Mechanisms and Treatment for Cancer- and Chemotherapy-Related Cognitive Impairment in Survivors of Non-CNS Malignancies

Up to 70% of survivors of adult-onset, non–central nervous system (CNS) solid tumors report cognitive symptoms, and approximately 30% have impairment on formal neuropsychological testing. The etiology of the impairment is unknown. There is a lack of robust evidence on how to prevent or treat cancer-related cognitive impairment (CRCI). Here, we review the evidence for the putative mechanisms of CRCI by examining clinical and preclinical models, primarily those associated with chemotherapy. Pharmacologic and nonpharmacologic options for treating CRCI are discussed based on the best evidence available. Practical clinical advice for health professionals managing patients with CRCI is also provided.

Introduction

Most cancer survivors report cognitive symptoms while undergoing chemotherapy, with gradual improvement over time after treatment ends. However, at least one-third of survivors experience sustained cognitive symptoms, which are often associated with fatigue, depression and anxiety, and poor quality of life.[1,2] Commonly reported complaints include increased difficulty with multitasking, word-finding, memory, and concentration.[3] Only a weak association has been found between cognitive symptoms and cognitive performance as assessed by formal neuropsychological testing.

The incidence of objective cognitive impairment varies by tumor type, as well as by the treatment received, time from treatment, neuropsychological tests performed, and the definition of impairment used. For instance, the largest longitudinal prospective clinical study to assess cognition in cancer patients found that, soon after diagnosis and prior to any chemotherapy, 43% of colorectal cancer patients had cognitive impairment, compared with 15% of non-cancer controls; in addition, 46% of survivors reported impairment 12 months later, compared with 13% of controls.[4] The cognitive domains most affected included attention/working memory, verbal memory, and processing speed. Interestingly, no difference was seen in neuropsychological performance related to chemotherapy, but the rate of cognitive symptoms at 6 months was significantly higher in those who received chemotherapy, although it improved over time. In studies of women with breast cancer, the incidence of impairment soon after diagnosis is approximately 30%.[5] Sustained cognitive impairment varies from 15% to 45%,[6] with a number of studies finding more impairment in survivors who have received chemotherapy. This is supported by neuroimaging studies reporting changes in brain activation and structure, sometimes persisting more than a decade later, in women who received chemotherapy compared with those who did not.[7]

This review focuses on the cognitive effects of cancer and chemotherapy on survivors of adult-onset, non-CNS solid tumors and the evidence for proposed underlying mechanisms. Options for treating cancer-related cognitive impairment (CRCI) will also be discussed.

Mechanisms of Cancer-Related Cognitive Impairment

Inflammation

The role of inflammation is the most extensively studied mechanism in the development of CRCI. It is based on the assumption that malignancy and systemic treatments, such as chemotherapy, induce inflammation in the body, which is then propagated to the brain via well-
characterized pathways of immune-to-brain signaling.[8,9] Neuroinflammation then regulates mood, cognitive, and behavioral changes associated with CRCI. Preclinical studies have helped confirm the potential role of inflammation in CRCI. Inflammatory factors, including cytokines and their receptors, NF-ÎºB and STAT3 signaling cascades, and enzymes (eg, IDO, COX, and iNOS), have been identified and tested in rodent models of CRCI.[10-14] Tumor-bearing mice show evidence of depression-like behaviors, with increased expression of proinflammatory cytokines in the tumor microenvironment, plasma or serum, and hippocampus.[15] Hippocampal interleukin (IL)-1Î²,[16] IL-6, and tumor necrosis factor (TNF)-Î±[17] have also been associated with cognitive impairment and reduced neurogenesis in tumor-bearing mice. Chemotherapy-treated rodents have elevated proinflammatory cytokines in the circulation, peripheral sensory neurons, and the brain.[18-20] While most studies suggest that proinflammatory cytokines are responsible for CRCI, several have demonstrated that chemotherapy also alters anti-inflammatory cytokine profiles.[18,20]

Several clinical studies in breast cancer survivors have shown an association between proinflammatory cytokines and CRCI. Higher circulating IL-1ra and TNF-RII expression levels induced by chemotherapy have been reported to be significantly correlated to memory complaints and lower brain metabolism compared with patients who did not receive chemotherapy[21,22]; in addition, IL-6 and TNF-Î± levels in the sera of patients post-chemotherapy have been associated with verbal memory performance and hippocampal volume.[23] A number of other clinical studies have described associations between circulating cytokines and aspects of cognitive function in breast cancer patients during and after treatment.

While a number of studies have demonstrated a relationship between inflammation and CRCI, several clinical studies have failed to find any such relationship. Most notably, our large study in colorectal cancer survivors failed to show an association between circulating markers of inflammation and global CRCI.[4] Several explanations are possible: 1) The association between inflammation and CRCI is weak. 2) The relationship between inflammation and CRCI differs by tumor type; most positive studies are in breast cancer. 3) Single cytokine analysis may not be the best approach to detect a relationship between inflammation and CRCI. Instead, downstream receptors, ratios of pro vs anti-inflammatory cytokines, or molecular signaling pathways may be more informative. 4) Circulating cytokines in serum may not reflect the inflammatory milieu of specific organs in which the required cytokine is used (eg, the brain). Given the discrepancy in findings between studies, the jury is still out regarding the role of inflammation in CRCI; if the relationship is positive, the potential exists to use anti-inflammatory agents to treat and prevent CRCI.

Direct Cytotoxic Damage to the Brain (Neurotoxicity)

Chemotherapy may impair metabolic and cellular function of the brain through direct cytotoxic damage to neurons and other cells. Most studies have used preclinical animal models of CRCI due to the need to access brain tissue. While many agents do not provide predictable responses across the CNS due to variable blood-brain barrier penetration, several studies have demonstrated the capacity of some chemotherapy agents, including fluorouracil, lapatinib, and temozolomide, to cross the blood-brain barrier despite efflux mechanisms, such as the P-glycoprotein transporter.[24]

Several studies have demonstrated increased apoptosis or necrosis[25-27] and reduced neurogenesis in response to chemotherapy.[28-30] While increased apoptosis/necrosis may play a role, chemotherapy agents are typically more effective in killing rapidly dividing cells (ie, tumor cells) compared with more stable neuronal cells.[31] Recent evidence suggests that chemotherapy-induced damage impedes metabolic function and energy utilization of brain cells, as opposed to causing the death of brain cells. This may help explain the relatively subtle effects on cognition that typify CRCI. Several studies support this mechanism. For example, cisplatin was shown to cause mitochondrial DNA damage in clinical studies and to reduce adenosine triphosphate production by 70% in vitro.[32,33] This has been confirmed in preclinical experiments connecting cognitive impairment, mitochondrial damage, and reduced dendritic branching and spine density in the brain after cisplatin.[34-36] Moreover, patients receiving platinum-based treatments have shown decreased glucose metabolism in both gray and white matter structures.[37]

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

Some have suggested that the HPA axis contributes to CRCI, but few studies have directly examined the validity of this statement. Changes in the diurnal rhythmicity of cortisol and blunted cortisol responses to stress, as well as reduced expression of genes that support the possibility of functional glucocorticoid receptor resistance, have been observed in breast cancer survivors.[38-40] However, these studies have focused on fatigue, and a direct examination of the HPA axis in CRCI has yet to be conducted. Regardless, studies in non-cancer populations have demonstrated that the HPA axis plays an integral role in learning and memory.[41,42] McEwen and colleagues postulated that chronic stress caused by cancer and cancer treatment may result in allostatic overload in survivors, which dysregulates stress hormones such as glucocorticoids and homeostasis. This has been reported to contribute to imbalances in metabolism and decreases in neurogenesis, size, or plasticity of the hippocampus.[43,44]

Genetic Associations

Several genetic variabilities have been associated with CRCI. Apolipoprotein E (ApoE) plays a role in lipid metabolism and is implicated in Alzheimer’s disease. Breast cancer survivors who carry the epsilon-4 allele with polymorphisms rs429358 and rs7412 on the ApoE gene may be more vulnerable to CRCI.[45,46] However, Vardy et al found only a non-significant trend for increased cognitive impairment in colorectal cancer survivors with at least one ApoE4 allele compared with those without the allele.[4] Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catecholamine neurotransmitters, such as dopamine, adrenaline, and noradrenaline in the prefrontal cortex and limbic system. The polymorphism of COMT represented by a valine (Val or G) and methionine (Met or A) substitution has a high association with cognitive function and dopamine levels in non-cancer patients. The COMT (rs4680) polymorphism has been shown to have decreased enzyme activity,[47] which impacts neural activation patterns.[48] Some research suggests an association between the COMT (rs165599) polymorphism and a higher risk of CRCI in post-chemotherapy breast cancer survivors.[49] Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates neuronal function and development. The polymorphism of BDNF (rs6265; Val66Met) has been linked to poor performance in episodic memory and working memory; it is also associated with reduced hippocampal volume and activity in non-cancer populations,[50-52] and may play a role in CRCI. There is limited evidence on the involvement of genetic associations in CRCI, and more research is required. Table 1 summarizes the mechanisms that have been associated with CRCI.

Interventions for Cancer-Related Cognitive Impairment

Nonpharmacologic Interventions

CRCI can be managed with several nonpharmacologic strategies that address brain changes through: 1) neuroplasticity models (cognitive training, rehabilitation); 2) coping (cognitive behavioral therapy [CBT], compensatory strategies); or 3) reducing related symptoms (physical activity, mind-body). The evidence to support each intervention is summarized here and in Table 2, and Table 3 provides a summary of the levels of evidence for each intervention category.

Cognitive Training

Cognitive training uses exercises targeting the underlying neural pathways, such as speed of information processing or auditory attention, to increase cognitive capacity through regular training with progressively increasing levels of difficulty. Three randomized controlled trials (RCTs), two of which were pilot/feasibility studies, demonstrated reduced cognitive symptoms in cancer survivors after cognitive training.[53-55] Results for neuropsychological performance were mixed, with the largest trial finding no improvement.[53] At a minimum, cognitive training can be delivered to survivors in a convenient format and at a relatively low cost to reduce cognitive symptoms. Further research is required to determine its effect on neuropsychological performance, as well as whether its effects extend beyond breast cancer populations.

CBT and Compensatory Strategies

CBT is a psychotherapeutic approach involving short-term, goal-oriented problem-solving strategies to change patterns of thinking. Four trials have assessed the efficacy of CBT or compensatory strategies training in women with breast cancer. Two were quasi-randomized,[56,57] one was a pilot study,[58] and the other was a small RCT.[59] Results across all trials were equivocal, with the RCT indicating an improvement in cognitive symptoms compared with active controls.[59]

Cognitive Rehabilitation

Cognitive rehabilitation aims to restore normal functioning through specific skills training and meta-cognitive strategies in individuals experiencing cognitive impairment. Four studies have reported on the efficacy of cognitive rehabilitation interventions: one in breast cancer survivors[60] and three in adult cancer survivors of non-CNS tumors.[61-63] Interventions included individual and group delivery, either in person or online. All trials demonstrated improved cognitive symptoms, but mixed results for neuropsychological performance; the same results also occurred in non-cancer control participants. Small sample sizes and multiple comparisons were utilized in all studies.

Mind-Body Interventions

Few studies have assessed the efficacy of mind-body interventions, such as mindfulness-based stress reduction (MBSR). Two pilot trials investigated MBSR in cancer survivors, but cancer-related fatigue was an inclusion criterion.[64,65] The largest (N = 71) demonstrated an improvement in cognitive symptoms, but not neuropsychological performance.[64]

Physical Activity Interventions

One RCT in breast cancer survivors, which assessed a 12-week program of goal setting, activity monitoring, and remote support, demonstrated improved cognitive symptoms but not neuropsychological performance.[66] Despite a number of cross-sectional and cohort studies suggesting improved cognitive performance and symptoms, research in this area has been limited; however, at least four RCTs are underway.

Nicole A. Shonka, MD

Chemobrain: Objectively Measuring an Elusive and Troubling Entity

“Chemobrain” is the most common phrase patients and clinicians use to describe cognitive deterioration resulting from cancer therapy. Affected survivors report distractibility, as well as impaired short-term memory and executive functioning. While recognition of chemobrain has increased in the last decade, its definition requires improvement, and its mechanisms and pathophysiological correlates need to be better understood.

As outlined in the thorough review by Chung and colleagues, a number of well-designed studies have prospectively measured changes in cognition before, during, and after chemotherapy-with greatly variable and frequently contradictory findings. The potential confounders affecting cognition in this vulnerable population are almost overwhelming, and several are subjectively assessed: age,[1,2] menopausal status,[2] educational level,[3] number of cycles and type of chemotherapy,[4] time since last treatment,[1] fatigue,[1] and depression and anxiety.[3,4] In regard to the latter two confounders, chemotherapy has been shown to decrease serotonin release in mice; in addition, glial cell line–derived neurotrophic factor produces a neuroprotective environment, which is further supported by a study showing an increase in MRI gray matter signal around the hippocampus in patients given selective serotonin reuptake inhibitors.[5]

Only in the last 2 decades has much research been conducted in this area. These studies are assessing the potential roles of hormones, exercise, educational programs, neurocognitive interventions, genetic markers, smoking, anesthesia, and many other factors. The previously discussed confounders, however, make this area of study increasingly complex.

Although researchers have a battery of validated cognitive tests in their arsenal, more is needed to objectively measure this elusive entity. First, studies should remove “healthy controls” and instead compare cognition in groups receiving chemotherapy vs those with cancer not receiving chemotherapy. Second, studies should follow survivors longitudinally to detect within-patient differences to determine acute vs latent effects or recovery. Third, studies should control for concurrent depression or anxiety via exclusion or stratification. Lastly, whenever possible, clinical biomarkers and imaging correlates should be explored and validated. Only through cooperative efforts can psychologists, neuro-psychologists, and medical oncologists learn to predict and protect those at greatest risk.

Dr. Shonka is an Associate Professor of Internal Medicine in the Division of Oncology & Hematology at the University of Nebraska Medical Center’s Fred & Pamela Buffett Cancer Center and the Cancer Center at Village Pointe in Omaha, Nebraska.

Qigong/tai chi has been assessed in two RCTs and one single-arm pilot study.[67] In one RCT, medical qigong demonstrated improved cognitive symptoms compared with usual care, but neuropsychological performance was not assessed.[68] A second RCT, which used a sham qigong control with both groups, found improved cognitive symptoms and neuropsychological performance, but no difference between the groups.[69]

Yoga interventions have been assessed in three RCTs, which reported positive effects on cognitive symptoms.[70-72] Cognitive symptoms were secondary outcomes, and none of the trials assessed neuropsychological performance.

Pharmacologic Interventions

Outside of clinical trials, there is a lack of evidence for the use of pharmacologic agents in treating CRCI. The following agents have been investigated, but are either not effective or have been evaluated in only pilot studies.

Erythropoietin

Two RCTs evaluated erythropoietin delivered during adjuvant chemotherapy in breast cancer survivors. Both were underpowered and did not use comprehensive neuropsychological assessments. One study in 94 women reported an improvement in cognitive function in the erythropoietin group at cycle four, but not at 6 months.[73] The second, which randomized 87 women with a hemoglobin level of less than 12 g/L to receive erythropoietin or a placebo with adjuvant chemotherapy, showed no difference in cognitive function when assessed 12 to 30 months later.[74]

Stimulants

Methylphenidate is commonly used to treat attention-deficit/hyperactivity disorder. Two placebo-controlled studies of this agent showed no improvement in CRCI.[75] Both were underpowered to show a difference, with one study closing early due to poor accrual; in addition, the cognitive assessment used was unlikely to detect subtle differences. Another study of 154 patients with fatigue at least 2 months after completion of chemotherapy randomized participants to 8 weeks of dexmethylphenidate or a placebo. An improvement in fatigue (primary endpoint) but not cognitive function was seen.[76]

Modafinil is a CNS stimulant generally used to treat narcolepsy. It has been shown to reduce severe fatigue in cancer patients.[77] A secondary analysis evaluating cognitive function in 82 breast cancer survivors with fatigue suggested some improvement in speed and episodic memory on a computerized test in the modafinil group.[78] Another study of 28 patients with advanced cancer found some improvement in psychomotor speed and visual information processing 4.5 hours after modafinil compared with placebo.[79]

Alzheimer Drugs

To date, most research has been conducted in animal models or in cancer patients with CNS involvement. A phase II RCT was conducted among 62 female breast cancer survivors with cognitive symptoms 1 to 5 years after adjuvant chemotherapy. Participants were randomized to receive a placebo or 5 mg of the acetylcholinesterase inhibitor donepezil daily for 6 weeks, then 10 mg/day if tolerated for 18 weeks.[80] Patients taking donepezil performed better on two verbal memory tasks at 24 weeks. More anxiety was reported in the donepezil group at 12 weeks, but this difference was not significant at 24 weeks. The authors are planning a larger study to evaluate donepezil further.

Antidepressants

Most research on the use of antidepressants to manage CRCI is currently in preclinical models. However, one unpublished RCT evaluated paroxetine hydrochloride in 781 breast cancer survivors. After adjusting for depression, participants on paroxetine reported a greater improvement in attention and memory symptoms compared with placebo.[81] Neuropsychological performance was not evaluated.

Complementary and Alternative Medicines

An RCT of a standardized extract of the Chinese herb Ginkgo biloba (Egb761) compared 10 weeks of Egb761 60 mg twice daily vs placebo during adjuvant chemotherapy in 166 women with breast cancer.[82] No improvement in neuropsychological performance or cognitive symptoms was seen, but the cognitive test selected was a poor measure of performance.

Miscellaneous

Other potential interventions based on putative mechanisms of CRCI are being evaluated in preclinical trials, and no data are yet available. These agents include aspirin, nonsteroidal anti-inflammatory drugs, cytokine inhibitors for inflammatory processes, and metformin for mitochrondrial protection of the microglia. A study is currently underway assessing metformin in breast cancer survivors.

Conclusion

Survivors reporting CRCI should be referred for an evaluation of fatigue, sleep disturbance, anxiety, or depression, and/or to a neuropsychologist for a formal assessment. The best evidence for treatment of cognitive symptoms associated with cancer and cancer treatment is for cognitive training; however, it is not clear if these approaches translate to improvement on formal neuropsychological tests or “real-world” tasks. The evidence for physical activity, MBSR, cognitive rehabilitation, and CBT is weaker, but physical activity and mindfulness are associated with other benefits and worth considering. Pharmacologic agents for CRCI should not be prescribed outside of clinical trials.

FINANCIAL DISCLOSURE: The authors have no financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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