Introduction
Pertinent Definitions and Terms
Individuals living with cancer often experience a multitude of adverse effects that can negatively impact quality of life. One of the most prevalent and disabling sequelae is cancer-related cognitive impairment (CRCI), defined as the pattern of cognitive deficits reflecting the CNS toxic effects of cancer and its treatment. CRCI is most commonly categorized by a pattern of cognitive deficits in verbal memory, sustained attention, executive function, and processing speed. It is important to note that visual memory was not assessed in most studies of CRCI. It is highly unlikely that the toxic effects of cancer treatment would only affect focal brain regions or be unilateral. Multiple bilateral areas of cerebral dysfunction are more likely. Other cognitive domains can also be affected such as visual memory, verbal fluency, and upper extremity fine motor dexterity.
This pattern of cognitive impairments is often referred to as “chemo brain.” This colloquial term was originally coined based upon the previously accepted understanding that chemotherapy treatments were the primary culprit for these types of cognitive changes. However, neuroscience research in this area reveals the neurotoxic effects of systemic chemotherapy are only one possible etiology for this debilitating syndrome. While an exact pathophysiology is still unknown, it is now widely thought that other factors such as systematic inflammation associated with cancer and its treatment (surgery, chemotherapy, radiotherapy), hormonal therapies, premorbid and/or comorbid depression/anxiety, chronic sleep disturbance, external stressors (e.g., marital/family problems, financial/health insurance issues), alcohol/substance abuse, and genetic predisposition to cognitive impairment may also contribute to the development of CRCI. In fact, many of these factors often overlap, making it challenging to distinguish the likely cause of cognitive changes in patients with cancer. The term “chemo brain” is now most commonly referred to in the medical literature as CRCI or cancer-related cognitive impairment.
Prevalence and Course of Cognitive Impairment in Patients With Breast and Gynecological Cancers
Multiple longitudinal prospective studies, comparing pre- and posttreatment cognitive function predominantly in breast cancer survivors, have been conducted to identify the prevalence and course of CRCI. These large, multicenter studies have used neuropsychological testing across multiple time points up to 6–24 months after the cancer diagnosis. These studies have found a CRCI prevalence rate ranging from 12% to 82% across the cancer treatment trajectory. A review by Janelsins et al. highlights studies of CRCI that found prevalence rates of 30% among breast cancer patients pretreatment, 75% of patients during treatment, and 35% of patients posttreatment. In the largest multicenter, longitudinal prospective controlled study of 581 breast cancer survivors and 364 controls matched for age, education, and menopausal status, Janelsins et al. assessed cognitive function at three time points, including prechemotherapy, postchemotherapy, and 6 months after chemotherapy. Janelsins et al. found a significantly higher rate of cognitive decline postchemotherapy compared to prechemotherapy among the breast cancer survivors and matched controls (45% and 10%, respectively, P <.001). Six months after completing chemotherapy, a statistically significant rate of cognitive decline persisted in the breast cancer survivors compared to the controls (37% and 14%, respectively, P <.001). Notably, pretreatment baseline cognitive reserve, as measured by the Wide Range Achievement Test, significantly correlated with cognitive decline rates in this sample.
In a longitudinal age-matched controlled study utilizing neuropsychological testing in 132 breast cancer patients after surgery but prior to adjuvant therapy (chemotherapy or radiotherapy), investigators found a significantly higher rate of cognitive deficits among 22% of breast cancer patients as compared to only 4% of age-matched healthy controls. This finding of postsurgery pretreatment cognitive decline in breast cancer patients (prior to receiving adjuvant therapy) propelled the hypothesis that the biology of the proinflammatory tumor microenvironment may contribute to the pathogenesis of CRCI, independent of the neurotoxicity of chemotherapy. However, other factors such as the effects of anesthesia, pain medication, and postsurgery emotional sequelae should be considered in future research.
Specifically, several studies have found that 20%–30% of patients with breast cancer have lower than expected cognitive performance pretreatment, based on age and education. In addition, a review done by Ahles et al. indicates that cross-sectional studies of breast cancer survivors have found that 17%–75% experienced cognitive deficits in domains, including attention, concentration, working memory, and executive function, from 6 months to 20 years after chemotherapy exposure. Furthermore, according to Van Arsdale et al., studies evaluating cognitive dysfunction in women with ovarian cancer have shown that 17%–80% have been reported to have cognitive deficits with symptoms, including decreased memory, attention, and executive function lasting 5–10 years following treatment. To date, the literature suggests that presentation and course of CRCI among breast and gynecological cancer patients are highly variable. This syndrome may manifest with subtle or dramatic cognitive deficits, and its course may be transient or permanent and stable or progressive. A possible contributing factor to the variable presentation of CRCI is the fact that not all the studies cited utilized the same neuropsychological tests. In addition, the testing that was done was more of a neuropsychological screening than a comprehensive battery. It is possible that a more comprehensive test battery would demonstrate other areas of cognitive dysfunction. However, time and cost constraints of a comprehensive neuropsychological test battery may limit its utility in clinical settings.
Much more research is needed to better understand the debilitating sequelae of CRCI. Most studies have been conducted with breast cancer patients under the age of 60. More studies evaluating the incidence of CRCI among patients with gynecological cancers (i.e., endometrial, ovarian, cervical, and vulvar) are needed. That said, the assessment approach for CRCI would likely be the same across cancer types; and its treatment is primarily tied to the specific cognitive deficits found on neuropsychological testing.
Impact of Cognitive Impairment on Quality of Life and Function in Breast and Gynecological Cancers
The highly variable and unpredictable course of CRCI can make its impact more challenging to manage and difficult to treat. For patients experiencing CRCI, returning to school and/or work can be quite daunting due to its negative impact on an individual’s daily functioning. Sometimes, patients may find themselves needing to temporarily interrupt their academic studies, extend a medical leave of absence from work, change jobs/careers, or even apply for disability, all of which can have financial implications on the heels of an already financially burdensome time. Furthermore, CRCI’s reach often extends its interference into other areas, including familial and societal roles as well as emotional consequences. Patients often describe becoming more withdrawn due to feelings of self-consciousness over cognitive difficulties that can sometimes lead to depression. Their self-confidence and self-esteem can be rattled and they often make statements such as “I can’t made decisions” or “I can no longer multitask.” They often feel guilty over their perceived burden placed on loved ones. Some other common descriptions given by patients include (1) “Going back to work has been very difficult because I’m not as sharp or quick on my feet as I was before and I’m afraid my co-workers will think I’m not capable anymore”; (2) “I always had the best memory, everyone knew me for it, and now I can’t even remember simple things like movies I’ve seen or things I’ve read”; (3) “I often have trouble finding words I want to say, I can picture it in my mind and can describe it, but I can’t think of the actual word, so I now avoid having conversations whenever possible because I’m embarrassed when it happens”; or (4) “I went back to graduate school a few months before my diagnosis and going back now after finishing chemo I’m finding it really hard to listen to lectures while keeping up with taking good notes.” Patients also frequently report discontinuing pleasurable activities or hobbies due to their CRCI symptoms. See Table 20.1 for more examples of CRCI symptom presentation.
| Cognitive Domains | Cognitive Functions | CRCI-Related Symptoms |
|---|---|---|
| Memory (verbal and visual) | Ability to register, encode, and retrieve verbal, visual, and spatial information; both in the short term (immediate) and long term (delayed) | Trouble remembering names, important dates, or appointments, what you have just read, details of conversations with others. Misplacing everyday items such as keys, wallet, and cell phone; difficulty navigating while driving; trouble remembering where parked |
| Visuospatial | Ability to analyze and synthesize abstract, nonverbal, visual material; fluid reasoning | Judging distance, rate of movement when driving, estimating how much water in a pot, reading a map or blueprint, putting a puzzle together |
| Working memory | Ability to temporarily hold (remember) information and manipulate it; ability to immediately process conscious perceptual and linguistic information | Difficulty taking notes in class, remembering a phone number long enough to dial it, mental arithmetic |
| Attention and concentration | Ability to tune into auditory and visual information; ability to sustain focus over time while effectively disregarding any competing distractions | Difficulty concentrating, short attention span, easily distracted, feel like they “space out,” trouble completing tasks |
| Processing speed | Ability to process information (simple and complex) with speed, efficiency, and accuracy (without making mistakes) | Take longer amount of time to finish simple or routine tasks, complain of disorganized or slow thinking, less time and mental energy for understanding new information or “thinking on your feet” |
| Executive function | Ability to manage multiple tasks simultaneously, cognitive flexibility, novel problem-solving; decision-making, judgment and impulse control, short- and long-term planning | Difficulty multitasking, can only do one thing at a time; hesitancy in making decisions when that normally would not be the case; trouble “thinking outside the box”; trouble learning something new |
Given the advancing age of the average gynecological cancer patient population, these women may present with other comorbid medical conditions that may contribute to or exacerbate any presenting cognitive difficulties, in addition to expected aging cognitive decline. Hence, a thorough assessment, including past and current medical history, is critical.
Structural and Functional Neuroanatomical Correlates of Cancer-Related Cognitive Impairment
Normal cognitive function can be characterized into six cognitive domains with specific functions that are mediated by different regions of the brain. Present research indicates that CRCI may impact up to four of these cognitive domains, including sustained attention, executive function, processing speed, and learning/working memory. The areas most impacted by chemotherapy include brain hub regions such as the prefrontal cortex and hippocampus that are critical for executive functioning and memory. Moreover, brain network connectivity is also impacted by chemotherapy that may interfere with sustained attention and processing speed. See Table 20.1 for a list of cognitive domains and their respective functions, including examples of related CRCI symptom presentation.
To date, the greatest body of research on CRCI includes structural and functional neuroimaging studies of breast cancer patients who have received chemotherapy. See Table 20.2 for neuroanatomical correlates of CRCI in breast cancer patients treated with chemotherapy. McDonald et al. conducted prospective longitudinal controlled voxel-based morphometry measurements of structural MRIs among 48 breast cancer patients with chemotherapy compared to age-matched breast cancer patients without chemotherapy and age-matched controls across three time points; baseline, 1 month postchemotherapy, and 12 months postchemotherapy. These studies showed reduced gray matter volume in the frontal lobe, medial temporal lobe, and cerebellum that correlated with neuropsychological testing deficits. A cross-sectional structural MRI study of 339 breast cancer patients with and without chemotherapy was compared with healthy controls at 1 and 3 years after treatment. This study found a reduction in neocortical gray matter persisted at year 1 and normalized by year 3 after chemotherapy. In two cross-sectional diffusion tensor imaging studies among breast cancer patients who received chemotherapy, reduced white matter integrity correlated with worsening attention and verbal memory.
| Neuroanatomy | Associated Cognitive Function |
|---|---|
| Frontal and parietal lobes | Attention, concentration |
| Prefrontal cortex (ventrolateral and dorsolateral areas) | Working memory, executive function |
| Prefrontal, anterior cingulate and orbitofrontal cortex | Emotional regulation, impulse control |
| Prefrontal cortex and subcortical white matter networks | Processing speed |
A review by Simó et al. reports that prospective structural neuroimaging (MRI) studies have shown that there is a widespread decrease in white matter volume prior to treatment with chemotherapy and with functional MRI an increased level of activation of the frontoparietal attentional network of cancer patients compared to controls. However, Simó et al. also report that once patients were exposed to chemotherapy, there was “an early diffuse decrease of gray matter volume and white matter volume together with a decrease of the over-activation in frontal regions” compared to controls.
A longitudinal prospective functional MRI study of 28 breast cancer patients with and without chemotherapy compared with healthy age-matched controls at baseline, 1 and 12 months after chemotherapy found hyperactivation of the prefrontal cortex during working memory task when compared to controls, with reduced activation after 1 month and only partial return to baseline hyperactivation after 1 year. These findings suggest that early brain hyperactivation reflects neural compensation; however, long-term reduced activation may correspond to established deficits.
Risk Factors and Pathogenesis of Cancer-Related Cognitive Impairment in Patients With Breast or Gynecological Cancer
Multiple risk factors and mechanisms of pathogenesis associated with CRCI include the following variables
- 1.
advanced age,
- 2.
chemotherapy-induced cellular mechanisms that lead to accelerated aging,
- 3.
direct neurotoxicity of chemotherapy,
- 4.
hormonal therapies,
- 5.
low baseline cognitive reserve,
- 6.
cytokine-mediated neuroinflammation driven by the systemic effects of the tumor microenvironment and cancer-related treatments, and
- 7.
genetic vulnerability to cognitive impairment.
It is well established that there is a natural cognitive decline with age that has led to speculation by researchers that older adults may be more vulnerable to the cognitive effects of cancer treatment. A review by Ahles et al. states that “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.” Specific biological processes by which chemotherapy accelerates aging include chemotherapy-induced neuronal injury with inadequate repair through oxidative DNA damage associated with neurodegenerative disease and chemotherapy-induced shortening of telomeres in glial cells.
Chemotherapy-induced direct neurotoxic effects on the brain have been shown in preclinical studies and clinical neuroimaging studies. Animal studies have found very minute leakage of chemotherapy can cause cell death and reduce cell division in the dentate gyrus of the hippocampus that is critical for memory. Direct neurotoxic effects of methyltrexate include coagulative necrosis of the white matter, axonal swelling, and demyelinization. In addition, 5 fluorouracil causes acute and delayed myelin damage. Areas that are most affected by chemotherapy include brain hub regions such as the prefrontal cortex (executive function, processing speed, working memory), hippocampus (verbal and visual memory), and frontal/parietal lobes (attention, concentration, spatial/perceptual ability). In addition, brain network connectivity is also impacted. In particular, platinum-based agents such as cisplatin, often used in the treatment of gynecological cancers, are highly neurotoxic. According to Pendergrass et al., it has been estimated that “13–70% of patients receiving cancer chemotherapy have measurable cognitive impairment” and that adjunct endocrine therapy, as is often used in breast cancer treatment for several years, can result in cognitive impairment.
A review of several studies found endocrine therapy significantly impacted cognitive function. Specifically, hormonal therapy was accompanied by deficits in verbal memory/fluency, motor speed, attention, and working memory. In a prospective controlled study neuropsychological testing was administered to 300 postmenopausal women at two time points: before hormonal therapy and after 1 year on hormonal therapy. The sample included 180 breast cancer patients on maintenance hormonal therapy with no systemic therapy exposure compared to 120 healthy age-matched controls. The study found that tamoxifen users ( N =80) had significant deterioration in verbal memory and executive function at 1 year compared to the healthy controls. In contrast, exemestane users ( N =98) did not have significant cognitive deficits at 1 year compared to the healthy controls. This is clinically relevant as therapy compliance can be affected by the experience of CRCI for many women.
The role of baseline cognitive reserve is important when discussing the potential risk for developing CRCI. Cognitive reserve as defined by Ahles et al. “represents innate and developed cognitive capacity (influenced by education, occupational attainment and lifestyle).” Baseline cognitive reserve was measured by the Wide Range Achievement Test (WRAT) reading subscale that measures baseline reading ability. This ability to read words is generally resistant to the effects of most types of cerebral dysfunction. A high cognitive reserve is associated with reduced cognitive decline. The promising aspect of this is that cognitive reserve potentially can be developed. More research is needed in this area.
Perhaps the most intriguing biological underpinning of CRCI includes cytokine-mediated neuroinflammation. Cancer patients have increased circulating levels of proinflammatory cytokines associated with the tumor microenvironment, cell death, and tissue injury due to surgery, chemotherapy and radiotherapy, and physical and psychological distress. A linear correlation has been found between an increase in peripheral cytokine levels (IL-6, MCP-1, IL-8) and cognitive dysfunction in breast cancer patients. In contrast, increased levels of circulating TNF receptor 2 associated with CRCI and decreased levels at 1 year after chemotherapy were associated with improved cognitive performance. In addition, reduced hippocampal volumes are associated with higher levels of proinflammatory cytokines, TNF-alpha, and IL-6, in breast cancer survivors exposed to chemotherapy as compared to age-matched controls. Increased systemic inflammation driven by the tumor microenvironment and cancer treatments triggers neuroinflammation which in turn creates changes in neurotransmission and gray matter volume which impacts cognition.
Polymorphisms of specific genes that regulate neural repair/plasticity and neurotransmission may predispose cancer patients to CRCI. Specifically, breast cancer survivors exposed to chemotherapy with the ApoE4 allele scored lower on visual memory. COMT (catechol- O -methyltransferase) is an enzyme that metabolizes dopamine, a critical biogenic amine needed for cognition. COMT val+ genotype carriers have increased COMT enzymatic activity that leads to decreased dopamine in the frontal networks interfering with cognitive performance. A COMT genotype study among breast cancer survivors with radiotherapy ( N =59) and/or chemotherapy ( N =72) found that COMT val+ carriers scored significantly lower on verbal memory, attention, and motor speed as compared to COMT Met+ homozygotes. In contrast to CRCI high-risk breast cancer survivor genotyping studies, genotyping for polymorphisms that influence neuronal plasticity such as brain-derived neurotrophic factor (BDNF) may identify those patients protected against CRCI. In a study of 145 breast cancer survivors, those survivors with BDNF Met+/Met+ homozygote genotyping were protected from chemotherapy-induced cognitive changes with preserved verbal memory and multitasking ability when compared to those with BDNF val+ carriers. These studies highlight the role of genotyping to identify high-risk and low-risk patients with respect to CRCI and instituting this genotyping as a protocol to mitigate CRCI among breast cancer patients.
Assessment of the Cancer Patient With Cognitive Impairment
- 1.
Assessment of CRCI requires a comprehensive biopsychosocial evaluation with an emphasis on the medical workup for altered mental status and the required objective neuropsychological testing to identify the extent and nature of subtle deficits of CRCI. A complete history and clinical examination, with baseline laboratory and neuroimaging workup for cognitive deficits in a breast cancer or gynecological cancer patients, should include the following:
- a.
Laboratory studies (complete blood count, comprehensive metabolic panel, C-reactive protein, vitamin B12, folate, thyroid-stimulating hormone level): Additional relevant labs if CNS paraneoplastic syndrome suspected.
- b.
Brain MRI with/without contrast and diffusion tensor imaging study to assess for metastatic disease, CVA, white matter integrity.
- c.
Neuropsychiatric consultation to assess for premorbid/comorbid mood and anxiety disorders, alcohol/substance abuse, premorbid history of attention deficit disorder, sleep disorders, dementia, mild cognitive impairment, or traumatic brain injury. Although administering the Montreal Cognitive Assessment (MoCA) should be a routine portion of the neuropsychiatric evaluation for cognition, this screening tool is insufficient to diagnose or rule out CRCI and a normal MoCA score ≥26 should not preclude administering the neuropsychological testing battery. Standardized self-report measures of depression and anxiety such as the Beck Depression Inventory-II and the Beck Anxiety Inventory should be repeatedly administered to help quantify a patient’s level of emotional distress as well as to monitor these distress levels over time.
- d.
Assess for antihistamine, antiemetic, benzodiazepine, and opiate-induced cognitive adverse effects.
2. The International Cognition and Cancer Task Force (ICCTF) was created in 2006 by experts in the neuroscience field to reach a consensus on how to assess, research, and treat CRCI. The task force determined that self-report alone was an inadequate measure of CRCI, and that objective neuropsychological testing was necessary. The proposed neuropsychological testing battery recommended by the ICCTF includes, at minimum, the following: Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Tests A and B, and Controlled Oral Word Association (COWA) (see Table 20.3 ). These tests evaluate the cognitive functions typically affected by CRCI such as noncontextualized verbal memory, visual processing speed, executive function (mental flexibility), and word-finding fluency. While this brief battery of tests provide valuable information, a more robust clinical picture of a patient’s cognitive strengths and weaknesses occurs by adding the following neuropsychological tests: Working Memory (e.g., Digit Span and Arithmetic subtests from the WAIS-IV), Processing Speed (Coding and Symbol Search subtests from the WAIS-IV), Visual Spatial Ability (Block Design and Matrix Reasoning subtests from the WAIS-IV), Contextualized Verbal Memory and Visual Memory (e.g., Logical Memory I & II; Visual Reproduction I & II from the WMS-IV), and one or more abbreviated test versions of Executive Functioning (e.g., WCST-64, Stroop test, Halstead Category test). This additional testing does not require extensive time to administer (approximately 2.5 hours to complete the entire battery), and this testing is well tolerated by the vast majority of patients we have examined. The results can provide important additional information about a patient’s cognitive capacity as well as provide a valuable blueprint identifying targets for cognitive rehabilitation. In addition, serial follow-up with these tests can provide objective evidence of cognitive recovery.
- a.
