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Cognitive changes associated with cancer and cancer treatments have become an increasing concern. Using breast cancer as the prototype, we reviewed the research from neuropsychological, imaging, genetic, and animal studies that have examined pre- and post-treatment cognitive change. An impressive body of research supports the contention that a subgroup of patients is vulnerable to post-treatment cognitive problems. We also propose that models of aging may be a useful conceptual framework for guiding research in this area and suggest that a useful perspective may be viewing cognitive change in patients with cancer within the context of factors that influence the trajectory of normal aging.
Cognitive changes associated with treatments for CNS and pediatric cancers have long been recognized.1,2 However, over the last 15 to 20 years, increasing evidence has suggested that treatments for non-CNS tumors can have both acute and long-term effects on cognitive functioning, which can affect educational and occupational goals and quality of life. Understanding these cognitive changes and the impact on survivors' functioning is critical, because hundreds of thousands of patients are treated worldwide each year, and the number of long-term survivors who may have to cope with these cognitive changes is growing dramatically. This review focuses on cognitive changes associated with adjuvant treatment for breast cancer as an example of the emerging findings in this field. Furthermore, we will explore the value of viewing this literature within the larger context of models of aging.
Although references to cognitive changes associated with chemotherapy can be found dating back to the 1980s,3 serious scientific attention was not paid to the topic until the mid 1990s.1 Post-treatment cognitive changes frequently include problems in attention, concentration, working memory, and executive function. Cross-sectional studies of breast cancer survivors have found that 17% to 75% of women experienced cognitive deficits in these domains from 6 months to 20 years after exposure to chemotherapy.4–6 The lack of prechemotherapy assessment of cognitive performance limited the conclusions that could be drawn from these studies; consequently, investigators began longitudinal studies that included pretreatment neuropsychological assessments. To date, 21 longitudinal studies7–27 including pre- and post-treatment assessments have been reported, and a majority of studies16 have found evidence for post-treatment cognitive change (Table 1). Consistent with the cross-sectional studies, the longitudinal studies suggest that a subgroup of patients experience post-treatment cognitive problems. Estimates of the frequency of post-treatment cognitive change vary among studies, likely because of differences in patient populations, assessment instruments used, criteria for defining change, and other aspects of study methods. Many investigators cite the incidence of post-treatment cognitive problems as ranging from 15% to 25%,28 although percentages as high as 61% have been reported.7 However, results of the longitudinal studies have challenged some basic assumptions made in the field and have shown a less consistent pattern of post-treatment cognitive decline (five studies had negative findings12,16,18,22,23).
Two basic assumptions were: one, patients with breast cancer have normal cognitive functioning before treatment; and two, chemotherapy is the major cause of post-treatment cognitive problems, hence the colloquial term chemobrain. Several studies have found that 20% to 30% of patients with breast cancer have lower than expected cognitive performance based on age and education at the pretreatment assessment.29,30 Interestingly, lower than expected level of performance does not seem to be related to psychological factors (eg, depression or anxiety), fatigue, or surgical factors (eg, type or length of general anesthesia).29 No explanation for this phenomenon currently exists; however, two nonmutually exclusive hypotheses have been proposed: one, the biology of cancer (eg, inflammatory response triggering neurotoxic cytokines) may contribute to lower than expected cognitive performance; and/or two, common risk factors for the development of both breast cancer and mild cognitive changes over years may exist (eg, poor DNA repair mechanisms have been linked to risk of cancer and neurodegenerative disorders).31
The assumption that cognitive changes result from chemotherapy exposure has also been questioned as evidence has emerged suggesting that the combination of chemotherapy and endocrine therapy or endocrine therapy alone may cause cognitive change.32 Initial examination of this issue has produced mixed results; however, most studies were not powered to adequately examine the independent effects of endocrine therapy. A longitudinal study examining patients not treated with chemotherapy who were randomly assigned to treatment with tamoxifen or exemestane demonstrated that those treated with tamoxifen, but not exemestane, experienced cognitive problems compared with healthy controls.33 Early investigators assumed they were studying the effects of chemotherapy; however, most patients with breast cancer receive multimodality treatment (eg, surgery with exposure to general anesthesia, radiation therapy, and endocrine therapy in addition to chemotherapy). This in combination with the evidence for pretreatment cognitive problems led Hurria et al34 to propose that the phenomenon is more accurately described as cancer- and cancer treatment–associated cognitive change.
Furthermore, if only a subgroup of patients experience persistent post-treatment cognitive decline, a critical step is to examine risk factors for cognitive change. Age is a well-established risk factor for cognitive decline, and researchers have speculated that older adults may be more vulnerable to cognitive adverse effects of cancer treatments. Cognitive reserve, which represents innate and developed cognitive capacity (influenced by education, occupational attainment, and lifestyle), has also been associated with resiliency (high) or vulnerability (low) to cognitive decline after various brain insults. Support for an interaction of age, cognitive reserve, and exposure to chemotherapy as a risk factor for cognitive decline has been reported21; older patients with lower levels of pretreatment cognitive reserve exposed to chemotherapy demonstrated significantly reduced performance on post-treatment processing speed (Figs 1A and and1B).1B). Exploratory analyses conducted by Schilder et al33 also revealed that in older patients with breast cancer (age > 65 years), tamoxifen had an effect on more cognitive domains, suggesting an age dependency of the impact of tamoxifen on cognitive functioning.
Genetic factors such as apolipoprotein E (APOE) and catechol-O-methyltransferase (COMT) have been associated with age-related cognitive decline.35 APOE is a complex glycolipoprotein that facilitates the uptake, transport, and distribution of lipids and plays a role in neuronal repair and plasticity after injury. The E4 allele has been associated with cognitive decline related to Alzheimer's disease, brain trauma, and aging. Ahles et al36 demonstrated that long-term cancer survivors who had been treated with chemotherapy and had at least one E4 allele scored significantly lower on a variety of domains of cognitive function, as compared with survivors who did not carry an E4 allele.
Small et al37 studied COMT, which influences the metabolic breakdown of catecholamines through the methylation of dopamine. Individuals homozygous for the Val allele have lower levels of dopamine in the frontal cortex, because they metabolize dopamine more rapidly than those with the Met allele. These researchers found that patients with breast cancer who had the COMT–Val allele combination and were treated with chemotherapy performed more poorly on tests of attention, verbal fluency, and motor speed, as compared with COMT-Met homozygotes.
Several studies did not find evidence for cognitive changes associated with chemotherapy or other treatments. This inconsistent pattern of results may be related to variability in study design and choice of comparison groups. Two of the studies compared patients treated with chemotherapy with patients treated with endocrine therapy but did not include a healthy control group.16,23 However, both chemotherapy- and endocrine-treated patients may experience cognitive change, which could explain the lack of group differences. Furthermore, the pattern of post-treatment cognitive deficits may be influenced by sample characteristics like age and cognitive reserve. Therefore, if a study population consists of young, highly educated (one proxy for cognitive reserve) patients, one might expect less evidence of post-treatment cognitive deficits, as compared with a study that includes older, less educated individuals. In two of the studies with negative findings, the mean ages of the patients with cancer were in the 40s.18,22 Furthermore, in modest-sized studies, the mix of patients with vulnerable alleles of genes like APOE and COMT can vary significantly.
Several cross-sectional, post-treatment studies38–42 (Table 2) using magnetic resonance imaging (MRI) have documented reductions in gray matter, primarily in frontal structures and the hippocampus, and white matter integrity in cancer survivors treated with chemotherapy, although negative results have also been reported.43 Longitudinal studies have reported similar results: first, decreased gray matter density in bilateral frontal, temporal (including hippocampus), and cerebellar regions and right thalamus at 1 month postchemotherapy, with only partial recovery at 1 year postchemotherapy in several structures, compared with no significant changes in gray matter over time in the no-chemotherapy cancer group or the healthy controls44; and second, decreased frontal, parietal, and occipital white matter integrity in chemotherapy-exposed patients, with no changes in the no-chemotherapy group or healthy controls post-treatment.45
Cross-sectional studies of cancer survivors using functional imaging techniques, including functional MRI (fMRI)46–49 and functional positron emission tomography (fPET),50 have demonstrated areas of decreased activation during performance of a cognitive task in survivors exposed to chemotherapy, as compared with controls, in areas similar to the structural differences described (Table 3). McDonald et al51 conducted a longitudinal study using fMRI and found frontal lobe hyperactivation to support a working memory task before treatment, decreased activation 1 month postchemotherapy, and a return to pretreatment hyperactivation at 1 year post-treatment. A similar pattern was seen in patients treated with endocrine therapy. Interestingly, two other studies reported overactivation during a memory task before treatment in patients with cancer compared with healthy controls, consistent with the reports of neuropsychological deficits at pretreatment.52,53 One interpretation is that pretreatment overactivation represents an attempt to compensate for preexisting deficits; however, over years, patients lose the ability for compensatory activation as a result of exposure to cancer treatments and/or age-associated changes in the brain.
Seigers et al54 recently reviewed the animal studies of chemotherapy-induced cognitive impairment. Studies using common chemotherapeutic agents demonstrated changes in memory and learning that parallel the deficits seen in cancer survivors. Furthermore, animal studies have demonstrated evidence for a variety of potential mechanisms for the effect of chemotherapy on the brain, including: one, inhibition of hippocampal neurogenesis; two, oxidative damage; three, white matter damage, including progressive change associated with fluorouracil (FU); four, decreased hypothalamic-pituitary-adrenal axis activity; and five, reduced brain vascularization and blood flow. Also, concentrations of chemotherapy agents that are ineffective in killing tumor cells increased cell death and decreased cell division in brain regions including the hippocampus, suggesting that small amounts of chemotherapy crossing the blood-brain barrier can have toxic effects.55
Emerging evidence supports the efficacy of antioxidants in blocking behavioral and physiologic effects when coadministered with chemotherapy.54 Although this is an interesting proof of principal, antioxidants may not be a treatment option because of concerns that they may decrease the efficacy of chemotherapy. Fluoxetine has been shown to prevent deficits in behavior and hippocampal function when administered before and during administration of FU and may represent a more promising preventative approach.56,57
Data from imaging and animal studies support the hypothesis that chemotherapy affects brain structure and function and begin to provide evidence for candidate mechanisms of chemotherapy-induced cognitive change. Similar studies examining other aspects of cancer treatments such as endocrine therapy for breast cancer and hormone ablation therapy for prostate cancer are clearly needed.
One gap in the field is the lack of a model to guide research. A potentially useful perspective is viewing cognitive change within the context of factors that influence the trajectory of normal aging. Cancer and aging are linked, although the molecular mechanisms responsible for the increasing risk of cancer with increasing age are not completely understood. Aging is associated with a variety of biologic changes, including increased cell senescence, DNA damage, oxidative stress, inflammation, and decreased telomere length (telomerase activity).58,59 Chemotherapy has been associated with increased DNA damage, oxidative stress, inflammation, and shortened telomeres.31,60 Furthermore, research has suggested that the targets for certain cancer treatments negatively affect biologic markers of aging (eg, increases in tumor suppressor mechanisms through the p53 pathway are associated with increased cell senescence systemically).61 Tamoxifen has also been shown to be genotoxic, and other endocrine therapies may be associated with increased DNA damage because of decreased antioxidant capacity.62 Finally, all of these processes have been implicated in cognitive decline and the development of neurodegenerative diseases.31,60 This research suggests that biologic processes underlying cancer, the impact of cancer treatments, aging, neurodegeneration, and cognitive decline are linked, leading to the hypothesis that cancer treatments may accelerate the aging process.60
In addition to examining specific pathways associated with aging, theoreticians have elucidated systems theories of aging, which provide interesting insights and hypotheses regarding cognition and cancer treatment. The reliability theory of aging is an example of a model of aging that is not specific to a particular biologic process but is consistent with a systems biology perspective.63 Reliability theory proposes that complex biologic systems have developed a high level of redundancy to support survival. In a highly redundant system, failure of one or more components may not be problematic if other components are available to support a specific pathway. Therefore, aging is determined by the failure rate of systems (loss of redundancy), which is influenced by the initial extent of system redundancy, the systems repair potential, and factors that increase failure rate such as poor health care, lifestyle risk factors, and/or exposure to environmental toxins. Someone with a low failure rate and/or high repair potential will show fewer signs of biologic aging as they age chronologically, whereas someone with a high failure rate and/or low repair potential will age more rapidly, as evidenced by the development of a disease associated with a specific set of system failures or frailty with a patchwork of failures across multiple systems.
One implication of reliability theory is that vulnerability to post-treatment cognitive change does not necessarily depend on a given treatment affecting a specific biologic pathway. Rather, different patterns of failure rate (redundancy loss) across various biologic systems may confer more or less vulnerability to specific treatments for each individual. Therefore, one patient may be vulnerable to the DNA damaging effects of a chemotherapy regimen, whereas another patient may be vulnerable to the impact on the hormonal milieu of endocrine treatments. This vulnerability may be strongly influenced by the pattern of systems failure before cancer diagnosis.
Furthermore, investigators have assumed that long-term cognitive problems result from the lack of recovery from the acute effects of treatment but remain stable after initial recovery.28 However, viewed within the context of models of aging, two additional hypotheses emerge: first, the initial effect of cancer treatment may produce a cascade of biologic events, which causes continued cognitive decline with aging; and second, a given treatment may not be sufficient to cause enough redundancy loss to immediately effect cognitive function but may produce a delayed effect as aging continues. Support for each of these patterns was reported by Wefel et al,24 who studied patients treated with regimens that included FU: first, stable cognitive functioning over time after an acute post-treatment decline; second, continued cognitive decline over 1 year; and third, no acute cognitive decline with new evidence of cognitive decline at 1 year post-treatment.
These considerations suggest the need for studying the short- and long-term effects of cancer treatments in older patients with cancer. Despite the fact that a majority of patients with breast cancer are diagnosed at age 65 years or older and that the number of older breast cancer survivors is growing dramatically, nearly all of the published research has focused on younger patients with breast cancer (mean age, < 60 years). Longitudinal studies11 suggest that older patients with breast cancer experience objective cognitive declines shortly after treatment; however, larger-scale prospective studies are needed. Additionally, a cross-sectional study of older (age > 65 years) long-term breast cancer survivors found lower performance on measures of executive function, working memory, and divided attention, as compared with healthy controls.64
Although the recent focus of research has been on longitudinal studies with pretreatment assessments, data suggesting the possibility of continued or delayed cognitive decline demonstrate the critical need for studies examining the impact of cancer and cancer treatments on the trajectory of age-associated cognitive change, particularly in older long-term survivors. Cross-sectional studies suggest that older long-term cancer survivors will have lower performance in various areas of neurocognitive functioning, as compared with matched older adults without a cancer history.64–66 However, longitudinal assessments are important to define whether age-associated declines parallel those of older adults with no cancer history (phase shift hypothesis) or follow a steeper slope of decline (accelerated aging hypothesis; Fig 2). These are not mutually exclusive hypotheses, in that one group of survivors may demonstrate the phase shift pattern, whereas another vulnerable population may demonstrate the accelerated aging pattern. Furthermore, it is critical to define whether the impact on the trajectory of cognitive aging is the same for someone treated as a younger versus older adult.
To the extent that cancer treatments may accelerate the effects of aging, some overlap in brain structures affected by cancer treatments and aging would be expected. Imaging studies have demonstrated that total gray matter volume reliably decreases with advancing age (beginning in the mid 40s), with regional changes exhibited mainly in the frontal cortex and in regions around the central sulcus.67 Global white matter decreases with advancing age, and a trend for anterior white matter integrity decreasing earlier than posterior sites has been found.67,68 Therefore, change in brain structure and function may be an interaction between the effects of cancer treatments and changes associated with aging.
Few studies designed to evaluate interventions to treat cognitive changes have been reported. In terms of medication management of cognitive deficits, two studies have found support for the efficacy of modafinil, a psychostimulant, in improving memory and attention and reducing fatigue.69,70 Cognitive rehabilitation approaches are also being developed, with initial reports of positive results.71 A recent review of factors associated with prevention of cognitive decline with aging reported evidence for cognitive training, physical exercise, and possibly diet as efficacious interventions.72 These data suggest the value of testing exercise and dietary interventions to preserve cognitive function in cancer survivors.
A legitimate question is the extent to which the breast cancer studies are generalizable to other types of cancers and treatment regimens. Research examining treatment-related cognitive change in other cancers is difficult to evaluate, because there are generally fewer studies. However, evidence for treatment-related cognitive changes has been found for patients with various tumors, including lymphoma,65 leukemia,73 ovarian,74 and prostate (hormone ablation75) cancers, although negative studies have been reported. On the other hand, studies of patients with testicular cancer suggest that cognitive deficits can be identified on self-report measures of cognitive functioning, but not on objective neuropsychological testing.76,77 Interestingly, the chemotherapy agents included in treatment regimens for testicular cancer (cisplatin, etoposide, bleomycin) have been implicated in cognitive change in other cancers. Therefore, questions remain as to whether there are aspects of the treatment regimen (eg, dose, timing) or the biology of the disease that are responsible for the lack of results on neurocognitive testing. Alternatively, patients with testicular cancer tend to be younger than most other cohorts studied. Consistent with the discussion of models of aging, it may be that younger patients have more physical and cognitive reserve, which allows them to maintain performance on neuropsychological testing. However, children treated for non-CNS cancers and adult survivors of these childhood cancers can experience persistent cognitive changes78; therefore, there may be a curvilinear relationship with age, in that younger and older patients with cancer are more vulnerable to cognitive change, whereas younger to middle-aged adults may be more resilient. Clearly, additional research is necessary to test this hypothesis.
A convincing body of evidence from neuropsychological, imaging, and animal studies demonstrates cognitive changes associated with cancer and cancer treatments in a subgroup of individuals. Future research will require larger sample sizes to identify predictors of vulnerability to pre- and post-treatment cognitive change and define the impact of cancer and cancer treatments on the trajectory of cognitive change in long-term, particularly older, cancer survivors. Models of aging may provide a conceptual framework to guide future research. Finally, this area represents an excellent example of how translational and team science can result in significant scientific progress.
Supported by Grants No. R01 CA87845, R01 CA101318, R01 CA129769, and U54 CA132378 from the National Cancer Institute, Bethesda, MD.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
The author(s) indicated no potential conflicts of interest.
Conception and design: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors