Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target

Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review... British Journal of Cancer (2004) 90, 1691 – 1696 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Minireview Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target 1,2 1,2 ,1,2 JS Wefel , AE Kayl and CA Meyers Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030-4009, USA; The Brain Tumor Center, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030-4009, USA Neuropsychological dysfunction associated with cancer and cancer treatment is a growing concern. Methodological limitations permeate the corpus of research in this area and have limited our understanding of the multifactorial nature of this process. The following review provides a summary of the current state of knowledge and highlights future directions. British Journal of Cancer (2004) 90, 1691 – 1696. doi:10.1038/sj.bjc.6601772 www.bjcancer.com Published online 6 April 2004 & 2004 Cancer Research UK While it is generally recognised that central nervous system (CNS) also affect CNS function (e.g. steroids, antiepileptics, immunosup- cancer and many of the therapeutic modalities used to treat cancer pressive agents, and drugs used for pain, nausea, and infection). can cause alterations in neurocognitive function, our knowledge There is a burgeoning literature on the neurocognitive effects of about the nature, severity, and course of neurocognitive dysfunc- cancer treatment. Unfortunately, few methodologically rigorous tion is limited. Traditionally, treatment outcome has focused on studies exist to guide clinical practice. Most studies are retro- the length of survival and neurological or physiological changes spective, fail to incorporate assessments of pretreatment neuro- such as peripheral neuropathy, ototoxicity, or encephalopathy cognitive and neurobehavioural function, consist of small and rather than indices of ‘quality of life’, such as neurocognitive heterogeneous samples, lack appropriate control groups, and function. Neurocognitive function has been demonstrated to be a suffer from poor measurement selection. Owing to the state of the sensitive, viable, and important end point that measures clinical literature, we will first describe principles that we believe underlie benefit on patient functioning that is not adequately captured in specific areas of practice and research. The empirical findings that clinical trials with measures of overall survival or patient support these principles will then be reviewed to provide a performance status (Meyers and Hess, 2003). In the United States, summary of the current knowledge with regard to neurocognitive dysfunction. These principles provide clinicians and researchers government agencies have emphasised the need to develop and utilise multifaceted end points in clinical trials that will measure with a starting point from which further refinement of these disease-related symptoms and/or quality of life. In addition to concepts are expected. Finally, we will highlight key issues that monitoring neurotoxicity, neurocognitive function has been may improve future research and patient care. demonstrated to be a sensitive predictor of patient survival (Meyers et al, 2000b), and change in neurocognitive function has been found to precede MRI evidence of tumour recurrence in RADIOTHERAPY glioma patients (Armstrong et al, 2003; Meyers and Hess, 2003). Such findings have prompted the incorporation of neuropsycho- Principle: Radiotherapy, whether incidental or directed principally logical evaluations in the clinical care of cancer patients (Meyers, at brain tissue, produces a predictable pattern of neurocognitive and 1997). neurobehavioural alterations. The development of these features Advances in the successful treatment of cancer have been and the time course are strongly related to treatment parameters, achieved largely by an increased aggressiveness of therapy, which concomitant adjuvant therapy, and patient characteristics. now generally combines surgery, radiation, cytotoxic drugs, and The adverse effects of radiation to the brain, both as primary immunotherapy. Unfortunately, cancer treatments are not highly CNS therapy and prophylactic treatment, have been previously specific and place normal tissues and organs at risk. The CNS is reviewed in detail (Crossen et al, 1994; Keime-Guibert et al, 1998). vulnerable to many types of cancer treatments, both systemic and The development of neurologic and/or neuropsychological dys- those directed against CNS tumours. In addition, many adjuvant function is often the greatest dose-limiting factor of radiotherapy medications necessary for the treatment of medical complications (XRT). Pathologically, autopsy reports have suggested that radio- therapy primarily affects the white matter tracts and cerebral vasculature of the brain via two mechanisms: (1) damaging *Correspondence: Dr CA Meyers, Department of Neuro-Oncology, oligodendrocytes, thereby creating axonal demyelination and (2) 1515 Holcombe Blvd., Unit 431, Houston, TX 77030-4009, USA; disrupting vascular endothelial cells contributing to coagulative E-mail: [email protected] necrosis, vessel wall thickening, and focal mineralisation. Owing to Received 25 November 2003; revised 16 February 2004; accepted 16 the relative density of white matter in frontal and subcortical areas, February 2004; published online 6 April 2004 cognitive impairments consistent with frontal network systems Neuropsychological dysfunction associated with cancer JS Wefel et al dysfunction are common, including impaired processing speed, Certain agents are known to be particularly neurotoxic. For attention (e.g. working memory), learning efficiency and memory instance, methotrexate and 5-FU can cause diffuse white matter retrieval, executive function (e.g. mental flexibility), and often changes on neuroimaging. Other agents have been found to affect bilateral decline in motor function (e.g. fine motor dexterity) specific neuroanatomical structures preferentially. For example, (Crossen et al, 1994; Gregor et al, 1996; Meyers et al, 2000a). CI-980 selectively affects memory by binding to tubulin at the col- The occurrence of radiation encephalopathy has been most well chicine binding site and selectively blocking choline acetyltrans- studied in patients receiving either conventional, hyperfractio- ferase in the hippocampus and basal forebrain (Meyers et al, 1997). nated, or whole brain radiotherapy. The effects of stereotactic Reports of neurophysiologic and functional neuroimaging radiosurgery and intensity modulated radiotherapy are currently abnormalities in breast cancer survivors previously treated with unknown. Radiation encephalopathy has been separated into three adjuvant chemotherapy have also been observed. However, the stages: acute reaction, early-delayed reaction, and late-delayed relationship between these indices of brain function and neuro- reaction (Sheline, 1977). Radiation to the brain is rarely cognitive function is not one-to-one. Schagen et al (2001) administered without systemic chemotherapy for the primary examined event-related potentials, quantitative electroencephalo- disease, and it is often not possible to separate the adverse effects graphy, and neurocognitive function approximately 2 years after of radiation from chemotherapy. The toxicity of radiation is likely chemotherapy in women with breast cancer who received high, synergistic with concurrent chemotherapy (Crossen et al, 1994). standard, or no chemotherapy. They found asymmetry of the alpha Thus, discussion of treatment effects will assume that the toxicity rhythm in a subset of the patients who previously received is caused primarily by cranial irradiation, although the possible chemotherapy that was not associated with neurocognitive test synergistic toxicity of multimodality therapy is yet to be fully results or emotional distress. Silverman et al (2003) examined the delineated. Risk factors for developing XRT-induced cognitive relationship between regional cerebral metabolism in breast cancer dysfunction and radiation necrosis include age 460 years old, survivors. Women who had previously received chemotherapy 42 Gy dose per fraction, higher total dose, greater volume of brain alone evidenced hypometabolism in the superior frontal gyrus of irradiated, hyperfractionated schedules, shorter overall treatment the dorsolateral prefrontal cortex as well as Broca’s area and its time, concomitant or subsequent use of chemotherapy, and homologous counterpart in the nondominant hemisphere. Further, presence of comorbid vascular risk factors (e.g. diabetes) (Crossen women who received tamoxifen (TAM) in addition to chemother- et al, 1994; Lee et al, 2002). apy evidenced even greater hypometabolism. A transient acute encephalopathy, resulting in generalised A recent meta-analysis examining the neurocognitive sequelae neurocognitive dysfunction, has been described, which is thought of chemotherapy in adults reported that compared to normative to be related to breakdown of the blood–brain barrier and is data, control samples, or baseline test performance, patients occasionally associated with focal neurologic signs, suggesting receiving adjuvant chemotherapy experienced declines in six out recurrent neoplasm (Crossen et al, 1994). However, the incidence of seven neurocognitive domains evaluated (i.e. attention, proces- of early-delayed effects of radiotherapy has been reduced with sing speed, verbal memory, visuospatial, executive and motor corticosteroid therapy. Studies of the neurocognitive functioning function). Memory and executive function reached statistical of patients surviving more than a year postradiotherapy have significance and demonstrated a rather large effect size (Cohen’s yielded conflicting results. Meyers et al (2000a) reported on a d approximately 0.9). Motor function exhibited a smaller effect size cohort of patients who received paranasal sinus radiation between (approximately 0.5), but also reached statistical significance. 20 months and 20 years prior. Neuropsychological test results Importantly, when only studies that used longitudinal designs revealed 80% of the patients exhibited impaired memory, incorporating baseline evaluations were examined, none of the approximately 33% manifested slowed visuomotor speed, execu- cognitive domains reached significance and all demonstrated only tive dysfunction, and poor fine motor dexterity. Others have failed modest effect sizes (Anderson-Hanley et al, 2003). to find significant late-delayed neurocognitive dysfunction as a Longitudinal investigations that measure patient’s baseline result of radiotherapy (Vigliani et al, 1996; Torres et al, 2003). neurocognitive and neurobehavioural function prior to adjuvant Differences in reported radiotherapy-associated cognitive dysfunc- therapy are required to measure idiographic change in function tion (incidence estimates that vary from 0 to 86%) may in part be and to parse out neurocognitive impairment caused by the disease related to differences in treatment variables, study methodology, from that caused by the treatment. For example, Meyers et al and the disease that is being treated. (1995a) demonstrated that a 70–80% of patients with small-cell lung cancer have memory deficits, 38% have deficits in executive functions, and 33% have impaired motor coordination before treatment is initiated. CHEMOTHERAPY Several centres (McAllister et al, 2000; Fliessbach et al, 2003) Principle: Adjuvant chemotherapy has been associated with have demonstrated the ability to deliver potentially neurotoxic decrements of neurocognitive and neurobehavioural functioning therapies without inducing neurocognitive dysfunction. These during the acute phase, but the persistence of these sequelae remain prospectively designed trials of treatment protocols involving controversial. intravenous, intra-arterial, or intraventricular multiagent che- Although chemotherapy has proven beneficial in the treatment motherapy with blood–brain barrier disruption for the treatment of a variety of malignancies, these treatments may have both acute of primary CNS lymphoma reported no significant neurocognitive and persistent adverse effects on the nervous system (Keime- dysfunction in patients who achieve a durable remission 1 year Guibert et al, 1998). A variety of nonspecific neurological after treatment. Despite limitations in our understanding of complications associated with chemotherapy have been described, chemotherapy-related neurotoxicity, there has been growing including: (1) an acute encephalopathy characterised by a concern that subgroups of patients develop iatrogenically pro- confusional state, insomnia, and often agitation, which is duced neurocognitive dysfunction that can be disabling in severity. commonly believed to resolve off treatment; (2) chronic encepha- lopathy characterised by cognitive dysfunction consistent with a ‘subcortical dementia’, incontinence, and gait disturbance; (3) BIOIMMUNOTHERAPY stroke-like episodes associated with transient motor impairments; (4) a cerebellar syndrome with symptoms ranging from ataxia to a Priniciple: Biologic response modifiers are frequently associated pancerebellar syndrome; and (5) a variety of peripheral neuro- with both acute neurobehavioural and neurocognitive alterations. pathies. Exogenous treatment with proinflammatory cytokines contributes British Journal of Cancer (2004) 90(9), 1691 – 1696 & 2004 Cancer Research UK Neuropsychological dysfunction associated with cancer JS Wefel et al to alterations of neurotransmitter systems, hypothalamic-pitui- coordination have been reported. The severity of these impair- tary–adrenal axis endocrine function, and secondary messengers. ments varies, but has occasionally been reported to result in However, the persistence of these untoward effects and the efficacy impairments of daily living and vocational function. of treatments that limit or prevent these effects are poorly Tamoxifen is a widely used selective oestrogen receptor understood. modulator (SERM) for the treatment of breast cancer. It is Proinflammatory cytokines have been reported to have both estimated that approximately 11% of women will develop breast direct and indirect effects on CNS function through the alteration cancer in their lifetime. Moreover, in the United States, it is of neurotransmitters, neuroendocrine function, and induction of estimated that based on year 2000 census data more than 2 million secondary cytokine activity. These cascades produce a host of women could benefit from prophylactic use of TAM (Freedman neurobehavioural sequelae that have been termed ‘sickness et al, 2003), highlighting the importance of understanding the behaviour’ (Kelley et al, 2003). Symptoms of sickness behaviour potential neurocognitive side effects of this agent. TAM is known include fever, weakness, malaise, listlessness, and concentration to have both agonist and antagonist effects in the periphery and in difficulties. In addition, more than 50% of patients receiving the brain (McKenna et al, 1992). It has also been reported to cytokine therapy have documented neurocognitive impairments influence the production of proinflammatory cytokines (IL-1, IL-6, (Meyers and Abbruzzese, 1992). For a review of these agents, their and TNF) that are associated with cognitive dysfunction (Jarvinen mechanisms of action, and potential treatment strategies refer to et al, 1996). Retrospective investigations examining the neurotoxic Meyers and Valentine (1995b) and Trask et al (2000). effects of chemotherapy on neurocognitive function in breast Patients who manifest neurotoxicity subsequent to endogenous cancer patients have not found differences between women who administration of cytokines develop neurocognitive deficits that either received or did not receive TAM subsequent to chemother- are consistent with frontal network systems dysfunction including apy (Schagen et al, 1999). However, PET imaging has demon- diminished information processing speed and simple reaction strated greater prefrontal hypometabolism in women with time, attentional and executive dysfunction, reduced learning and treatment histories that included both chemotherapy and TAM memory, impaired fine motor dexterity, and neurobehavioural compared to women treated with chemotherapy alone (Silverman sequelae including ‘sickness behaviour’, depression, and anxiety et al, 2003). (Valentine et al, 1998; Trask et al, 2000). Investigations utilising Paganini-Hill and Clark (2000) reported that women who functional neuroimaging have demonstrated abnormalities in previously used TAM performed similarly on a neurocognitive frontal regions that parallel the neurocognitive findings (Meyers screen when compared to a group of breast cancer survivors never et al, 1994; Juengling et al, 2000). exposed to TAM, while current TAM users had slightly less The neurovegetative and somatic symptoms associated with complex narrative writing samples. However, this methodology is IFN-a neurotoxicity have been reported to occur within the first 2 ineffective for examining cognitive function and potentially yields weeks of treatment, whereas the cognitive and mood symptoms useless data. We have been engaged in a prospective, longitudinal often develop within 8–12 weeks after initiating treatment trial utilising a comprehensive neuropsychological assessment to (Capuron et al, 2001). This observation is consistent with other determine the neurocognitive and neurobehavioural sequelae reports that the length of treatment, dose, and route of associated with adjuvant TAM therapy. Our unpublished pre- administration appear to be key factors related to the development liminary findings suggest that a subgroup of women taking TAM of neurotoxicity (Meyers, 1997). Although these symptoms may experience a significant neurotoxicity consisting of memory, persist for a small subgroup, most can be successfully palliated executive, and motor dysfunction associated with increased with prophylactic or symptomatic antidepressant therapy for affective distress, decreased QOL, and diminished ability to neurobehavioural symptoms (Musselman et al, 2001), stimulant maintain productive activities. This trial is also examining therapy for fatigue and neurobehavioural slowing, and opiate potential mechanisms responsible for this neurotoxicity including antagonist therapy for cognitive disorders (Valentine et al, 1998). alterations in circulating levels of proinflammatory cytokines as well as fluctuations in stress and sex hormones. A number of other SERMs and aromotase inhibitors are currently being investigated for clinical use and may also be associated with similar reports of HORMONAL THERAPY neurotoxicity. Principle: Abrupt alteration of an individual’s hormonal milieu has Testosterone supplementation has been reported to enhance been associated with neurocognitive and neurobehavioural impair- cognitive function in healthy older men (Cherrier et al, 2001). The ments. The effects of more insidious and less direct hormonal hippocampus contains testosterone receptors as well as estradiol alterations are largely unknown. receptors, and thus it is unclear if these beneficial effects arise Oestrogen receptors have been discovered in many areas of the through the androgen receptors or via aromitisation to estradiol, brain important for cognitive functioning including the hypotha- or both. Hormonal challenges in men via administration of lamus, anterior pituitary, amygdala, and CA1 of the hippocampus luteinising hormone-releasing hormone agonists, such as leupro- (McEwen and Alves, 1999). Human and animal studies (Yaffe et al, lide or goserelin, also may adversely affect hippocampal function 1998) have elucidated several possible mechanisms through which through these hormonal channels. There are inconsistent findings oestrogen affects neurocognitive and neurobehavioural function with regard to the safety profile of androgen ablating agents, with including: (1) increasing cholinergic activity through its actions on some authors reporting no evidence of neurocognitive decline or choline acetyltransferase; (2) maintenance of dendritic spine neurobehavioural dysfunction (Salminen et al, 2003), and others density on CA1 pyramidal cells of the hippocampus; (3) facilitating finding impaired memory, attention, and executive function induction of long-term potentiation in the hippocampus; (4) (Green et al, 2002). increasing serotonergic and cholinergic activity, thereby main- taining neural circuitry; (5) altering lipoprotein; and (6) decreasing the risk of cerebral ischaemia. ADJUVANT MEDICATIONS AND MEDICAL The effects of hormonal challenges in women (e.g. antioestro- COMPLICATIONS gens) have been examined with both neuroimaging (Berman et al, 1997) and neurocognitive probes (Varney et al, 1993, Rich and Priniciple: The assessment of cognitive dysfunction secondary to Maki, 1999). In summary, a pattern of relative hypometabolism in cancer treatment is complicated by the use of supportive medica- prefrontal cortex has been demonstrated with PET, and neuro- tions (e.g. steroids, immunosuppressive agents, anticonvulsants) cognitive impairments in memory, executive function, and motor that can alter cognitive function. & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1691 – 1696 Neuropsychological dysfunction associated with cancer JS Wefel et al In addition to the neurotoxic effects of primary cancer therapy, diverse skills. Although the administration of tests is a relatively adjuvant medications such as steroids, anticonvulsants, and pain simple endeavour, interpretation of test scores relies heavily on the medications may also cause neurocognitive and neurobehavioural clinician’s interviewing skills, appreciation of social and cultural symptoms. The use of glucocorticoids is ubiquitous and is factors, understanding of test construction and psychometrics, associated with a 5–50% incidence of steroid-induced psychiatric psychodiagnostic skills, and knowledge of the human nervous syndromes including euphoria, mania, insomnia, restlessness, and system (see Figure 1). increased motor activity. Glucocorticoids have been implicated in The contemporary scientific literature is cluttered with poorly the development of memory dysfunction across a variety of designed studies that may lead investigators and the readership to conditions including chronic stress and post-traumatic stress incorrect conclusions. Clinicians and researchers must keep a few disorder. Certain anticonvulsants (e.g. topiramate, phenobarbital) basic principles in mind when developing a plan for assessment. are also known to have adverse neurocognitive effects. Both First, test selection will vary depending on the question under seizure frequency and the use of anticonvulsants have been consideration. Second, the measures chosen should have alternate demonstrated to adversely impact neurocognitive function in forms or be relatively resistant to practice effects, characteristics brain tumour patients (Klein et al, 2003). Pharmacologic inter- that are especially important if one plans to test patients vention for symptoms of pain may cause sedation and associated repeatedly. Third, selected measures should be psychometrically diminution of neurocognitive function. sound, with established reliability and validity, and appropriate Abnormalities in endocrinologic function secondary to hy- normative studies. Finally, it is important to select measures that pothalamic/pituitary injury are very common following radio- are sensitive to subtle changes in cognitive function often therapy. Thyroid dysfunction, loss of libido, and erectile experienced by patients with cancer. Attention, processing speed, dysfunction are present in a large proportion of patients. learning/memory functions, and motor skills are particularly Endocrinologic replacement therapy has the potential to improve vulnerable and should be carefully evaluated for signs of neurocognitive and neurobehavioural function in patients who dysfunction. have abnormal hormone levels. Anaemia is a side effect of some chemotherapeutic regimens that is associated with both fatigue and neurocognitive dysfunction. Epoetin alpha therapy has been SUMMARY found to minimise neurocognitive decline in breast cancer patients receiving anthracycline-based chemotherapies relative to placebo Cancer is becoming a chronic illness, requiring on-going symptom (O’Shaughnessy, 2002). The aetiology of cancer-related fatigue is assessment and intervention. The number of long-term cancer likely multifactorial and includes anaemia, cachexia, systemic survivors will continue to increase as will the number of survivors illness, pain, and medications (Kurzrock, 2001). Both peripheral with neurocognitive and/or neurobehavioural impairment. It is and central factors associated with cytokine production may be important to note that treatment-related cognitive decline is not involved in the development and maintenance of this state. universal among cancer patients. Some individuals are able to tolerate treatment with little physical discomfort and no obvious neurocognitive impairments, while others will develop significant toxicities that seriously compromise their perceived quality of life NEUROPSYCHOLOGICAL ASSESSMENT and prevent them from resuming their usual social and occupa- Although the importance of cognitive evaluations in the care of tional roles. However, any adverse effects of cancer treatment must cancer patients and in clinical cancer trials is receiving greater always be considered in the light of potential therapeutic benefits. recognition, assessment methods remain less than optimal in most The nature of neurocognitive and neurobehavioural dysfunction cases. Cognitive assessment is a complex undertaking that requires is yet to be fully characterised. Methodological challenges have Seed Soil Pesticides (patient factors) (disease factors) (treatment factors) e.g. Diagnosis, location, tumour burden, e.g. Age, education, medical history, e.g. Primary and adjuvant therapies, disease course current symptoms, behavioural observations medications for symptom control, complementary therapies Test selection e.g. Psychometric issues, relevance and compatibility with the purpose of the assessment Interpretation, prognostication and treatment Integration of these sources of information requires understanding of human behaviour, CNS function, disease process, treatment effects, test pattern analysis, and knowledge of cognitive/behavioural/pharmacological interventions Figure 1 Considerations for the cognitive assessment of the oncology patient. British Journal of Cancer (2004) 90(9), 1691 – 1696 & 2004 Cancer Research UK Neuropsychological dysfunction associated with cancer JS Wefel et al plagued research in this area and seemingly contradictory findings disease, treatment, and patient factors in the manifestation of saturate the existing literature. Increased inclusion of comprehen- altered neurocognitive and neurobehavioural function. These sive neuropsychological evaluations in clinical research will further multidisciplinary investigations will identify which agents are our understanding of the nature, severity, and processes under- most neurotoxic in the context of different treatment regimens, the lying neurocognitive dysfunction in the patient with cancer. course of the neurocognitive and neurobehavioural dysfunction, Multidisciplinary investigations are essential. Utilising advances the cognitive and neurobehavioural domains most affected, the in neuropsychology, cognitive neuroscience, genomics, proteo- mechanisms for these effects, the host risk factors that create a nomics, molecular epidemiology, functional neuroimaging, neu- diathesis for the expression of this neurotoxicity, and which roimmunology, and traditional oncologic disciplines will neuroprotective or rehabilitative therapies may be most efficacious ultimately contribute to understanding the relationships between in preventing or treating these adverse symptoms. REFERENCES Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE (2003) affecting risk of symptomatic temporal lobe necrosis: significance of Neuropsychological effects of treatments for adults with cancer: a meta- fractional dose and treatment time. Int J Radiat Oncol Biol Phys 53: 75– analysis and review of the literature. J Int Neuropsychol Soc 9: 967–982 85 Armstrong CL, Goldstein B, Shera D, Ledakis GE, Tallent EM (2003) The McAllister L, Doolittle N, Guastadisegni PE, Kraemer DF, Lacy C, Crossen predictive value of longitudinal neuropsychologic assessment in the early JR, Neuwalt EA (2000) Cognitive outcomes and long-term follow-up detection of brain tumor recurrence. Cancer 97: 649–656 results after enhanced chemotherapy delivery for primary central Berman KF, Schmidt PJ, Rubinow DR, Danaceau MA, Van Horn JD, nervous system lymphoma. Neurosurgery 46: 51–61 Esposito G, Ostrem JL, Weinberger DR (1997) Modulation of cognition- McEwen BS, Alves SE (1999) Estrogen actions in the central nervous specific cortical activity by gonadal steroids: a positron-emission system. Endocr Rev 20: 279–307 tomography study in women. Proc Natl Acad Sci USA 94: 8836–8841 McKenna SE, Simon NG, Cologer-Clifford A (1992) An assessment of Capuron L, Ravaud A, Dantzer R (2001) Timing and specificity of the agonist/antagonist effects of tamoxifen in the female mouse brain. Horm cognitive changes induced by interleukin-2 and interferon-alpha Behav 26: 536–544 treatments in cancer patients. Psychosom Med 63: 376–386 Meyers CA (1997) Issues of quality of life in neuro-oncology. In Handbook Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, of Clinical Neurology, Neuro-Oncology, Part 1. Brain Tumors: Principles Raskind MA, Brodkin K, Bremmer W, Petrova A, LaTendresse S, Craft S of Biology, Diagnosis and Therapy, Vol. 23, Vecht ChJ (ed) pp 389–409. (2001) Testosterone supplementation improves spatial and verbal Amsterdam: Elsevier Science B.V. memory I healthy older men. Neurology 57: 80–89 Meyers CA, Abbruzzese JL (1992) Cognitive functioning in cancer patients: Crossen JR, Garwood D, Glatstein E, Neuwalt EA (1994) Neurobehavioral effect of previous treatment. Neurology 42: 434–436 sequelae of cranial irradiation in adults: a review of radiation-induced Meyers CA, Byrne KS, Komaki R (1995a) Cognitive deficits in patients with encephalopathy. J Clin Oncol 12: 627–642 small cell lung cancer before and after chemotherapy. Lung Cancer 12: Fliessbach K, Urbach H, Helmstaedter C, Pels H, Glasmacher A, Kraus JA, 231–235 Klockgether T, Schmidt-Wolf I, Schlegel U (2003) Cognitive performance Meyers CA, Geara F, Wong P-F, Morrison WH (2000a) Neurocognitive and magnetic resonance imaging findings after high-dose systemic and effects of therapeutic irradiation for base of skull tumors. Int J Radiat intraventricular chemotherapy for primary central nervous system Oncol Biol Phys 46: 51–55 lymphoma. Arch Neurol 60: 53–568 Meyers CA, Hess KR (2003) Multifaceted end points in brain tumor clinical Freedman AN, Graubard BI, Rao SR, McCaskill-Stevens W, Ballrad-Barbash trials: cognitive deterioration precedes MRI progression. Neuro-Oncology R, Gail MH (2003) Estimates of the number of US women who could 5: 89–95 benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Meyers CA, Hess KR, Yung WKA, Levin VA (2000b) Cognitive function as a Inst 95: 526–532 predictor of survival in patients with recurrent malignant glioma. J Clin Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, Oncol 18: 646– 650 Swanson C, Watson RB, Gardiner RA (2002) Altered cognitive function Meyers CA, Kudelka AP, Conrad CA, Gelke CK, Grove W, Pazdur R (1997) in men treated for prostate cancer with luteinizing hormone-releasing Neurotoxicity of CI-980, a novel mitotic inhibitor. Clin Cancer Res 3: hormone analogues and cyproterone acetate: a randomized controlled 419–422 trial. Br J Urol 90: 427–432 Meyers CA, Valentine AD (1995b) Neurological and psychiatric adverse Gregor A, Cull A, Traynor E, Stewart M, Lander F, Love S (1996) effects of immunological therapy. CNS Drugs 3: 56–68 Neuropsychometric evaluation of long-term survivors of adult brain Meyers CA, Valentine AD, Wong FCL, Leeds NE (1994) Reversible tumours: relationship with tumour and treatment parameters. Radiother neurotoxicity of interleukin-2 and tumor necrosis factor: correlation of Oncol 41: 55–59 SPECT with neuropsychological testing. J Neuropsychiatry 6: 285–288 Ja¨rvinen LS, Pyrho¨nen S, Kairemo KJA, Paavonen T (1996) The effect of Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, anti-oestrogens on cytokine production in vitro. Scand J Immunol 44: Goodkin RS Greiner K, Nemeroff CB, Miller AH (2001) Paroxetine for the 15–20 prevention of depression induced by high-dose interferon alfa. N Engl J Juengling FD, Ebert D, Gut O, Engelbrecht MA, Rasenack J, Nitsche EU, Med 344: 961–966 Bauer J, Lieb K (2000) Prefrontal cortical hypometabolism during low- O’Shaughnessy JA (2002) Effects of epoetin alpha on cognitive function, dose interferon alpha treatment. Psychopharmacology (Berl) 152: 383– mood, asthenia, and quality of life in women with breast cancer 389 undergoing adjuvant chemotherapy. Clin Breast Cancer 3: S116–S120 Keime-Guibert F, Napolitano M, Delattre J-Y (1998) Neurological Paganini-Hill A, Clark LJ (2000) Preliminary assessment of cognitive complications of radiotherapy and chemotherapy. J Neurol 245: 695–708 function in breast cancer patients treated with tamoxifen. Breast Cancer Kelley KW, Bluthe R-M, Dantzer R, Zhou J-H, Shen W-H, Johnson RW, Res Treat 64: 165–176 Broussard SR (2003) Cytokine-induced sickness behavior. Brain Behav Rich JB, Maki P (1999) Estrogen, testosterone, and the brain: a review of Immun 17: S112–S118 neuropsychological, aging, and neuroimaging studies. J Int Neuropsychol Klein M, Engelberts HJ, van der Ploeg H, Kasteleijn-Nolst Trenite DGA, Soc 6: iii Aaronson NK, Taphoorn MJB, Baaijen H, Vandertop WP, Muller M, Salminen E, Portin R, Korpela J, Backman H, Parvinen L-M, Helenius H, Postma TJ, Heimans JJ (2003) Epilepsy in low-grade gliomas: the impact Nurmi M (2003) Androgen deprivation and cognition in prostate cancer. on cognitive function and quality of life. Ann Neurol 54: 514–520 Br J Cancer 89: 971–976 Kurzrock R (2001) The role of cytokines in cancer-related fatigue. Cancer Schagen SB, Hamburger HL, Muller MJ, Boogerd W, van Dam FSAM (2001) 92: 1684–1688 Neurophysiological evaluation of late effects of adjuvant high-dose Lee AW, Kwong DLW, Leung S-F, Tung SY, Sze W-M, Sham JST, Teo PML, chemotherapy on cognitive function. J Neurooncol 51: 159–165 Leung t-W, Wu P-M, Chappell R, Peters LJ, Fowler JF (2002) Factors Sheline GE (1977) Radiation therapy of brain tumors. Cancer 39: 873–881 & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1691 – 1696 Neuropsychological dysfunction associated with cancer JS Wefel et al Silverman DH, Castellon SA, Abraham L, Dy CJ, Pio BS, Ganz PA (2003) Varney NR, Syrop C, Kubu CS, Struchen M, Hahn S, Franzen K Abnormal regional brain metabolism in breast cancer survivors after (1993) Neuropsychologic dysfunction in women following leuprolide adjuvant chemotherapy is associated with cognitive changes. Proc Am acetate induction of hypoestrogenism. J Assist Reprod Genet 10: Soc Clin Oncol 22: 12 53–57 Torres IJ, Mundt AJ, Sweeney PJ, Llanes-Macy S, Dunaway L, Castillo M, Vigliani M-C, Sichez N, Poisson M, Delattre J-Y (1996) A prospective study Macdonald RL (2003) A longitudinal neuropsychological study of partial of cognitive functions following conventional radiotherapy for supra- brain radiation in adults with brain tumors. Neurology 60: 1113 –1118 tentorial gliomas in young adults: 4-year results. Int J Radiat Oncol Biol Trask PC, Esper P, Riba M, Redman B (2000) Psychiatric side effects of Phys 35: 527–533 interferon therapy: prevalence, proposed mechanisms, and future Yaffe K, Sawaya G, Lieberburg I, Grady D (1998) Estrogen therapy in directions. J Clin Oncol 18: 2316–2326 postmenopausal women effects of cognitive function and dementia. Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P (1998) Mood JAMA 279: 688–695 and cognitive side effects of interferon-alpha therapy. Semin Oncol 25: 39–47 British Journal of Cancer (2004) 90(9), 1691 – 1696 & 2004 Cancer Research UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target

Wefel, J S; Kayl, A E; Meyers, C A
British Journal of Cancer , Volume 90 (9) – Apr 6, 2004
Download PDF
6 pages

Loading next page...
 
/lp/springer-journals/neuropsychological-dysfunction-associated-with-cancer-and-cancer-0uAvaoN6LV

References (91)

Publisher
Springer Journals
Copyright
Copyright © 2004 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1038/sj.bjc.6601772
Publisher site
See Article on Publisher Site

Abstract

British Journal of Cancer (2004) 90, 1691 – 1696 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Minireview Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target 1,2 1,2 ,1,2 JS Wefel , AE Kayl and CA Meyers Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030-4009, USA; The Brain Tumor Center, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030-4009, USA Neuropsychological dysfunction associated with cancer and cancer treatment is a growing concern. Methodological limitations permeate the corpus of research in this area and have limited our understanding of the multifactorial nature of this process. The following review provides a summary of the current state of knowledge and highlights future directions. British Journal of Cancer (2004) 90, 1691 – 1696. doi:10.1038/sj.bjc.6601772 www.bjcancer.com Published online 6 April 2004 & 2004 Cancer Research UK While it is generally recognised that central nervous system (CNS) also affect CNS function (e.g. steroids, antiepileptics, immunosup- cancer and many of the therapeutic modalities used to treat cancer pressive agents, and drugs used for pain, nausea, and infection). can cause alterations in neurocognitive function, our knowledge There is a burgeoning literature on the neurocognitive effects of about the nature, severity, and course of neurocognitive dysfunc- cancer treatment. Unfortunately, few methodologically rigorous tion is limited. Traditionally, treatment outcome has focused on studies exist to guide clinical practice. Most studies are retro- the length of survival and neurological or physiological changes spective, fail to incorporate assessments of pretreatment neuro- such as peripheral neuropathy, ototoxicity, or encephalopathy cognitive and neurobehavioural function, consist of small and rather than indices of ‘quality of life’, such as neurocognitive heterogeneous samples, lack appropriate control groups, and function. Neurocognitive function has been demonstrated to be a suffer from poor measurement selection. Owing to the state of the sensitive, viable, and important end point that measures clinical literature, we will first describe principles that we believe underlie benefit on patient functioning that is not adequately captured in specific areas of practice and research. The empirical findings that clinical trials with measures of overall survival or patient support these principles will then be reviewed to provide a performance status (Meyers and Hess, 2003). In the United States, summary of the current knowledge with regard to neurocognitive dysfunction. These principles provide clinicians and researchers government agencies have emphasised the need to develop and utilise multifaceted end points in clinical trials that will measure with a starting point from which further refinement of these disease-related symptoms and/or quality of life. In addition to concepts are expected. Finally, we will highlight key issues that monitoring neurotoxicity, neurocognitive function has been may improve future research and patient care. demonstrated to be a sensitive predictor of patient survival (Meyers et al, 2000b), and change in neurocognitive function has been found to precede MRI evidence of tumour recurrence in RADIOTHERAPY glioma patients (Armstrong et al, 2003; Meyers and Hess, 2003). Such findings have prompted the incorporation of neuropsycho- Principle: Radiotherapy, whether incidental or directed principally logical evaluations in the clinical care of cancer patients (Meyers, at brain tissue, produces a predictable pattern of neurocognitive and 1997). neurobehavioural alterations. The development of these features Advances in the successful treatment of cancer have been and the time course are strongly related to treatment parameters, achieved largely by an increased aggressiveness of therapy, which concomitant adjuvant therapy, and patient characteristics. now generally combines surgery, radiation, cytotoxic drugs, and The adverse effects of radiation to the brain, both as primary immunotherapy. Unfortunately, cancer treatments are not highly CNS therapy and prophylactic treatment, have been previously specific and place normal tissues and organs at risk. The CNS is reviewed in detail (Crossen et al, 1994; Keime-Guibert et al, 1998). vulnerable to many types of cancer treatments, both systemic and The development of neurologic and/or neuropsychological dys- those directed against CNS tumours. In addition, many adjuvant function is often the greatest dose-limiting factor of radiotherapy medications necessary for the treatment of medical complications (XRT). Pathologically, autopsy reports have suggested that radio- therapy primarily affects the white matter tracts and cerebral vasculature of the brain via two mechanisms: (1) damaging *Correspondence: Dr CA Meyers, Department of Neuro-Oncology, oligodendrocytes, thereby creating axonal demyelination and (2) 1515 Holcombe Blvd., Unit 431, Houston, TX 77030-4009, USA; disrupting vascular endothelial cells contributing to coagulative E-mail: [email protected] necrosis, vessel wall thickening, and focal mineralisation. Owing to Received 25 November 2003; revised 16 February 2004; accepted 16 the relative density of white matter in frontal and subcortical areas, February 2004; published online 6 April 2004 cognitive impairments consistent with frontal network systems Neuropsychological dysfunction associated with cancer JS Wefel et al dysfunction are common, including impaired processing speed, Certain agents are known to be particularly neurotoxic. For attention (e.g. working memory), learning efficiency and memory instance, methotrexate and 5-FU can cause diffuse white matter retrieval, executive function (e.g. mental flexibility), and often changes on neuroimaging. Other agents have been found to affect bilateral decline in motor function (e.g. fine motor dexterity) specific neuroanatomical structures preferentially. For example, (Crossen et al, 1994; Gregor et al, 1996; Meyers et al, 2000a). CI-980 selectively affects memory by binding to tubulin at the col- The occurrence of radiation encephalopathy has been most well chicine binding site and selectively blocking choline acetyltrans- studied in patients receiving either conventional, hyperfractio- ferase in the hippocampus and basal forebrain (Meyers et al, 1997). nated, or whole brain radiotherapy. The effects of stereotactic Reports of neurophysiologic and functional neuroimaging radiosurgery and intensity modulated radiotherapy are currently abnormalities in breast cancer survivors previously treated with unknown. Radiation encephalopathy has been separated into three adjuvant chemotherapy have also been observed. However, the stages: acute reaction, early-delayed reaction, and late-delayed relationship between these indices of brain function and neuro- reaction (Sheline, 1977). Radiation to the brain is rarely cognitive function is not one-to-one. Schagen et al (2001) administered without systemic chemotherapy for the primary examined event-related potentials, quantitative electroencephalo- disease, and it is often not possible to separate the adverse effects graphy, and neurocognitive function approximately 2 years after of radiation from chemotherapy. The toxicity of radiation is likely chemotherapy in women with breast cancer who received high, synergistic with concurrent chemotherapy (Crossen et al, 1994). standard, or no chemotherapy. They found asymmetry of the alpha Thus, discussion of treatment effects will assume that the toxicity rhythm in a subset of the patients who previously received is caused primarily by cranial irradiation, although the possible chemotherapy that was not associated with neurocognitive test synergistic toxicity of multimodality therapy is yet to be fully results or emotional distress. Silverman et al (2003) examined the delineated. Risk factors for developing XRT-induced cognitive relationship between regional cerebral metabolism in breast cancer dysfunction and radiation necrosis include age 460 years old, survivors. Women who had previously received chemotherapy 42 Gy dose per fraction, higher total dose, greater volume of brain alone evidenced hypometabolism in the superior frontal gyrus of irradiated, hyperfractionated schedules, shorter overall treatment the dorsolateral prefrontal cortex as well as Broca’s area and its time, concomitant or subsequent use of chemotherapy, and homologous counterpart in the nondominant hemisphere. Further, presence of comorbid vascular risk factors (e.g. diabetes) (Crossen women who received tamoxifen (TAM) in addition to chemother- et al, 1994; Lee et al, 2002). apy evidenced even greater hypometabolism. A transient acute encephalopathy, resulting in generalised A recent meta-analysis examining the neurocognitive sequelae neurocognitive dysfunction, has been described, which is thought of chemotherapy in adults reported that compared to normative to be related to breakdown of the blood–brain barrier and is data, control samples, or baseline test performance, patients occasionally associated with focal neurologic signs, suggesting receiving adjuvant chemotherapy experienced declines in six out recurrent neoplasm (Crossen et al, 1994). However, the incidence of seven neurocognitive domains evaluated (i.e. attention, proces- of early-delayed effects of radiotherapy has been reduced with sing speed, verbal memory, visuospatial, executive and motor corticosteroid therapy. Studies of the neurocognitive functioning function). Memory and executive function reached statistical of patients surviving more than a year postradiotherapy have significance and demonstrated a rather large effect size (Cohen’s yielded conflicting results. Meyers et al (2000a) reported on a d approximately 0.9). Motor function exhibited a smaller effect size cohort of patients who received paranasal sinus radiation between (approximately 0.5), but also reached statistical significance. 20 months and 20 years prior. Neuropsychological test results Importantly, when only studies that used longitudinal designs revealed 80% of the patients exhibited impaired memory, incorporating baseline evaluations were examined, none of the approximately 33% manifested slowed visuomotor speed, execu- cognitive domains reached significance and all demonstrated only tive dysfunction, and poor fine motor dexterity. Others have failed modest effect sizes (Anderson-Hanley et al, 2003). to find significant late-delayed neurocognitive dysfunction as a Longitudinal investigations that measure patient’s baseline result of radiotherapy (Vigliani et al, 1996; Torres et al, 2003). neurocognitive and neurobehavioural function prior to adjuvant Differences in reported radiotherapy-associated cognitive dysfunc- therapy are required to measure idiographic change in function tion (incidence estimates that vary from 0 to 86%) may in part be and to parse out neurocognitive impairment caused by the disease related to differences in treatment variables, study methodology, from that caused by the treatment. For example, Meyers et al and the disease that is being treated. (1995a) demonstrated that a 70–80% of patients with small-cell lung cancer have memory deficits, 38% have deficits in executive functions, and 33% have impaired motor coordination before treatment is initiated. CHEMOTHERAPY Several centres (McAllister et al, 2000; Fliessbach et al, 2003) Principle: Adjuvant chemotherapy has been associated with have demonstrated the ability to deliver potentially neurotoxic decrements of neurocognitive and neurobehavioural functioning therapies without inducing neurocognitive dysfunction. These during the acute phase, but the persistence of these sequelae remain prospectively designed trials of treatment protocols involving controversial. intravenous, intra-arterial, or intraventricular multiagent che- Although chemotherapy has proven beneficial in the treatment motherapy with blood–brain barrier disruption for the treatment of a variety of malignancies, these treatments may have both acute of primary CNS lymphoma reported no significant neurocognitive and persistent adverse effects on the nervous system (Keime- dysfunction in patients who achieve a durable remission 1 year Guibert et al, 1998). A variety of nonspecific neurological after treatment. Despite limitations in our understanding of complications associated with chemotherapy have been described, chemotherapy-related neurotoxicity, there has been growing including: (1) an acute encephalopathy characterised by a concern that subgroups of patients develop iatrogenically pro- confusional state, insomnia, and often agitation, which is duced neurocognitive dysfunction that can be disabling in severity. commonly believed to resolve off treatment; (2) chronic encepha- lopathy characterised by cognitive dysfunction consistent with a ‘subcortical dementia’, incontinence, and gait disturbance; (3) BIOIMMUNOTHERAPY stroke-like episodes associated with transient motor impairments; (4) a cerebellar syndrome with symptoms ranging from ataxia to a Priniciple: Biologic response modifiers are frequently associated pancerebellar syndrome; and (5) a variety of peripheral neuro- with both acute neurobehavioural and neurocognitive alterations. pathies. Exogenous treatment with proinflammatory cytokines contributes British Journal of Cancer (2004) 90(9), 1691 – 1696 & 2004 Cancer Research UK Neuropsychological dysfunction associated with cancer JS Wefel et al to alterations of neurotransmitter systems, hypothalamic-pitui- coordination have been reported. The severity of these impair- tary–adrenal axis endocrine function, and secondary messengers. ments varies, but has occasionally been reported to result in However, the persistence of these untoward effects and the efficacy impairments of daily living and vocational function. of treatments that limit or prevent these effects are poorly Tamoxifen is a widely used selective oestrogen receptor understood. modulator (SERM) for the treatment of breast cancer. It is Proinflammatory cytokines have been reported to have both estimated that approximately 11% of women will develop breast direct and indirect effects on CNS function through the alteration cancer in their lifetime. Moreover, in the United States, it is of neurotransmitters, neuroendocrine function, and induction of estimated that based on year 2000 census data more than 2 million secondary cytokine activity. These cascades produce a host of women could benefit from prophylactic use of TAM (Freedman neurobehavioural sequelae that have been termed ‘sickness et al, 2003), highlighting the importance of understanding the behaviour’ (Kelley et al, 2003). Symptoms of sickness behaviour potential neurocognitive side effects of this agent. TAM is known include fever, weakness, malaise, listlessness, and concentration to have both agonist and antagonist effects in the periphery and in difficulties. In addition, more than 50% of patients receiving the brain (McKenna et al, 1992). It has also been reported to cytokine therapy have documented neurocognitive impairments influence the production of proinflammatory cytokines (IL-1, IL-6, (Meyers and Abbruzzese, 1992). For a review of these agents, their and TNF) that are associated with cognitive dysfunction (Jarvinen mechanisms of action, and potential treatment strategies refer to et al, 1996). Retrospective investigations examining the neurotoxic Meyers and Valentine (1995b) and Trask et al (2000). effects of chemotherapy on neurocognitive function in breast Patients who manifest neurotoxicity subsequent to endogenous cancer patients have not found differences between women who administration of cytokines develop neurocognitive deficits that either received or did not receive TAM subsequent to chemother- are consistent with frontal network systems dysfunction including apy (Schagen et al, 1999). However, PET imaging has demon- diminished information processing speed and simple reaction strated greater prefrontal hypometabolism in women with time, attentional and executive dysfunction, reduced learning and treatment histories that included both chemotherapy and TAM memory, impaired fine motor dexterity, and neurobehavioural compared to women treated with chemotherapy alone (Silverman sequelae including ‘sickness behaviour’, depression, and anxiety et al, 2003). (Valentine et al, 1998; Trask et al, 2000). Investigations utilising Paganini-Hill and Clark (2000) reported that women who functional neuroimaging have demonstrated abnormalities in previously used TAM performed similarly on a neurocognitive frontal regions that parallel the neurocognitive findings (Meyers screen when compared to a group of breast cancer survivors never et al, 1994; Juengling et al, 2000). exposed to TAM, while current TAM users had slightly less The neurovegetative and somatic symptoms associated with complex narrative writing samples. However, this methodology is IFN-a neurotoxicity have been reported to occur within the first 2 ineffective for examining cognitive function and potentially yields weeks of treatment, whereas the cognitive and mood symptoms useless data. We have been engaged in a prospective, longitudinal often develop within 8–12 weeks after initiating treatment trial utilising a comprehensive neuropsychological assessment to (Capuron et al, 2001). This observation is consistent with other determine the neurocognitive and neurobehavioural sequelae reports that the length of treatment, dose, and route of associated with adjuvant TAM therapy. Our unpublished pre- administration appear to be key factors related to the development liminary findings suggest that a subgroup of women taking TAM of neurotoxicity (Meyers, 1997). Although these symptoms may experience a significant neurotoxicity consisting of memory, persist for a small subgroup, most can be successfully palliated executive, and motor dysfunction associated with increased with prophylactic or symptomatic antidepressant therapy for affective distress, decreased QOL, and diminished ability to neurobehavioural symptoms (Musselman et al, 2001), stimulant maintain productive activities. This trial is also examining therapy for fatigue and neurobehavioural slowing, and opiate potential mechanisms responsible for this neurotoxicity including antagonist therapy for cognitive disorders (Valentine et al, 1998). alterations in circulating levels of proinflammatory cytokines as well as fluctuations in stress and sex hormones. A number of other SERMs and aromotase inhibitors are currently being investigated for clinical use and may also be associated with similar reports of HORMONAL THERAPY neurotoxicity. Principle: Abrupt alteration of an individual’s hormonal milieu has Testosterone supplementation has been reported to enhance been associated with neurocognitive and neurobehavioural impair- cognitive function in healthy older men (Cherrier et al, 2001). The ments. The effects of more insidious and less direct hormonal hippocampus contains testosterone receptors as well as estradiol alterations are largely unknown. receptors, and thus it is unclear if these beneficial effects arise Oestrogen receptors have been discovered in many areas of the through the androgen receptors or via aromitisation to estradiol, brain important for cognitive functioning including the hypotha- or both. Hormonal challenges in men via administration of lamus, anterior pituitary, amygdala, and CA1 of the hippocampus luteinising hormone-releasing hormone agonists, such as leupro- (McEwen and Alves, 1999). Human and animal studies (Yaffe et al, lide or goserelin, also may adversely affect hippocampal function 1998) have elucidated several possible mechanisms through which through these hormonal channels. There are inconsistent findings oestrogen affects neurocognitive and neurobehavioural function with regard to the safety profile of androgen ablating agents, with including: (1) increasing cholinergic activity through its actions on some authors reporting no evidence of neurocognitive decline or choline acetyltransferase; (2) maintenance of dendritic spine neurobehavioural dysfunction (Salminen et al, 2003), and others density on CA1 pyramidal cells of the hippocampus; (3) facilitating finding impaired memory, attention, and executive function induction of long-term potentiation in the hippocampus; (4) (Green et al, 2002). increasing serotonergic and cholinergic activity, thereby main- taining neural circuitry; (5) altering lipoprotein; and (6) decreasing the risk of cerebral ischaemia. ADJUVANT MEDICATIONS AND MEDICAL The effects of hormonal challenges in women (e.g. antioestro- COMPLICATIONS gens) have been examined with both neuroimaging (Berman et al, 1997) and neurocognitive probes (Varney et al, 1993, Rich and Priniciple: The assessment of cognitive dysfunction secondary to Maki, 1999). In summary, a pattern of relative hypometabolism in cancer treatment is complicated by the use of supportive medica- prefrontal cortex has been demonstrated with PET, and neuro- tions (e.g. steroids, immunosuppressive agents, anticonvulsants) cognitive impairments in memory, executive function, and motor that can alter cognitive function. & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1691 – 1696 Neuropsychological dysfunction associated with cancer JS Wefel et al In addition to the neurotoxic effects of primary cancer therapy, diverse skills. Although the administration of tests is a relatively adjuvant medications such as steroids, anticonvulsants, and pain simple endeavour, interpretation of test scores relies heavily on the medications may also cause neurocognitive and neurobehavioural clinician’s interviewing skills, appreciation of social and cultural symptoms. The use of glucocorticoids is ubiquitous and is factors, understanding of test construction and psychometrics, associated with a 5–50% incidence of steroid-induced psychiatric psychodiagnostic skills, and knowledge of the human nervous syndromes including euphoria, mania, insomnia, restlessness, and system (see Figure 1). increased motor activity. Glucocorticoids have been implicated in The contemporary scientific literature is cluttered with poorly the development of memory dysfunction across a variety of designed studies that may lead investigators and the readership to conditions including chronic stress and post-traumatic stress incorrect conclusions. Clinicians and researchers must keep a few disorder. Certain anticonvulsants (e.g. topiramate, phenobarbital) basic principles in mind when developing a plan for assessment. are also known to have adverse neurocognitive effects. Both First, test selection will vary depending on the question under seizure frequency and the use of anticonvulsants have been consideration. Second, the measures chosen should have alternate demonstrated to adversely impact neurocognitive function in forms or be relatively resistant to practice effects, characteristics brain tumour patients (Klein et al, 2003). Pharmacologic inter- that are especially important if one plans to test patients vention for symptoms of pain may cause sedation and associated repeatedly. Third, selected measures should be psychometrically diminution of neurocognitive function. sound, with established reliability and validity, and appropriate Abnormalities in endocrinologic function secondary to hy- normative studies. Finally, it is important to select measures that pothalamic/pituitary injury are very common following radio- are sensitive to subtle changes in cognitive function often therapy. Thyroid dysfunction, loss of libido, and erectile experienced by patients with cancer. Attention, processing speed, dysfunction are present in a large proportion of patients. learning/memory functions, and motor skills are particularly Endocrinologic replacement therapy has the potential to improve vulnerable and should be carefully evaluated for signs of neurocognitive and neurobehavioural function in patients who dysfunction. have abnormal hormone levels. Anaemia is a side effect of some chemotherapeutic regimens that is associated with both fatigue and neurocognitive dysfunction. Epoetin alpha therapy has been SUMMARY found to minimise neurocognitive decline in breast cancer patients receiving anthracycline-based chemotherapies relative to placebo Cancer is becoming a chronic illness, requiring on-going symptom (O’Shaughnessy, 2002). The aetiology of cancer-related fatigue is assessment and intervention. The number of long-term cancer likely multifactorial and includes anaemia, cachexia, systemic survivors will continue to increase as will the number of survivors illness, pain, and medications (Kurzrock, 2001). Both peripheral with neurocognitive and/or neurobehavioural impairment. It is and central factors associated with cytokine production may be important to note that treatment-related cognitive decline is not involved in the development and maintenance of this state. universal among cancer patients. Some individuals are able to tolerate treatment with little physical discomfort and no obvious neurocognitive impairments, while others will develop significant toxicities that seriously compromise their perceived quality of life NEUROPSYCHOLOGICAL ASSESSMENT and prevent them from resuming their usual social and occupa- Although the importance of cognitive evaluations in the care of tional roles. However, any adverse effects of cancer treatment must cancer patients and in clinical cancer trials is receiving greater always be considered in the light of potential therapeutic benefits. recognition, assessment methods remain less than optimal in most The nature of neurocognitive and neurobehavioural dysfunction cases. Cognitive assessment is a complex undertaking that requires is yet to be fully characterised. Methodological challenges have Seed Soil Pesticides (patient factors) (disease factors) (treatment factors) e.g. Diagnosis, location, tumour burden, e.g. Age, education, medical history, e.g. Primary and adjuvant therapies, disease course current symptoms, behavioural observations medications for symptom control, complementary therapies Test selection e.g. Psychometric issues, relevance and compatibility with the purpose of the assessment Interpretation, prognostication and treatment Integration of these sources of information requires understanding of human behaviour, CNS function, disease process, treatment effects, test pattern analysis, and knowledge of cognitive/behavioural/pharmacological interventions Figure 1 Considerations for the cognitive assessment of the oncology patient. British Journal of Cancer (2004) 90(9), 1691 – 1696 & 2004 Cancer Research UK Neuropsychological dysfunction associated with cancer JS Wefel et al plagued research in this area and seemingly contradictory findings disease, treatment, and patient factors in the manifestation of saturate the existing literature. Increased inclusion of comprehen- altered neurocognitive and neurobehavioural function. These sive neuropsychological evaluations in clinical research will further multidisciplinary investigations will identify which agents are our understanding of the nature, severity, and processes under- most neurotoxic in the context of different treatment regimens, the lying neurocognitive dysfunction in the patient with cancer. course of the neurocognitive and neurobehavioural dysfunction, Multidisciplinary investigations are essential. Utilising advances the cognitive and neurobehavioural domains most affected, the in neuropsychology, cognitive neuroscience, genomics, proteo- mechanisms for these effects, the host risk factors that create a nomics, molecular epidemiology, functional neuroimaging, neu- diathesis for the expression of this neurotoxicity, and which roimmunology, and traditional oncologic disciplines will neuroprotective or rehabilitative therapies may be most efficacious ultimately contribute to understanding the relationships between in preventing or treating these adverse symptoms. REFERENCES Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE (2003) affecting risk of symptomatic temporal lobe necrosis: significance of Neuropsychological effects of treatments for adults with cancer: a meta- fractional dose and treatment time. Int J Radiat Oncol Biol Phys 53: 75– analysis and review of the literature. J Int Neuropsychol Soc 9: 967–982 85 Armstrong CL, Goldstein B, Shera D, Ledakis GE, Tallent EM (2003) The McAllister L, Doolittle N, Guastadisegni PE, Kraemer DF, Lacy C, Crossen predictive value of longitudinal neuropsychologic assessment in the early JR, Neuwalt EA (2000) Cognitive outcomes and long-term follow-up detection of brain tumor recurrence. Cancer 97: 649–656 results after enhanced chemotherapy delivery for primary central Berman KF, Schmidt PJ, Rubinow DR, Danaceau MA, Van Horn JD, nervous system lymphoma. Neurosurgery 46: 51–61 Esposito G, Ostrem JL, Weinberger DR (1997) Modulation of cognition- McEwen BS, Alves SE (1999) Estrogen actions in the central nervous specific cortical activity by gonadal steroids: a positron-emission system. Endocr Rev 20: 279–307 tomography study in women. Proc Natl Acad Sci USA 94: 8836–8841 McKenna SE, Simon NG, Cologer-Clifford A (1992) An assessment of Capuron L, Ravaud A, Dantzer R (2001) Timing and specificity of the agonist/antagonist effects of tamoxifen in the female mouse brain. Horm cognitive changes induced by interleukin-2 and interferon-alpha Behav 26: 536–544 treatments in cancer patients. Psychosom Med 63: 376–386 Meyers CA (1997) Issues of quality of life in neuro-oncology. In Handbook Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, of Clinical Neurology, Neuro-Oncology, Part 1. Brain Tumors: Principles Raskind MA, Brodkin K, Bremmer W, Petrova A, LaTendresse S, Craft S of Biology, Diagnosis and Therapy, Vol. 23, Vecht ChJ (ed) pp 389–409. (2001) Testosterone supplementation improves spatial and verbal Amsterdam: Elsevier Science B.V. memory I healthy older men. Neurology 57: 80–89 Meyers CA, Abbruzzese JL (1992) Cognitive functioning in cancer patients: Crossen JR, Garwood D, Glatstein E, Neuwalt EA (1994) Neurobehavioral effect of previous treatment. Neurology 42: 434–436 sequelae of cranial irradiation in adults: a review of radiation-induced Meyers CA, Byrne KS, Komaki R (1995a) Cognitive deficits in patients with encephalopathy. J Clin Oncol 12: 627–642 small cell lung cancer before and after chemotherapy. Lung Cancer 12: Fliessbach K, Urbach H, Helmstaedter C, Pels H, Glasmacher A, Kraus JA, 231–235 Klockgether T, Schmidt-Wolf I, Schlegel U (2003) Cognitive performance Meyers CA, Geara F, Wong P-F, Morrison WH (2000a) Neurocognitive and magnetic resonance imaging findings after high-dose systemic and effects of therapeutic irradiation for base of skull tumors. Int J Radiat intraventricular chemotherapy for primary central nervous system Oncol Biol Phys 46: 51–55 lymphoma. Arch Neurol 60: 53–568 Meyers CA, Hess KR (2003) Multifaceted end points in brain tumor clinical Freedman AN, Graubard BI, Rao SR, McCaskill-Stevens W, Ballrad-Barbash trials: cognitive deterioration precedes MRI progression. Neuro-Oncology R, Gail MH (2003) Estimates of the number of US women who could 5: 89–95 benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Meyers CA, Hess KR, Yung WKA, Levin VA (2000b) Cognitive function as a Inst 95: 526–532 predictor of survival in patients with recurrent malignant glioma. J Clin Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, Oncol 18: 646– 650 Swanson C, Watson RB, Gardiner RA (2002) Altered cognitive function Meyers CA, Kudelka AP, Conrad CA, Gelke CK, Grove W, Pazdur R (1997) in men treated for prostate cancer with luteinizing hormone-releasing Neurotoxicity of CI-980, a novel mitotic inhibitor. Clin Cancer Res 3: hormone analogues and cyproterone acetate: a randomized controlled 419–422 trial. Br J Urol 90: 427–432 Meyers CA, Valentine AD (1995b) Neurological and psychiatric adverse Gregor A, Cull A, Traynor E, Stewart M, Lander F, Love S (1996) effects of immunological therapy. CNS Drugs 3: 56–68 Neuropsychometric evaluation of long-term survivors of adult brain Meyers CA, Valentine AD, Wong FCL, Leeds NE (1994) Reversible tumours: relationship with tumour and treatment parameters. Radiother neurotoxicity of interleukin-2 and tumor necrosis factor: correlation of Oncol 41: 55–59 SPECT with neuropsychological testing. J Neuropsychiatry 6: 285–288 Ja¨rvinen LS, Pyrho¨nen S, Kairemo KJA, Paavonen T (1996) The effect of Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, anti-oestrogens on cytokine production in vitro. Scand J Immunol 44: Goodkin RS Greiner K, Nemeroff CB, Miller AH (2001) Paroxetine for the 15–20 prevention of depression induced by high-dose interferon alfa. N Engl J Juengling FD, Ebert D, Gut O, Engelbrecht MA, Rasenack J, Nitsche EU, Med 344: 961–966 Bauer J, Lieb K (2000) Prefrontal cortical hypometabolism during low- O’Shaughnessy JA (2002) Effects of epoetin alpha on cognitive function, dose interferon alpha treatment. Psychopharmacology (Berl) 152: 383– mood, asthenia, and quality of life in women with breast cancer 389 undergoing adjuvant chemotherapy. Clin Breast Cancer 3: S116–S120 Keime-Guibert F, Napolitano M, Delattre J-Y (1998) Neurological Paganini-Hill A, Clark LJ (2000) Preliminary assessment of cognitive complications of radiotherapy and chemotherapy. J Neurol 245: 695–708 function in breast cancer patients treated with tamoxifen. Breast Cancer Kelley KW, Bluthe R-M, Dantzer R, Zhou J-H, Shen W-H, Johnson RW, Res Treat 64: 165–176 Broussard SR (2003) Cytokine-induced sickness behavior. Brain Behav Rich JB, Maki P (1999) Estrogen, testosterone, and the brain: a review of Immun 17: S112–S118 neuropsychological, aging, and neuroimaging studies. J Int Neuropsychol Klein M, Engelberts HJ, van der Ploeg H, Kasteleijn-Nolst Trenite DGA, Soc 6: iii Aaronson NK, Taphoorn MJB, Baaijen H, Vandertop WP, Muller M, Salminen E, Portin R, Korpela J, Backman H, Parvinen L-M, Helenius H, Postma TJ, Heimans JJ (2003) Epilepsy in low-grade gliomas: the impact Nurmi M (2003) Androgen deprivation and cognition in prostate cancer. on cognitive function and quality of life. Ann Neurol 54: 514–520 Br J Cancer 89: 971–976 Kurzrock R (2001) The role of cytokines in cancer-related fatigue. Cancer Schagen SB, Hamburger HL, Muller MJ, Boogerd W, van Dam FSAM (2001) 92: 1684–1688 Neurophysiological evaluation of late effects of adjuvant high-dose Lee AW, Kwong DLW, Leung S-F, Tung SY, Sze W-M, Sham JST, Teo PML, chemotherapy on cognitive function. J Neurooncol 51: 159–165 Leung t-W, Wu P-M, Chappell R, Peters LJ, Fowler JF (2002) Factors Sheline GE (1977) Radiation therapy of brain tumors. Cancer 39: 873–881 & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1691 – 1696 Neuropsychological dysfunction associated with cancer JS Wefel et al Silverman DH, Castellon SA, Abraham L, Dy CJ, Pio BS, Ganz PA (2003) Varney NR, Syrop C, Kubu CS, Struchen M, Hahn S, Franzen K Abnormal regional brain metabolism in breast cancer survivors after (1993) Neuropsychologic dysfunction in women following leuprolide adjuvant chemotherapy is associated with cognitive changes. Proc Am acetate induction of hypoestrogenism. J Assist Reprod Genet 10: Soc Clin Oncol 22: 12 53–57 Torres IJ, Mundt AJ, Sweeney PJ, Llanes-Macy S, Dunaway L, Castillo M, Vigliani M-C, Sichez N, Poisson M, Delattre J-Y (1996) A prospective study Macdonald RL (2003) A longitudinal neuropsychological study of partial of cognitive functions following conventional radiotherapy for supra- brain radiation in adults with brain tumors. Neurology 60: 1113 –1118 tentorial gliomas in young adults: 4-year results. Int J Radiat Oncol Biol Trask PC, Esper P, Riba M, Redman B (2000) Psychiatric side effects of Phys 35: 527–533 interferon therapy: prevalence, proposed mechanisms, and future Yaffe K, Sawaya G, Lieberburg I, Grady D (1998) Estrogen therapy in directions. J Clin Oncol 18: 2316–2326 postmenopausal women effects of cognitive function and dementia. Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P (1998) Mood JAMA 279: 688–695 and cognitive side effects of interferon-alpha therapy. Semin Oncol 25: 39–47 British Journal of Cancer (2004) 90(9), 1691 – 1696 & 2004 Cancer Research UK

Journal

British Journal of Cancer – Springer Journals

Published: Apr 6, 2004

There are no references for this article.