (25%) high-risk breast cancer patients who had received high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTC),
      • Schagen S.B.
      • Muller M.J.
      • Boogerd W.
      • Mellenbergh G.J.
      • van Dam F.S.
      Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients.
      whereas in another longitudinal study, up to 17% of women with breast cancer enrolled showed a significant decline in verbal learning and memory, abstract reasoning, and motor coordination postchemotherapy. Moreover, this study revealed that some psychological (decreased hemoglobin levels and increased anxiety over the course of chemotherapy) and health factors (baseline levels of fatigue, depression, and functional well-being) may increase vulnerability to cognitive dysfunction after chemotherapy.
      • Vearncombe K.J.
      • Rolfe M.
      • Wright M.
      • et al.
      Predictors of cognitive decline after chemotherapy in breast cancer patients.
      A great proportion of patients treated with androgen deprivation therapy for prostate cancer also experienced a significant decline in spatial reasoning, spatial abilities, and working memory during treatment compared with the period before chemotherapy.
      • Cherrier M.M.
      • Aubin S.
      • Higano C.S.
      Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer.
      In addition to those longitudinal studies, the literature contains four meta-analyses, including 60 studies.
      • Anderson-Hanley C.
      • Sherman M.L.
      • Riggs R.
      • Agocha V.B.
      • Compas B.E.
      Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature.
      • Jansen C.E.
      • Miaskowski C.
      • Dodd M.
      • Dowling G.
      • Kramer J.
      A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function.
      • Falleti M.G.
      • Sanfilippo A.
      • Maruff P.
      • Weih L.
      • Phillips K.A.
      The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature.
      • Stewart A.
      • Bielajew C.
      • Collins B.
      • Parkinson M.
      • Tomiak E.
      A metaanalysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer.
      However, it should be emphasized that most of the longitudinal studies published to date are not presented in these meta-analyses, because all of them were published before 2006, whereas most longitudinal studies appeared only after early 2006. Therefore, available meta-analyses, even though they include thousands of patients, are obsolete. In any case, all of them disclosed subtle, albeit significant negative effects of chemotherapy on cognitive tasks.
      Jansen et al.
      • Jansen C.E.
      • Miaskowski C.
      • Dodd M.
      • Dowling G.
      • Kramer J.
      A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function.
      reviewed 16 studies enrolling 653 patients and 343 controls and found that only visual memory had significant chemotherapy-induced impairment across all comparison types. However, significant effect sizes were found for executive function, information processing speed, verbal memory, and visual memory, when the NP test scores of chemotherapy patients were compared with normative data.
      • Jansen C.E.
      • Miaskowski C.
      • Dodd M.
      • Dowling G.
      • Kramer J.
      A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function.
      Another similar type of publication on breast cancer patients (nine treatment-control comparisons) emerged, according to which the main domains that were affected were language, short-term memory, and spatial ability.
      • Stewart A.
      • Bielajew C.
      • Collins B.
      • Parkinson M.
      • Tomiak E.
      A metaanalysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer.
      The heterogeneity in patient populations, the chemotherapy regimen administered, and the NP battery applied are potential reasons to justify the differences in the reported data from these meta-analyses. Furthermore, it seems that most impairments are found if the chemotherapy patients’ cognitive performance is compared with normative data; there is less impairment if a control group is used for comparison and little to no impairment if baseline data from the patients themselves are used.
      Overall, as several methodological issues limit the interpretation of available data on the incidence of CICI, further prospective, randomized, longitudinal studies that incorporate a pretreatment assessment of cognitive decline and perceived QOL are necessary to define the incidence of this treatment-related toxicity.

      Risk Factors for Chemotherapy-Induced Cognitive Impairment

      As previously mentioned in the pathogenesis section, the epsilon 4 allele of APOE may be a potential genetic marker to suggest an increased vulnerability to chemotherapy-induced cognitive decline, and thus, patients carrying this allele are at an increased risk of manifesting CICI. In support of this view are the results of a study that compared the NP performance of long-term survivors of breast cancer (n=51) and lymphoma (n=29) with standard-dose chemotherapy who carried the epsilon 4 allele of the APOE gene (n=17) with those who carried other APOE alleles (n=63). This study observed that survivors with at least one epsilon 4 allele scored significantly lower in the visual memory (P<0.03) and the spatial ability (P<0.05) domains and tended to score lower in the psychomotor functioning (P<0.08) domain than the controls.
      • Ahles T.A.
      • Saykin A.J.
      • Noll W.W.
      • et al.
      The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy.
      The incidence of CICI also appears to be related to clinical factors related to chemotherapy, including the type of treatment schedule. It seems that patients receiving the cyclophosphamide/methotrexate/5-fluorouracil regimen, the bleomycin/etoposide/cisplatin scheme, or taxane-containing regimens are at increased risk of developing increased incidence and severity of CICI.
      • Vardy J.
      • Tannock I.
      Cognitive function after chemotherapy in adults with solid tumours.
      • Schagen S.B.
      • Boogerd W.
      • Muller M.J.
      • et al.
      Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer.
      Moreover, several studies have consistently associated the cumulative dose, intensity, and duration of treatment with increased incidence of CICI. In the Schagen et al.
      • Schagen S.B.
      • Muller M.J.
      • Boogerd W.
      • Mellenbergh G.J.
      • van Dam F.S.
      Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients.
      study, high-risk breast cancer patients were randomized to either receive high-dose chemotherapy with CTC (n=28) or standard-dose chemotherapy with 5-fluorouracil/epirubicin and cyclophosphamide (FEC) (n=39). Patients treated with the high-dose CTC scheme experienced a significant deterioration in cognitive performance over time, whereas this was not found in patients treated with the standard FEC regimen.
      • Schagen S.B.
      • Muller M.J.
      • Boogerd W.
      • Mellenbergh G.J.
      • van Dam F.S.
      Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients.
      Other factors that may confer liability to increased risk of developing CICI in cancer survivors include advanced age, history of head trauma, other neurological diseases, developmental disorders, and micrometastatic CNS involvement, particularly in patients with lung cancer. Demographic characteristics, such as educational status and intelligence quotient, also might increase the vulnerability to CICI.
      • Vardy J.
      • Tannock I.
      Cognitive function after chemotherapy in adults with solid tumours.

      Potential Confounding Factors of Chemotherapy-Induced Cognitive Impairment

      Emotional Distress

      The emotional distress associated with the disclosure of cancer diagnosis and/or the administration of chemotherapy represents a strong reason for psychosomatic manifestations in patients with cancer. There is evidence in the literature suggesting that once emotional distress, particularly depression, appears in cancer patients, it can be a long-term and persistent complication even after treatment has been completed.
      • Patrick D.L.
      • Ferketich S.L.
      • Frame P.S.
      • et al.
      National Institutes of Health State-of-the-Science Panel
      National Institutes of Health state-of-the-science conference statement: symptom management in cancer: pain, depression, and fatigue.
      Wefel et al.
      • Wefel J.S.
      • Lenzi R.
      • Theriault R.
      • et al.
      “Chemobrain” in breast carcinoma?: a prologue.
      performed a comprehensive NP evaluation in 84 patients with breast carcinoma before receiving adjuvant therapy for nonmetastatic primary breast carcinoma. To date, this study represents one of the two studies reporting a significant association between CICI and affective distress (P=0.002). In line with the latter study, a Danish group observed that distress significantly predicted cognitive decline in cancer patients who received chemotherapy.
      • Mehlsen M.
      • Pedersen A.D.
      • Jensen A.B.
      • Zachariae R.
      No indications of cognitive side-effects in a prospective study of breast cancer patients receiving adjuvant chemotherapy.
      All other similar studies have failed to show significant associations.
      • Brezden C.B.
      • Phillips K.A.
      • Abdolell M.
      • Bunston T.
      • Tannock I.F.
      Cognitive function in breast cancer patients receiving adjuvant chemotherapy.
      • Castellon S.A.
      • Ganz P.A.
      • Bower J.E.
      • et al.
      Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.
      • Jenkins V.
      • Shilling V.
      • Deutsch G.
      • et al.
      A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.
      However, several studies have reported that perceived (self-reported) cognitive impairment was strictly related to the occurrence and degree of anxiety and/or depression QOL measures and cognitive failures without any impact on objective testing of cognitive function.
      • Castellon S.A.
      • Ganz P.A.
      • Bower J.E.
      • et al.
      Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.
      • Jenkins V.
      • Shilling V.
      • Deutsch G.
      • et al.
      A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.

      Fatigue (Without Anemia)

      Previous research indicates that cancer survivors who experience severe fatigue also have many problems with regard to NP functioning, cognition, and physical activity, usually measured with self-report questionnaires. However, similar to emotional distress, fatigue has not been proven to be significantly associated with abnormalities in objective NP testing but only with altered perceived cognitive impairment.
      • Castellon S.A.
      • Ganz P.A.
      • Bower J.E.
      • et al.
      Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.
      • Jenkins V.
      • Shilling V.
      • Deutsch G.
      • et al.
      A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.
      As such, fatigue is thought to usually correlate strongly with daily self-reported NP functioning but not with objective NP functioning.

      Hormonal Therapy

      Hormonal therapy with tamoxifen, aromatase inhibitors, or androgens appears to represent the most significant confounder of CICI. There are several lines of evidence advocating in favor of the view that hormonal therapy might be able to induce cognitive decline in cancer patients.
      • Collins B.
      • Mackenzie J.
      • Stewart A.
      • Bielajew C.
      • Verma S.
      Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study.
      Estrogen receptors are widely found in the CNS, and reduced levels are thought to induce cognitive decline. Tamoxifen is an antagonist of the estrogen receptor in breast tissue. It has been the standard endocrine (anti-estrogen) therapy for hormone-positive early breast cancer. Available data on the negative effects of tamoxifen on cognition are conflicting.
      Two studies have disclosed differences in the cognitive ability of patients on chemotherapy+tamoxifen compared with chemotherapy alone. Preliminary results of a large-sized study enrolling 1163 patients with breast cancer, of whom 710 also had received tamoxifen, showed that current tamoxifen users had a significantly lower mean complexity score (P=0.03) on the narrative writing task than women who had received chemotherapy alone.
      • Paganini-Hill A.
      • Clark L.J.
      Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen.
      The design of this study was weak, as the cognitive tests were not administered by study personnel but sent to the patients by mail. In line with the results of the latter study, a recently published report on 53 survivors of breast cancer found that patients receiving chemotherapy and tamoxifen showed a greater compromise in the domains of verbal learning, visuospatial functioning, and visual memory compared with patients treated with chemotherapy alone.
      • Castellon S.A.
      • Ganz P.A.
      • Bower J.E.
      • et al.
      Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.
      Other studies have failed to demonstrate that systemic chemotherapy, especially in combination with tamoxifen, can have adverse yet subtle effects on cognitive functioning.
      • Tchen N.
      • Juffs H.G.
      • Downie F.P.
      • et al.
      Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer.
      • Schagen S.B.
      • van Dam F.S.
      • Muller M.J.
      • et al.
      Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma.
      Of note, there is evidence from a recent study to suggest that tamoxifen exerts only estrogen-like effects on the brain. The authors of this study concluded that their results may alleviate concerns about the safety of using tamoxifen to reduce breast cancer risk in elderly women.
      • Ernst T.
      • Chang L.
      • Cooray D.
      • et al.
      The effects of tamoxifen and estrogen on brain metabolism in elderly women.
      Further study of tamoxifen and cognition is needed to definitely clarify the important clinical issue concerning whether the use of tamoxifen may adversely impact cognition.
      Aromatase inhibitors, including irreversible steroidal inhibitors (exemestane) and nonsteroidal inhibitors (anastrozole, letrozole), work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by aromatization. The mode of their action is based in blocking the synthesis of estrogens. An interim analysis from the anastrozole, tamoxifen, and combined trial on 94 patients and 35 noncancer controls demonstrated that patients significantly differ from controls on measures of verbal memory (P=0.026) and processing speed (P=0.032).
      • Shilling V.
      • Jenkins V.
      • Fallowfield L.
      • Howell T.
      The effects of hormone therapy on cognition in breast cancer.
      In contrast, the results of a randomized, double-blind chemoprevention trial on the effects of anastrozole on cognitive performance of postmenopausal women (111 patients treated with anastrozole and 116 with placebo) showed little or no impairment of cognitive performance with the use of anastrozole vs. placebo.
      • Jenkins V.A.
      • Ambroisine L.M.
      • Atkins L.
      • et al.
      Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II).
      Altogether, at present, it remains uncertain whether aromatase inhibitors have potential consequences on cognition.
      Finally, endocrine manipulation with androgens for prostate cancer also may be linked with subtle yet significant cognitive decline, most commonly in visuospatial abilities and executive functioning.
      • Salminen E.K.
      • Portin R.I.
      • Koskinen A.
      • Helenius H.
      • Nurmi M.
      Associations between serum testosterone fall and cognitive function in prostate cancer patients.
      • Green H.J.
      • Pakenham K.I.
      • Headley B.C.
      • et al.
      Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial.
      • Beer T.M.
      • Bland L.B.
      • Bussiere J.R.
      • et al.
      Testosterone loss and estradiol administration modify memory in men.
      In the Salminen et al.
      • Salminen E.K.
      • Portin R.I.
      • Koskinen A.
      • Helenius H.
      • Nurmi M.
      Associations between serum testosterone fall and cognitive function in prostate cancer patients.
      study, androgen ablation therapy significantly affected the visuomotor speed and reaction time of 26 patients with prostate cancer. It is noteworthy to mention that the decline in testosterone coincided with a decline in visuomotor processing, reaction time, working memory speed, sustained attention, and recognition speed.
      • Salminen E.K.
      • Portin R.I.
      • Koskinen A.
      • Helenius H.
      • Nurmi M.
      Associations between serum testosterone fall and cognitive function in prostate cancer patients.
      In contrast to these studies, a recently published cross-sectional study of 57 patients receiving androgen ablation therapy for prostate cancer and 51 healthy controls demonstrated no differences in cognitive function between groups on either the HSCS or the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-COG).
      • Joly F.
      • Alibhai S.M.
      • Galica J.
      • et al.
      Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer.
      Notwithstanding the methodological limitations of existing studies and the use of relatively small sample sizes, it seems that endocrine manipulation does have implications for cognitive functioning. Further larger longitudinal studies are warranted to elucidate the issue.

      Neuroimaging and Neurophysiology of Chemotherapy-Induced Cognitive Impairment

      There is evidence from imaging studies using either magnetic resonance imaging or positron emission tomography (PET), which suggests that structural brain abnormalities, including reduction of gray matter and cortical/subcortical white matter, occur in patients after cessation of chemotherapy.
      • Saykin A.J.
      • Ahles T.A.
      • McDonald B.C.
      Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives.
      These findings support a causal relationship between chemotherapy and cognitive changes.
      A recent study explored the regional brain volume difference among breast cancer survivors exposed to adjuvant chemotherapy, using voxel-based morphometry, and found smaller gray matter and white matter in the prefrontal, parahippocampal, cingulate gyrous, and precuneus regions one year after the discontinuation of treatment. These changes were significantly correlated with indices of attention, concentration, and visual memory. However, regional volumes were smaller compared with those of cancer patients who had not received chemotherapy, but comparisons with those of healthy controls did not show any significant differences. In the same study, no differences in regional brain volumes were found among chemotherapy patients, other cancer patients, and healthy controls, three years after completion of chemotherapy.
      • Inagaki M.
      • Yoshikawa E.
      • Matsuoka Y.
      • et al.
      The Breast Cancer Survivors’ Brain MRI Database Group
      Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy.
      In another small study, researchers sought to measure white matter integrity in 10 patients with breast cancer, using diffusion tensor imaging to calculate fractional anisotropy. Processing-speed skills also were assessed. This study concluded that adjuvant chemotherapy for breast cancer affects normal-appearing white matter in the genu of the corpus callosum and that this is related to the cognitive deficits (graphomotor speed) experienced by patients.
      • Abraham J.
      • Haut M.W.
      • Moran M.T.
      • et al.
      Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging.
      Another recent functional imaging study used [O-15] water PET scans and [F-18] fluorodeoxyglucose PET to evaluate cognition-related cerebral blood flow and cerebral metabolism in 16 patients with breast cancer who had received chemotherapy 5–10 years previously. Eleven of those patients also had received tamoxifen. This study demonstrated significant functional changes in breast cancer survivors related to chemotherapy, consisting of decreased metabolism in the frontal cortex, cerebellum, and basal ganglia. The resting glucose metabolism in the inferior frontal gyrous correlated with the altered performance in short-term-memory tests. Participants treated with tamoxifen+chemotherapy had decreased metabolism in basal ganglia compared with women treated with chemotherapy alone.
      • Silverman D.H.
      • Dy C.J.
      • Castellon S.A.
      • et al.
      Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5-10 years after chemotherapy.
      Overall, the small samples, most likely leading to reduced power, pose a significant methodological limitation of the available studies, thereby bolstering the need for larger long-term longitudinal studies to accurately assess the importance of neuroimaging changes in cancer survivors and their relationship with CICI. To our knowledge, a five-year longitudinal study in patients with breast cancer is ongoing, and its results are awaited with great interest.
      Finally, as concerning neurophysiology, abnormalities in event-related potentials and electroencephalography were reported from studies by the Dutch group in 42% of patients treated with high-dose chemotherapy regimens, as opposed to 12.5% of patients allocated in the standard-dose group and none of the locally treated patients.
      • Schagen S.B.
      • Hamburger H.L.
      • Muller M.J.
      • Boogerd W.
      • van Dam F.S.
      Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function.
      The results from neurophysiological studies further support the view that structural brain abnormalities secondary to chemotherapy are related to the occurrence of CICI in cancer survivors.

      Treatment Strategies

      To date, a few agents with putative neuroprotective effects, including methylphenidate, modafinil, gingko biloba, and the cholinesterase inhibitor donepezil, have been tested for their efficacy in CICI. However, the clinical data are rather modest, as most of the relevant trials were not randomized controlled trials (RCTs) and have drawn conclusions from recruitment of small case series. The evaluation of some of the aforementioned interventions is ongoing. Hence, a neuroprotective agent that has documented efficacy and safety against CICI is still lacking.
      • Correa D.D.
      • Ahles T.A.
      Neurocognitive changes in cancer survivors.
      Table 2 summarizes the agents that have been evaluated in clinical trials or are undergoing evaluation for their potential efficacy against CICI.
      Table 2Agents that Have Been or Are Being Evaluated in Clinical Trials for Their Efficacy in Treating CICI
      TreatmentReferenceDesignNo. of PatientsCancer TypeOutcome
      d-MethylphenidateMar Fan et al., 2008
      • Mar Fan H.G.
      • Clemons M.
      • Xu W.
      • et al.
      A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer.
      DB-RCT57BreastIneffective
      Lower et al., 2009
      • Lower E.E.
      • Fleishman S.
      • Cooper A.
      • et al.
      Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial.
      RCT154Breast/ovarianIneffective
      Gingko bilobaMayo groupDB-RCT220BreastOngoing
      ModafinilKohli et al., 2009
      • Kohli S.
      • Fisher S.G.
      • Tra Y.
      • et al.
      The effect of modafinil on cognitive function in breast cancer survivors.
      RCT68BreastEffective
      Donepezil+vitamin EJatoi et al., 2005
      • Jatoi A.
      • Kahanic S.P.
      • Frytak S.
      • et al.
      Donepezil and vitamin E for preventing cognitive dysfunction in small cell lung cancer patients: preliminary results and suggestions for future study designs.
      DB-RCT104SCLCTerminated early
      DB-RCT=double-blind, randomized controlled trial; SCLC=small-cell lung cancer.

      Symptomatic Treatment Approaches

      Methylphenidate has strong evidence of clinical activity against attention-deficit/hyperactivity disorder and narcolepsy.
      • Jensen P.S.
      Clinical considerations for the diagnosis and treatment of ADHD in the managed care setting.
      Considering that methylphenidate has been successfully used to treat cognitive decline in children with cancer and in patients with brain tumors,
      • Vardy J.
      • Tannock I.
      Cognitive function after chemotherapy in adults with solid tumours.
      its use in treating the cognitive decline in survivors with solid tumors appeared to have a solid rationale and is very promising. Disappointingly, in two recently published RCTs, methylphenidate failed to improve the cognitive function of cancer survivors and was found only active in ameliorating the chemotherapy-induced fatigue.
      In a double-blind, placebo-controlled trial, 57 women undergoing adjuvant chemotherapy for breast cancer were randomized early during their chemotherapy in a 1:1 ratio to either receive d-methylphenidate (d-MPH), a form of methylphenidate, or placebo. The cognitive ability of participants was assessed at baseline, end of chemotherapy, and at approximately six months’ follow-up with the HSCS and the Hopkins Verbal Learning Test-Revised. This study showed no significant benefit in the cognitive function of patients treated with methylphenidate.
      • Mar Fan H.G.
      • Clemons M.
      • Xu W.
      • et al.
      A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer.
      Likewise, in another RCT enrolling 154 patients with breast and ovarian cancers, cognitive function was not significantly improved after d-MPH supplementation.
      • Lower E.E.
      • Fleishman S.
      • Cooper A.
      • et al.
      Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial.
      Overall, it seems that d-MPH is effective in ameliorating cancer-related fatigue, but not CICI.
      • Minton O.
      • Stone P.
      • Richardson A.
      • Sharpe M.
      • Hotopf M.
      Drug therapy for the management of cancer related fatigue.
      Psychostimulants have previously been used to treat cancer-related fatigue and cognitive dysfunction associated with malignancies. Modafinil, a new generation psychostimulant, may improve some aspects of cognitive function in cancer survivors. However, there is no adequate evidence to support its routine use against CICI.
      • Prommer E.
      Modafinil: is it ready for prime time?.
      A double-blind RCT assessed the effects of modafinil (200 mg for eight weeks) in improving the cognitive function of 68 patients after chemotherapy for breast cancer. This study showed that modafinil improved cognitive performance in breast cancer survivors by enhancing certain memory and attention skills, namely, speed of memory (P=0.03), quality of episodic memory (P=0.01), and mean continuity of attention (P=0.01).
      • Kohli S.
      • Fisher S.G.
      • Tra Y.
      • et al.
      The effect of modafinil on cognitive function in breast cancer survivors.

      Neuroprotective Treatment Approaches

      The herbal product ginkgo biloba is taken frequently with the intention of preventing cognitive decline in the elderly.
      • Birks J.
      • Grimley Evans J.
      Ginkgo biloba for cognitive impairment and dementia.
      Although, it appears to have some measure of success in the latter case, there has been a paucity of data concerning its efficacy against CICI. To our knowledge, a double-blind RCT conducted by the Mayo group on the efficacy of ginkgo biloba to prevent CICI or to improve the cognitive ability of breast cancer patients is ongoing, and the results are awaited with great interest.
      • North Central Cancer Treatment Group
      The use of ginkgo biloba for the prevention of chemotherapy-related cognitive dysfunction.
      Donepezil, a cholinesterase inhibitor, is currently indicated for mild to moderate dementia, and it also may be effective for moderate to severe disease.
      • Winblad B.
      • Black S.E.
      • Homma A.
      • et al.
      Donepezil treatment in severe Alzheimer’s disease: a pooled analysis of three clinical trials.
      Just one trial tested the efficacy of donepezil (5 mg/day with dose escalation to 10 mg after one month) plus vitamin E (1,000 IU/day) to either prevent CICI or to improve the cognitive ability of patients with small-cell lung cancer. This trial was terminated early because of a very low recruitment rate over a period of 15 months.
      • Jatoi A.
      • Kahanic S.P.
      • Frytak S.
      • et al.
      Donepezil and vitamin E for preventing cognitive dysfunction in small cell lung cancer patients: preliminary results and suggestions for future study designs.
      Overall, as no medication exists to convincingly prevent or treat CICI, further prospective studies on the topic are clearly warranted. In our opinion, the use of antioxidants, particularly vitamin E, might merit further study. Previous data in the noncancer setting show that high-dose supplementation with vitamin E is able to prevent or improve cognitive decline by scavenging free radicals.
      • Usoro O.B.
      • Mousa S.A.
      Vitamin E forms in Alzheimer’s disease: a review of controversial and clinical experiences.
      Taking into consideration that systemic cytotoxic therapy for cancer is able to release free radicals and also interfere with the cholinergic trajectories of the brain, thus leading to CICI,
      • Selden N.R.
      • Gitelman D.R.
      • Salamon-Murayama N.
      • Parrish T.B.
      • Mesulam M.M.
      Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain.
      one could suggest that vitamin E also may be effective in protecting the cognitive ability of cancer survivors.

      Nonpharmacological Approaches

      Cognitive rehabilitation strategies have been tested in cancer survivors to improve chemotherapy-related cognitive changes with some measure of success. In a single-arm pilot study, a brief cognitive-behavioral treatment strategy was tested in 29 breast cancer survivors to improve the cognitive decline associated with adjuvant chemotherapy. Considering that a significant improvement in self-report cognitive function, in standard NP test performance and in ability to compensate for memory problems, was disclosed, this cognitive-behavioral program appears to be promising and warrants further study before definitive conclusions can be drawn.
      • Ferguson R.J.
      • Ahles T.A.
      • Saykin A.J.
      • et al.
      Cognitive-behavioral management of chemotherapy-related cognitive change.
      Other nonpharmacological interventions, such as psychosocial support, also should be evaluated for their ability to manage CICI.

      Future Research Perspectives

      Available data advocate in favor of the view that the condition called either chemobrain or chemofog is a recognizable syndrome of long-term, chemotherapy-induced cognitive decline in cancer survivors. It may thoroughly compromise the QOL of cancer survivors. There is relatively little known about the condition, however, because methodological problems limit the interpretation of data relevant to the nature of this toxicity.
      To date, there has been a lack of a reliable method on either clinical or molecular grounds to detect patients at high risk of developing CICI or to predict its final outcome. Toward this view, research should be focused on the identification of a genetic or molecular biomarker conferring liability to CICI.
      The reliable assessment of CICI is mandatory. Therefore, validation studies should be conducted to recommend the most comprehensive, suitable, and generally applicable NP battery to detect and grade the subtle cognitive deficit secondary to chemotherapy. Overall, prospective and longitudinal clinical and functional studies that control for important confounding factors are needed to accurately assess the incidence, clinical picture, and prognostic factors, as well as the underlying mechanisms of CICI; hence, enough insights are provided toward the initiation of drug trials to prevent or treat this important chemotherapy-induced neurotoxicity.

      Disclosures and Acknowledgments

      No funding source had a role in the preparation of this article or in the decision to submit it for publication. The authors declare no conflicts of interest.

      References

        • Sioka C.
        • Kyritsis A.P.
        Central and peripheral nervous system toxicity of common chemotherapeutic agents.
        Cancer Chemother Pharmacol. 2009; 63: 761-767
        • Ferguson R.J.
        • Ahles T.A.
        Chemotherapy associated cognitive impairment in patients with cancer and cancer survivors.
        Curr Neurol Neurosci Rep. 2003; 3: 215-222
        • Saykin A.J.
        • Ahles T.A.
        • McDonald B.C.
        Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives.
        Semin Clin Neuropsychiatry. 2003; 8: 201-216
        • Anderson-Hanley C.
        • Sherman M.L.
        • Riggs R.
        • Agocha V.B.
        • Compas B.E.
        Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature.
        J Int Neuropsychol Soc. 2003; 9: 967-982
        • Ahles T.A.
        • Saykin A.J.
        Candidate mechanisms for chemotherapy-induced cognitive changes.
        Nat Rev Cancer. 2007; 7: 192-201
        • Hoffmeyer S.
        • Burk O.
        • von Richter O.
        • et al.
        Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
        Proc Natl Acad Sci USA. 2000; 97: 3473-3478
        • Vardy J.
        • Wefel J.S.
        • Ahles T.
        • Tannock I.F.
        • Schagen S.B.
        Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop.
        Ann Oncol. 2008; 19: 623-629
        • Dietrich J.
        • Han R.
        • Yang Y.
        • Mayer-Pröschel M.
        • Noble M.
        CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.
        J Biol. 2006; 5: 22
        • Vardy J.
        • Rourke S.
        • Tannock I.F.
        Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research.
        J Clin Oncol. 2007; 25: 2455-2463
        • Tchen N.
        • Juffs H.G.
        • Downie F.P.
        • et al.
        Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer.
        J Clin Oncol. 2003; 21: 4175-4183
        • Blasiak J.
        • Arabski M.
        • Krupa R.
        • et al.
        Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer.
        Mutat Res. 2004; 554: 139-148
        • Valko M.
        • Leibfritz D.
        • Moncol J.
        • et al.
        Free radicals and antioxidants in normal physiological functions and human disease.
        Int J Biochem Cell Biol. 2007; 39: 44-84
        • Wardell T.M.
        • Ferguson E.
        • Chinnery P.F.
        • et al.
        Changes in the human mitochondrial genome after treatment of malignant disease.
        Mutat Res. 2003; 525: 19-27
        • Barton D.
        • Loprinzi C.
        Novel approaches to preventing chemotherapy-induced cognitive dysfunction in breast cancer: the art of the possible.
        Clin Breast Cancer. 2002; 3: S121-S127
        • Heras P.
        • Argyriou A.A.
        • Papapetropoulos S.
        • et al.
        The impact of weekly dosing of epoetin alfa on the haematological parameters and on the quality of life of anaemic cancer patients.
        Eur J Cancer Care (Engl). 2005; 14: 108-112
        • Jacobsen P.B.
        • Garland L.L.
        • Booth-Jones M.
        • et al.
        Relationship of hemoglobin levels to fatigue and cognitive functioning among cancer patients receiving chemotherapy.
        J Pain Symptom Manage. 2004; 28: 7-18
        • O’Shaughnessy J.A.
        • Vukelja S.J.
        • Holmes F.A.
        • et al.
        Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.
        Clin Breast Cancer. 2005; 5: 439-446
        • Massa E.
        • Madeddu C.
        • Lusso M.R.
        • Gramignano G.
        • Mantovani G.
        Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy.
        Crit Rev Oncol Hematol. 2006; 57: 175-182
        • Iconomou G.
        • Koutras A.
        • Karaivazoglou K.
        • et al.
        Effect of epoetin alpha therapy on cognitive function in anaemic patients with solid tumours undergoing chemotherapy.
        Eur J Cancer Care (Engl). 2008; 17: 535-541
        • Cleeland C.S.
        • Bennett G.J.
        • Dantzer R.
        • et al.
        Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms.
        Cancer. 2003; 97: 2919-2925
        • Meyers C.A.
        Mood and cognitive disorders in cancer patients receiving cytokine therapy.
        Adv Exp Med Biol. 1999; 461: 75-81
        • Tsavaris N.
        • Kosmas C.
        • Vadiaka M.
        • Kanelopoulos P.
        • Boulamatsis D.
        Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes.
        Br J Cancer. 2002; 87: 21-27
        • Booth C.M.
        • Vardy J.
        • Crawley A.
        • et al.
        Cognitive impairment associated with chemotherapy for breast cancer: an exploratory case-control study.
        J Clin Oncol. 2006; 24 ([abstract]): 8501
        • Vardy J.
        • Rourke S.
        • Galica J.
        • et al.
        Cytokine levels in patients (pts) with localized colorectal cancer (CRC) after surgery and their relationship to fatigue and cognitive function.
        J Clin Oncol. 2006; 24 ([abstract]): 3623
        • Taillibert S.
        • Voillery D.
        • Bernard-Marty C.
        Chemobrain: is systemic chemotherapy neurotoxic?.
        Curr Opin Oncol. 2007; 19: 623-627
        • Fogel B.S.
        The high sensitivity cognitive screen.
        Int Psychogeriatr. 1991; 3: 273-288
        • Brezden C.B.
        • Phillips K.A.
        • Abdolell M.
        • Bunston T.
        • Tannock I.F.
        Cognitive function in breast cancer patients receiving adjuvant chemotherapy.
        J Clin Oncol. 2000; 18: 2695-2701
        • Vardy J.
        • Wong K.
        • Yi Q.L.
        • et al.
        Assessing cognitive function in cancer patients.
        Support Care Cancer. 2006; 14: 1111-1118
        • Iconomou G.
        • Mega V.
        • Koutras A.
        • Iconomou A.V.
        • Kalofonos H.P.
        Prospective assessment of emotional distress, cognitive function, and quality of life in patients with cancer treated with chemotherapy.
        Cancer. 2004; 101: 404-411
        • Shilling V.
        • Jenkins V.
        • Trapala I.S.
        The (mis)classification of chemo-fog—methodological inconsistencies in the investigation of cognitive impairment after chemotherapy.
        Breast Cancer Res Treat. 2006; 95: 125-129
        • Schagen S.B.
        • van Dam F.S.
        • Muller M.J.
        • et al.
        Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma.
        Cancer. 1999; 85: 640-650
        • Ahles T.A.
        • Saykin A.J.
        • Noll W.W.
        • et al.
        The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy.
        Psychooncology. 2003; 12: 612-619
        • Vardy J.
        • Tannock I.
        Cognitive function after chemotherapy in adults with solid tumours.
        Crit Rev Oncol Hematol. 2007; 63: 183-202
        • Wefel J.S.
        • Lenzi R.
        • Theriault R.L.
        • Davis R.N.
        • Meyers C.A.
        The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial.
        Cancer. 2004; 100: 2292-2299
        • Jansen C.E.
        • Dodd M.J.
        • Miaskowski C.A.
        • Dowling G.A.
        • Kramer J.
        Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide.
        Psychooncology. 2008; 17: 1189-1195
        • Hermelink K.
        • Untch M.
        • Lux M.P.
        • et al.
        Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study.
        Cancer. 2007; 109: 1905-1913
        • Schagen S.B.
        • Muller M.J.
        • Boogerd W.
        • Mellenbergh G.J.
        • van Dam F.S.
        Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients.
        J Natl Cancer Inst. 2006; 98: 1742-1745
        • Vearncombe K.J.
        • Rolfe M.
        • Wright M.
        • et al.
        Predictors of cognitive decline after chemotherapy in breast cancer patients.
        J Int Neuropsychol Soc. 2009; 15: 951-962
        • Cherrier M.M.
        • Aubin S.
        • Higano C.S.
        Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer.
        Psychooncology. 2009; 18: 237-247
        • Jansen C.E.
        • Miaskowski C.
        • Dodd M.
        • Dowling G.
        • Kramer J.
        A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function.
        Cancer. 2005; 104: 2222-2233
        • Falleti M.G.
        • Sanfilippo A.
        • Maruff P.
        • Weih L.
        • Phillips K.A.
        The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature.
        Brain Cogn. 2005; 59: 60-70
        • Stewart A.
        • Bielajew C.
        • Collins B.
        • Parkinson M.
        • Tomiak E.
        A metaanalysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer.
        Clin Neuropsychol. 2006; 20: 76-89
        • Schagen S.B.
        • Boogerd W.
        • Muller M.J.
        • et al.
        Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer.
        Acta Oncol. 2008; 47: 63-70
        • Patrick D.L.
        • Ferketich S.L.
        • Frame P.S.
        • et al.
        • National Institutes of Health State-of-the-Science Panel
        National Institutes of Health state-of-the-science conference statement: symptom management in cancer: pain, depression, and fatigue.
        J Natl Cancer Inst. 2003; 95: 1110-1117
        • Wefel J.S.
        • Lenzi R.
        • Theriault R.
        • et al.
        “Chemobrain” in breast carcinoma?: a prologue.
        Cancer. 2004; 101: 466-475
        • Mehlsen M.
        • Pedersen A.D.
        • Jensen A.B.
        • Zachariae R.
        No indications of cognitive side-effects in a prospective study of breast cancer patients receiving adjuvant chemotherapy.
        Psychooncology. 2009; 18: 248-257
        • Castellon S.A.
        • Ganz P.A.
        • Bower J.E.
        • et al.
        Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.
        J Clin Exp Neuropsychol. 2004; 26: 955-969
        • Jenkins V.
        • Shilling V.
        • Deutsch G.
        • et al.
        A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.
        Br J Cancer. 2006; 94: 828-834
        • Collins B.
        • Mackenzie J.
        • Stewart A.
        • Bielajew C.
        • Verma S.
        Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study.
        Psychooncology. 2009; 18: 811-821
        • Paganini-Hill A.
        • Clark L.J.
        Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen.
        Breast Cancer Res Treat. 2000; 64: 165-176
        • Ernst T.
        • Chang L.
        • Cooray D.
        • et al.
        The effects of tamoxifen and estrogen on brain metabolism in elderly women.
        J Natl Cancer Inst. 2002; 94: 592-597
        • Shilling V.
        • Jenkins V.
        • Fallowfield L.
        • Howell T.
        The effects of hormone therapy on cognition in breast cancer.
        J Steroid Biochem Mol Biol. 2003; 86: 405-412
        • Jenkins V.A.
        • Ambroisine L.M.
        • Atkins L.
        • et al.
        Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II).
        Lancet Oncol. 2008; 9: 953-961
        • Salminen E.K.
        • Portin R.I.
        • Koskinen A.
        • Helenius H.
        • Nurmi M.
        Associations between serum testosterone fall and cognitive function in prostate cancer patients.
        Clin Cancer Res. 2004; 10: 7575-7582
        • Green H.J.
        • Pakenham K.I.
        • Headley B.C.
        • et al.
        Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial.
        BJU Int. 2002; 90: 427-432
        • Beer T.M.
        • Bland L.B.
        • Bussiere J.R.
        • et al.
        Testosterone loss and estradiol administration modify memory in men.
        J Urol. 2006; 175: 130-135
        • Joly F.
        • Alibhai S.M.
        • Galica J.
        • et al.
        Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer.
        J Urol. 2006; 176: 2443-2447
        • Inagaki M.
        • Yoshikawa E.
        • Matsuoka Y.
        • et al.
        • The Breast Cancer Survivors’ Brain MRI Database Group
        Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy.
        Cancer. 2007; 109: 146-156
        • Abraham J.
        • Haut M.W.
        • Moran M.T.
        • et al.
        Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging.
        Clin Breast Cancer. 2008; 8: 88-91
        • Silverman D.H.
        • Dy C.J.
        • Castellon S.A.
        • et al.
        Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5-10 years after chemotherapy.
        Breast Cancer Res Treat. 2007; 103: 303-311
        • Schagen S.B.
        • Hamburger H.L.
        • Muller M.J.
        • Boogerd W.
        • van Dam F.S.
        Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function.
        J Neurooncol. 2001; 51: 159-165
        • Correa D.D.
        • Ahles T.A.
        Neurocognitive changes in cancer survivors.
        Cancer J. 2008; 14: 396-400
        • Jensen P.S.
        Clinical considerations for the diagnosis and treatment of ADHD in the managed care setting.
        Am J Manag Care. 2009; 15: S129-S140
        • Mar Fan H.G.
        • Clemons M.
        • Xu W.
        • et al.
        A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer.
        Support Care Cancer. 2008; 16: 577-583
        • Lower E.E.
        • Fleishman S.
        • Cooper A.
        • et al.
        Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial.
        J Pain Symptom Manage. 2009; 38: 650-662
        • Minton O.
        • Stone P.
        • Richardson A.
        • Sharpe M.
        • Hotopf M.
        Drug therapy for the management of cancer related fatigue.
        Cochrane Database Syst Rev. 2008; 1 (CD006704)
        • Prommer E.
        Modafinil: is it ready for prime time?.
        J Opioid Manag. 2006; 2: 130-136
        • Kohli S.
        • Fisher S.G.
        • Tra Y.
        • et al.
        The effect of modafinil on cognitive function in breast cancer survivors.
        Cancer. 2009; 115: 2605-2616
        • Birks J.
        • Grimley Evans J.
        Ginkgo biloba for cognitive impairment and dementia.
        Cochrane Database Syst Rev. 2009; 1 (CD003120)
        • North Central Cancer Treatment Group
        The use of ginkgo biloba for the prevention of chemotherapy-related cognitive dysfunction.
        (Available from) (Identifier: NCT00046891. Accessed February 26, 2010)
        • Winblad B.
        • Black S.E.
        • Homma A.
        • et al.
        Donepezil treatment in severe Alzheimer’s disease: a pooled analysis of three clinical trials.
        Curr Med Res Opin. 2009; 25: 2577-2587
        • Jatoi A.
        • Kahanic S.P.
        • Frytak S.
        • et al.
        Donepezil and vitamin E for preventing cognitive dysfunction in small cell lung cancer patients: preliminary results and suggestions for future study designs.
        Support Care Cancer. 2005; 13: 66-69
        • Usoro O.B.
        • Mousa S.A.
        Vitamin E forms in Alzheimer’s disease: a review of controversial and clinical experiences.
        Crit Rev Food Sci Nutr. 2010; 50: 414-419
        • Selden N.R.
        • Gitelman D.R.
        • Salamon-Murayama N.
        • Parrish T.B.
        • Mesulam M.M.
        Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain.
        Brain. 1998; 121: 2249-2257
        • Ferguson R.J.
        • Ahles T.A.
        • Saykin A.J.
        • et al.
        Cognitive-behavioral management of chemotherapy-related cognitive change.
        Psychooncology. 2007; 16: 772-777