Breast Cancer Chemotherapy-Related Cognitive Dysfunction

Breast Cancer Chemotherapy-Related Cognitive Dysfunction Tim A. Ahles,1 Andrew J. Saykin2,3 Abstract Cognitive side effects of systemic chemotherapy have become an increasing concern among breast cancer survivors, their families, and health care professionals. A growing body of research supports the hypothesis that chemotherapy can produce long-term cognitive changes in at least a subgroup of cancer survivors. We review evidence implicating systemic chemotherapy as the cause of cognitive changes; describe the limitations due to lack of longitudinal studies and gaps in knowledge (ie, no clear mechanism by which chemotherapy can produce cognitive changes has been proposed); discuss possible factors like age, intelligence quotient/education, and psychological, genetic, and hormonal factors that might increase risk for chemotherapy-induced cognitive changes; and outline future directions for research. Such future research includes large-scale, longitudinal studies of pretreatment neuropsychological assessments, use of imaging techniques and the development of animal models to study the mechanisms of chemotherapy-induced changes in cognitive functioning, and the development of interventions to prevent or reduce the negative cognitive effects of chemotherapy. Clinical Breast Cancer, Vol. 3, Suppl. 3, S84-S90, December 2002 Key words: Central nervous system, Long-term effects, Genetics, Hormonal factors, Imaging, Neuropsychological assessment

Introduction Systemic chemotherapy continues to be the mainstay of treatment for many types of cancer. However, despite many successes in terms of curing cancer or significantly prolonging survival of patients with cancer, chemotherapy continues to produce significant acute and long-term side effects.1,2 Cognitive deficits associated with cancer treatment can have a dramatic effect on patients’ quality of life and have been recognized by the President’s Cancer Panel3 and the National Coalition for Cancer Survivorship as a challenge for people with cancer.4 For some patients, the cognitive deficits experienced have been a relatively minor nuisance, whereas for others decrements in cognitive functioning have significantly interfered with the attainment of educational and career goals. Importantly, many cancer survivors report no significant change in cognitive functioning 1-2 years following treatment.4 1 Department

of Psychiatry and Center for Psycho-Oncology Research, Dartmouth-Hitchcock Medical Center, Lebanon, NH 2 Department of Psychiatry (Neuropsychology Program), Dartmouth-Hitchcock Medical Center, Lebanon, NH 3 New Hampshire Hospital, Concord, NH Submitted: Sep 5, 2002; Revised: Oct 10, 2002; Accepted: Oct 21, 2002 Address for correspondence: Tim A. Ahles, PhD, Department of Psychiatry, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 Fax: 603-650-5842; e-mail: [email protected]

This review addresses strengths and limitations of the literature relevant to the neuropsychological impact of chemotherapy in women with breast cancer and describes future directions for research in this area. As detailed in this review and throughout this special issue, it is an exciting time to study cognitive side effects of chemotherapy because we now have the tools available to carefully describe the clinical phenomenon, to potentially understand the mechanisms of chemotherapy-induced cognitive decline, and to develop interventions that could prevent or reduce the negative impact of cognitive changes associated with chemotherapy.

Acute Versus Long-Term Effects of Chemotherapy on Cognitive Functioning A significant proportion of patients will report changes in their memory and in their ability to concentrate and focus their attention during chemotherapy. Studies that have used standardized neuropsychological assessments during or shortly after treatment (within 6 months) have documented cognitive dysfunction in 48%-95% of patients undergoing high-dose and standard-dose chemotherapy.5-8 In addition to chemotherapy, there are multiple factors that can contribute to the acute cognitive effects of chemotherapy, including emotional distress associated with cancer diagnosis and treatment, sedation, antinausea pain medications, anemia, fatigue, menopause, hypercortisolism, adrenal insufficiency,

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Chemotherapy-Related Cognitive Dysfunction thyroid dysregulation, and electrolyte disturbances.9 Fortunately, many of these problems resolve over time following treatment, with resulting improvement in cognitive functioning. The greater concern among cancer survivors is the possibility of long-term changes in cognitive functioning associated with chemotherapy.

Evidence for Long-Term Cognitive Deficits Studies that have examined neuropsychological functioning of breast cancer survivors ≥ 2 years following treatment have provided evidence for long-term cognitive deficits associated with chemotherapy. Van Dam and colleagues10 conducted neuropsychological assessments on women with breast cancer an average of 2 years following treatment. Patients had been randomized to either 4 cycles of FEC (5-fluorouracil [5-FU]/epirubicin/cyclophosphamide) followed by high-dose CTC (cyclophosphamide/thiotepa/carboplatin) or to 4-5 cycles of FEC alone. Each group received locoregional radiation therapy following chemotherapy and 2 years of tamoxifen. The investigators also recruited a matched group of stage I breast cancer patients who received local therapy only (surgery plus radiation therapy) as a comparison group. Patients in the high-dose arm were significantly more likely to demonstrate cognitive impairment (37%) compared with patients in the standard-dose arm (17%) and patients who had received local therapy only (9%). Although the comparison with the standard-dose and local-therapy groups did not reach statistical significance, it suggested that standarddose chemotherapy might have some impact on cognitive functioning. Similar results were recently reported for longterm survivors of hematologic malignancies treated with bone marrow transplantation (high-dose chemotherapy and total body irradiation) who were significantly more likely to experience cognitive deficits as compared with published norms.11 Schagen and colleagues studied 39 breast cancer patients treated with CMF (cyclophosphamide/methotrexate/5-FU) with or without tamoxifen and a control group of 34 agematched axillary node–negative breast cancer patients who received surgery and local radiation therapy but no systemic chemotherapy.12 Neuropsychological testing was performed approximately 2 years following treatment. The results demonstrated that patients treated with CMF had significantly more problems with concentration (31% vs. 6%) and memory (21% vs. 3%). Across all domains, cognitive impairment was seen in 28% of chemotherapy patients and 12% of controls. Brezden and colleagues compared cognitive functioning in women with breast cancer who were currently receiving adjuvant chemotherapy (CMF or CEF [cyclophosphamide /epirubicin/5-FU]) for ≥ 1 year following chemotherapy (median, 25 months) to that of healthy controls.8 Consistent with the studies described above, a greater number of patients in both chemotherapy treatment groups had moderate or severe cognitive impairment compared with healthy controls as measured by the High Sensitivity Cognitive Screen.

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The Dartmouth group investigated long-term survivors of breast cancer and lymphoma (average, 10 years following treatment) who had been treated with standard-dose chemotherapy or local therapy only.13 Consistent with the studies described above, there was a significant multivariate effect across 9 domains of neuropsychological functioning, with survivors treated with chemotherapy scoring significantly lower on the neuropsychological assessment battery of tests than survivors treated with local therapy only. When survivors were categorized by neuropsychological performance, a significantly greater number of chemotherapy survivors (39%) compared with local-therapy survivors (14%) scored within the low neuropsychological performance range.

Summary Overall, these studies support the hypothesis that chemotherapy can cause cognitive impairments that could be long lasting or permanent. The cognitive deficits reported tend to be diffuse, occurring across a variety of domains of functioning including verbal and visual memory, attention and concentration, and executive functioning. The cognitive deficits are relatively subtle compared to people with Alzheimer’s disease or major head trauma. Despite differences in neuropsychological test results between survivors treated with chemotherapy and survivors treated with local therapy, the scores for the chemotherapy group are typically in the normal range compared with published norms for the tests.13 Additionally, other conditions such as psychological distress can produce subtle cognitive deficits similar to those reported by cancer survivors; therefore, these additional factors must be ruled out as explanations for the group differences. Importantly, all of the studies described controlled for potential confounding factors that could influence performance on neuropsychological tests, including depression, anxiety, and fatigue. Finally, the data suggest that not all cancer patients have been equally affected. Rather, there appears to be a subgroup of patients who score in the low-performance range. Table 1 summarizes the breast cancer studies described above and displays the percentage of patients who scored in the low neuropsychological performance range.6-8,10,12 A certain percentage of participants in the comparison group scored in the low-performance range. Therefore, it is the difference in frequency of low performance between the chemotherapy and comparison groups that provides the most accurate estimate of the percentage of patients treated with chemotherapy who might experience long-term cognitive deficits. Examination of this difference score reveals that 8%-39% of survivors who have received chemotherapy experience cognitive deficits. This pattern of results suggests that there might be treatment factors (eg, type of chemotherapy regimen) or individual factors (eg, age, intelligence quotient [IQ], education, genetic factors, estrogen levels) that predispose certain patients to experience more significant cognitive deficits secondary to chemotherapy.

Tim A. Ahles, Andrew J. Saykin Table 1 Overview of Studies Examining Chemotherapy-Induced Cognitive Changes in Breast Cancer Survivors Study

Wieneke and Dienst6

Ahles et al7

Sample Size

Chemotherapy Regimen

Assessment Timing Following Treatment

Chemotherapy (% in the LowPerformance Range)

Local Therapy (% in the LowPerformance Range)

28

CMF, CAF, or CMF followed by CAF

Average 6.6 months

75%

NA

35 chemo 35 local

CMF, CAF, CC, CMF plus vincristine and prednisone

Average 10 years

34%

18%

Group A: 48% Group B: 50% Group C: 11%

NA

Group A: After minimum of 2 cycles

Group A: 31 Group B: 40 Group C: 36 (healthy controls)

CMF or CEF

van Dam et al10

34 high-dose chemo 36 standard-dose chemo 34 local

FEC followed by high-dose CTC or FEC alone

Average 2 years

High dose: 32% Standard dose: 17%

9%

Schagen et al12

39 chemo 34 local

CMF

Median 1.9 years

28%

12%

Brezden et al8

Group B: Median 2 years

Abbreviations: CAF = cyclophosphamide/doxorubicin/5-fluorouracil; CC = carboplatin/cyclophosphamide; CEF = cyclophosphamide/epirubicin/5-fluorouracil; CMF = cyclophosphamide/methotrexate/5-fluorouracil; CTC = cyclophosphamide/thiotepa/carboplatin; FEC = 5-fluorouracil/epirubicin/cyclophosphamide; NA = not assessed

Limitations of the Current Research The major limitation of the literature relevant to chemotherapy-induced cognitive decline is that all of the published studies of the long-term cognitive effects of chemotherapy have used cross-sectional, posttreatment-only designs. Most of the studies have included appropriate control groups matched for age, gender, and education, which strengthens the interpretation that the deficits seen are related to chemotherapy. However, without pretreatment assessments, it is not possible to assess changes over time that can be attributed to chemotherapy. Recent data have suggested that a percentage of patients might score in the impaired range prior to receiving any cancer treatment.14 Therefore, a certain percentage of patients who scored in the impaired range following treatment might have demonstrated no change over time because they would have scored in the impaired range before treatment.15,16 Conversely, some patients who scored in the normal range following treatment might have demonstrated a significant change because of high pretreatment performance scores. Consequently, in order to adequately test the hypothesis that a subgroup of patients experiences ongoing cognitive problems following treatment, it is critical to use a prospective design that includes both pretreatment and posttreatment neuropsychological assessments. This design will also allow for the pretreatment measurement of potential confounding variables (eg, mood, fatigue) and for examination of the impact of disease stage at diagnosis on cognitive functioning over time. The Dartmouth group, with funding from the National Cancer Institute Office of Cancer Survivorship

(RO1 CA87845), is conducting a longitudinal study of the cognitive effects of chemotherapy. Patients with breast cancer and lymphoma who are being treated with standard-dose chemotherapy (n = 100) or local therapy (n = 100) are completing a set of neuropsychological and psychological instruments before treatment (after surgery but before chemotherapy or radiation therapy) and at 1, 6, and 18 months following treatment. A matched healthy control group is completing the same battery of tests at analogous time intervals. The primary aim of this study is to test the hypothesis that patients treated with systemic chemotherapy will demonstrate significantly greater global decrements in performance from pretreatment to post treatment on standardized measures of neuropsychological functioning as compared to patients treated with local therapy only. The inclusion of healthy controls will also allow for the evaluation of whether local therapy or the stress of the diagnosis of cancer has long-term cognitive consequences.

Impact of Chemotherapy on the Central Nervous System A major difficulty in studying the cognitive effects of chemotherapy is that there is no clear understanding of the mechanism by which chemotherapy impacts the brain. Many cytotoxic drugs commonly used in both standard-dose and high-dose chemotherapy regimens have documented neurotoxicity affecting both the central nervous system (CNS) and peripheral nerves, including central and peripheral neuropathy, encephalopathy, leukoencephalopathy, ototoxicity, and cerebellar symptoms.17-19 Many investigators initially

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Chemotherapy-Related Cognitive Dysfunction thought that antineoplastic agents had little ability to penetrate the blood-brain barrier. However, more recent studies have indicated higher than expected concentrations in cerebrospinal fluid and brain tissue.17-19 Although the specific pathophysiological mechanisms leading to cognitive deficits are not well understood,20 3 major, nonexclusive mechanisms have been hypothesized18: (1) direct neurotoxicity to the cerebral parenchyma, including the microglia, oligodendrocytes, and neuronal axons producing demyelination; (2) secondary inflammatory response, an immunologic mechanism including allergic hypersensitivity and autoimmune vasculitis; and (3) microvascular injury leading to obstruction of small and medium-sized vessels, spontaneous thrombosis, ischemia/infarction, and parenchymal necrosis. It should also be noted that the metabolic changes associated with the acute effects of chemotherapy mentioned earlier (hypercortisolism, adrenal insufficiency, thyroid dysregulation, and electrolyte disturbances) might also play a role in the long-term cognitive consequences of chemotherapy. For example, increased levels of cortisol over extended periods of time have been associated with memory deficits and reduced hippocampal volumes in both human21,22 and animal studies.23 At this point, it is not possible to identify which cytotoxic drugs or combinations of drugs are primarily associated with chemotherapy-induced cognitive decline. However, a review of Table 1 suggests that all of the major treatment regimens for breast cancer have been implicated.6-8,10,12 To date, no systematic neuropsychological data are available on regimens that include taxanes; however, the Dartmouth longitudinal study and current studies by other groups are including data collected on regimens that include taxanes. The neurotoxic effects of chemotherapy have also been supported by imaging (magnetic resonance imaging [MRI]) and electrophysiological studies. Magnetic resonance imaging studies have identified cerebral changes, primarily white matter abnormalities, in adults treated with high-dose chemotherapy alone24,25 and in children with acute lymphoblastic leukemia treated with chemotherapy only.26 The Dartmouth group has completed a pilot investigation using structural and functional MRI to study long-term survivors of breast cancer and lymphoma who had received systemic chemotherapy or local therapy only. Initial morphometric analyses suggest diffuse changes in both gray and white matter in survivors treated with chemotherapy compared with healthy controls matched for age, gender, and education.27 Finally, a recent study by Schagen and colleagues identified asymmetrical alpha rhythm as measured on electroencephalogram in 41% of breast cancer patients treated with high-dose chemotherapy and 12.5% of patients treated with standard-dose chemotherapy compared to none in the patients treated with local therapy.28 Clearly, additional longitudinal studies of breast cancer patients receiving chemotherapy using imaging techniques like structural and functional MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography would

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greatly enhance our understanding of the impact of chemotherapy on the human brain. The understanding of the mechanism by which chemotherapy causes cognitive changes would also be greatly enhanced by the development of an animal model of chemotherapy-induced cognitive decline. Several well-established animal models of learning, memory, and executive function with known neuroanatomic underpinnings have been developed.29,30 Therefore, the tools should be available for examining the impact of cytotoxic agents on these behavioral paradigms and for examining the CNS anatomic and histopathologic changes associated with the administration of these agents. In addition, several studies have implicated neurotoxic cytokines in the disruption of memory processes in animals; therefore, these models can be used to begin identifying and isolating the direct effects of cytotoxic agents on the CNS and the effects of an immunologic response triggered by chemotherapy.31,32 An animal model of chemotherapy-induced cognitive changes would also permit the administration of single agents or combinations of agents that would not be given clinically in order to understand which drugs or drug combinations are predominantly implicated in the development of chemotherapy-induced cognitive deficits.

Factors That Influence Cognitive Functioning There are several factors that can influence cognitive function, either independently or by interacting with chemotherapy, that must be recognized to understand the potential impact of chemotherapy on cognitive functioning. Additionally, since only a subgroup of cancer patients might develop longterm chemotherapy-induced cognitive changes, several of these factors might be implicated as increasing risk for cognitive changes associated with chemotherapy.

Age As adults age, there are fairly predictable changes in performance on neuropsychological tests. Therefore, age-adjusted norms are required for most standardized tests used by neuropsychologists.33 This creates a methodological issue, in that patients treated with chemotherapy should be compared to age-matched patients who receive only local therapy or to healthy controls. There has also been speculation that older adults might be more vulnerable to cognitive side effects of chemotherapy; thus, age at treatment might be a predictor of the degree of chemotherapy-induced cognitive changes.

Intelligence and Education Intelligence quotient and education level clearly influence scores on neuropsychological tests; therefore, comparisons between groups of cancer patients treated with systemic chemotherapy and those treated with local therapy or healthy control groups must either match on IQ and educa-

Tim A. Ahles, Andrew J. Saykin tion or, less desirably, co-vary their effects in the analyses. Additionally, data suggest that higher IQ and education levels might reduce the negative neurocognitive impact of trauma to the brain.33 This protective phenomenon, recently referred to as cognitive reserve, might involve greater synaptic density associated with enriched cognitive stimulation over many years. The concept of cognitive reserve has been examined in Alzheimer’s disease34 and human immunodeficiency virus (HIV)-1 infection35; however, it has not been directly examined in a cancer population. Conversely, conditions existing prior to cancer diagnosis that negatively impact cognitive functioning might make people more vulnerable to cognitive problems secondary to chemotherapy. Such conditions include a history of learning disabilities, attention deficit hyperactivity disorder, or other developmental disabilities; traumatic head injury; or illnesses that can affect the CNS (including seizure disorders and diabetes).

Psychological Factors Patients with symptoms of anxiety and depression frequently demonstrate reduced performance on neuropsychological tests similar to the deficits seen in cancer survivors who have received chemotherapy.33 In addition, fatigue, whether biologically based or related to a psychological state like depression, can influence cognitive functioning.36 Selfreports of cognitive problems also tend to correlate with selfreport measures of depression, anxiety, and fatigue and tend not to correlate well with actual performance on standardized neuropsychological tests.37 Therefore, as with age, IQ, and education level, psychological factors need to be carefully controlled in studies examining the cognitive impact of chemotherapy. As stated above, most of the studies reviewed found evidence for chemotherapy-induced cognitive changes after controlling for factors like depression, anxiety, and fatigue. However, to a certain extent, this was accomplished by excluding patients with any evidence of a Diagnostic and Statistical Manual (of Mental Disorders) IV diagnosis of anxiety or depression. When clinically evaluating an individual who reports cognitive problems, conditions such as depression, anxiety-based disorders, and fatigue and sleep disorders need to be ruled out. If identified and treated appropriately, the cognitive symptoms will often improve. On the other hand, survivors who have comorbid cognitive problems and a psychiatric disorder might experience the greatest amount of disability following chemotherapy. Clearly, more research is needed to examine the variables that account for the level of disability across a variety of domains of functioning that some cancer survivors continue to experience following treatment.

Genetic Factors Advances in genetics research has led to increasing interest in the identification of genes that predispose individuals to a variety of medical conditions. Apolipoprotein E (APOE) was initially studied in relation to cardiovascular disease and

Alzheimer’s disease.38,39 The APOE gene is polymorphic and occurs in 3 common alleles, APOE ε2, ε3, and ε4, which give rise to 6 genotype combinations. The presence of the APOE ε4 allele increases risk for Alzheimer’s disease and shifts the age at onset to an earlier age.38 However, the APOE ε4 allele has also been associated with poorer cognitive outcomes from various types of insults to the brain, including neuropsychological deficits following cardiac bypass surgery,39,40 traumatic brain injury,36 repeated head trauma associated with boxing41,42 and football,43 and as a modulating factor of other risk factors (eg, diabetes) for cognitive decline in the elderly.44 If receiving chemotherapy is conceptualized as a type of insult to the brain, then it is reasonable to hypothesize that APOE ε4 carriers will be more vulnerable to chemotherapy-induced cognitive decline. We examined this issue in our study of long-term survivors of breast cancer and lymphoma. The results supported the hypothesis that survivors who had been treated with chemotherapy and had at least one ε4 allele scored significantly lower in several domains of neuropsychological functioning. Although supportive of the hypothesis that the ε4 allele is associated with an increased risk of cognitive problems secondary to chemotherapy, these data require further examination. To that end, we are examining the role of APOE in cognitive functioning in the longitudinal study described above.

Menopausal Status and the Impact of Estrogen Increasing evidence has implicated estrogen in the maintenance of normal memory functioning in women, particularly short- and long-term verbal memory.45,46 Placebo-controlled studies of estrogen replacement therapy in postmenopausal women have demonstrated improvement in cognitive functioning in the estrogen replacement groups.47-49 Additionally, premenopausal women who have experienced surgically induced menopause (bilateral salpingo-oophorectomy) demonstrated a presurgical-to-postsurgical decline in tests of verbal memory and the retention of new material, which was improved by estrogen replacement.50 These later data suggest that women who experience chemotherapyinduced menopause might experience similar deficits in cognitive functioning although no studies have directly addressed this issue. As the use of chemotherapy to treat early-stage breast cancer increases, the impact of chemotherapy-induced menopause on cognitive function must be better understood. Interestingly, the bulk of evidence suggests that the estrogen effect is at least somewhat specific to verbal memory,45,46 whereas the effects of chemotherapy are much more global. Therefore, there might be an important interaction between menopausal status and chemotherapy in the verbal memory domain, since verbal memory functioning as measured by similar neuropsychological tests is affected by both estrogen level and chemotherapy. Further, fluctuations in estrogen levels in postmenopausal women might also impact cognitive function.51

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Chemotherapy-Related Cognitive Dysfunction Hormonal Therapy Tamoxifen and raloxifene are selective estrogen-receptor modulators (SERMs), with organ-dependent antagonist and agonist effects at the estrogen receptor. Due to its antiestrogen and vascular effects, tamoxifen has been implicated in memory problems of women treated for breast cancer.52 Paganini-Hill and Clark found no differences between tamoxifen users and nonusers on 3 cognitive tests administered via mail.53 However, tamoxifen users reported seeing their physician more frequently for memory problems than nonusers. Other studies, using more traditionally administered (ie, face-to-face administration) neuropsychological tests, have not found a difference in performance when comparing tamoxifen users to nonusers.12,13 Additionally, Yaffe and colleagues found no differences in cognitive performance among postmenopausal women with osteoporosis taking raloxifene 60 mg or 120 mg or placebo.54 Finally, a recent study using magnetic resonance spectroscopy suggested that tamoxifen and estrogen have a similar effect on the brain of elderly women.55 Taken together, the evidence to date does not support the hypothesis that therapy with SERMs has a negative impact on the cognitive functioning of women although additional research is necessary. At this time, tamoxifen remains the standard adjuvant hormonal therapy for women with hormone receptor–positive breast cancer, and the vast majority of women with receptor-positive tumors will be taking tamoxifen.56 In the years ahead, aromatase inhibitors might replace tamoxifen and could, theoretically, influence cognitive functioning to a greater degree because of their dramatic effects on estrogen levels. However, no data regarding the cognitive impact of aromatase inhibitors are available.

Treatment As described by Joyce O’Shaughnessy, MD,57 and Barton and Loprinzi,58 various interventions designed to reduce or prevent chemotherapy-induced cognitive decline are being evaluated. In other disorders, cognitive rehabilitation approaches have been shown to be effective, particularly with patients with relatively mild cognitive deficits.59 Investigators at Dartmouth are developing and conducting initial testing of a cognitive rehabilitation intervention for chemotherapy-induced cognitive problems experienced by long-term survivors of breast cancer that focuses on compensatory skills and arousal-reduction techniques.60 Initial results of this intervention are encouraging.

Conclusion Increasing evidence supports the hypothesis that chemotherapy can produce long-term cognitive declines in cancer survivors. However, the extent of the cognitive deficits created by chemotherapy, the percentage of patients actually affected, and the factors that contribute to the risk of long-term cognitive deterioration will only be defined by conducting large-scale, longitudinal studies. Nonetheless, this is a very important and exciting area of study because

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the tools exist for describing the clinical phenomenon, understanding the mechanisms of chemotherapy-induced cognitive changes, and developing treatments designed to prevent or reduce the negative impact of chemotherapy on cognitive functioning.

Acknowledgements This research was supported by a grant (CA87845) from the Office of Cancer Survivorship, National Cancer Institute, Bethesda, MD.

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