Review Article

Chemobrain: -induced cognitive impairment Sindhu R1, Sri Harsha Chalasani2, Santhepete N. Manjula1*

ABSTRACT

The association between cancer chemotherapy and cognitive impairment is well recorded and much sought after. At times, the diagnosis of cancer itself may induce cognitive impairment. The stress experienced by cancer patients after diagnosis or during or after treatment may also result in cognitive impairment. The chemotherapy drugs themselves are stressors that cause adaptive signals and these could limit their clinical values. It is important to skim through the confounding factors and establish a stronger link between chemotherapy and cognitive impairment. This review article is aimed at evaluating the available information on cancer chemotherapy and cognitive impairment. KEY WORDS: Adverse drug reactions, Chemobrain, Chemotherapy, Cognitive impairment, Malignancy, Medication errors

INTRODUCTION contribute to CICI, and this shows that further studies are required to characterize the role of CICI.[4,7] Since the 1970s, the studies relating cognitive variations The chemotherapy considered as a vulnerability for with cancer chemotherapy have been established, but the cognitive dysfunction and the degree of impairment may systematic reviews on the adverse cognitive outcomes be influenced by various treatments, and the pathway [1-3] of chemotherapy appeared only after the 1990s. excreted by these cytotoxic compounds.[8] The proof implicating the impact of chemotherapy on cognitive function over a decade has emerged from Single therapy is not sufficient to treat the cancer the neuropsychological studies of cancer survivors patients while the failure to respond to multiple and also from the longitudinal studies that include pre- drug therapy against chemotherapy adds further treatment neuropsychological assessments.[4] complications to the treatment.[9] The genotoxic stress response induced by anticancer agents is coupled with Chemobrain often referred to as chemofog or the additional stress response.[10,11] chemotherapy-induced cognitive impairment (CICI) is a common adverse effect in cancer patients In this review, we consider how stress affects receiving chemotherapy. Chemobrain refers to the cognitive impairment, and also this review has patients experiencing diverse cognitive changes that focused on how chemotherapy will induce stress and happen before or post-chemotherapy.[5] The common the relation between chemotherapy and cognitive manifestations include impairment in memory, difficulty impairment that is chemobrain. The brief periods of in word finding, decrease in executive function, stress that potentiate the formation of memory shown, difficulty in organizing tasks, and lower information and also the recent work has uncovered some of processing speed. Nearly 17–75% of cancer patients the mechanisms. The present review focuses on the receiving chemotherapy suffer from chemotherapy- pathways, vulnerability, assessment, and management mediated cognitive dysfunction.[6] The review of of cognitive dysfunction related to chemotherapy literature showed that in the United States, there are 15.5 drugs for cancer patients. The future areas of research million individuals who survived cancer and are likely to pursue are also high lightened in this review. facing long-term cognitive impairments due to cancer or its related treatments. Several hypothesized mechanisms EFFECT OF STRESS ON COGNITIVE FUNCTION Access this article online Cognition is affected by stress in many ways. Website: jprsolutions.info ISSN: 0975-7619 Stress affects cognition by acting rapidly through

1Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore, Karnataka, India, 2Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore, Karnataka, India

*Corresponding author: Dr. Santhepete N. Manjula, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore - 570 015, Karnataka, India. Phone: +91-9916264940. E-mail: [email protected]

Received on: 18-07-2019; Revised on: 20-08-2019; Accepted on: 26-09-2019

Drug Invention Today | Vol 11 • Special Issue 2 • 2019 199 Sindhu R, et al. catecholamines and more slowly through environment.[19] In solid tumors, the stress response glucocorticoids. The two types of stressors, such leads to the development of resistance to anticancer as physical and psychological stressors, elicit the drugs that act on tumor cells. This inability to respond production of catecholamines such as epinephrine can be reversed or deteriorated on amputation of and norepinephrine through the sympathetic stress conditions.[20] The stressful stimuli, along with nervous system, and the adrenal gland secretes anticancer drugs, cause overexpression of multidrug glucocorticoids.[12] The cognitive dysfunction resistance 1 gene that encodes with P-glycoprotein. occurs mainly due to change in the This encoding creates an ionic gradient that reduces activity. the accumulation of drugs in cancer cells which are regulated by heat shock protein (HSP) (heat-shock Catecholamines: Epinephrine and Norepinephrine factor 1).[21] The literature review has demonstrated that Ventral tegmental area and locus coeruleus are the hyperthermia, along with chemotherapy, induces anti- primary sources of epinephrine and norepinephrine, inflammatory stress response to modulate the action respectively, which respond to the prefrontal of anticancer drugs such as , , cortex.[13] Overstimulation of dopamine that is , mitomycin C, and .[22] The role of D1 receptor occurs due to stress which further each type of stress response and the individual degree activates cyclic adenosine monophosphate, causing of contribution to the resulting phenotype is hard to hyperpolarization of nucleotide-gated channels to allocate in the tumor environment. Thus, hyperthermia open. This results in shoving of incoming excitation. is allied with regional hypoxia, anticancer drugs, and In addition, activation of norepinephrine alpha-1 oxidative or metabolic stress may provoke genotoxic receptor initiates phospholipase C signaling series stress response through reactive oxygen species- that leads to loss of excitation through potassium dependent potentiation of the C-Jun-N-terminal and channel in the soma. This causes cognitive p38 mitogen-activated protein kinase pathways.[11] impairment.[14] Under stress condition, the lipase C releases norepinephrine throughout the brain, and in Besides, their direct interactions with DNA anticancer the prefrontal cortex, it binds to the alpha-1 receptor drugs elicit adverse effects by interfering with at lower affinity.[15] Activation of this receptor either stress response cascade.[23,24] The ribosomal protein pharmacologically or due to stress-induced release RPL36 and HSP 10 are responsible for resistance to of norepinephrine causes impairment in memory, chemotherapy drugs.[25] The overexpression of HSP70 cognitive impairment.[16] in patients undergoing chemotherapy and a small increase in HSPs acts as an oxidative Glucocorticoids stressor.[23] In response to stress, many cochaperones Hypothalamic pituitary adrenal axis gets activated of HSP90 produce marked reallocation to the under stressful condition, which in turn causes nucleus.[26] However, only 17alpha-1 acid glycoprotein release glucocorticoids from the adrenal cortex. induces stress response on long-term treatment with These released glucocorticoids move through the chemotherapeutic agents.[27] bloodstream and cross the blood–brain barrier to trigger the glucocorticoid receptor in the brain, which CHEMOBRAIN causes memory impairment.[17] Chemobrain is also known as chemofog, or CICI Glucocorticoids interact with catecholamine by the refers to dysfunction of patients memory, learning, extraneuronal catecholamine transport system. These attention, speech, intellectual functioning, decision- carriers are present in the glia, which removes extra making, and visuospatial skills during the pre- or post- epinephrine and norepinephrine from the synapse chemotherapy.[28] Chemotherapy-related cognitive region. This keeps adrenergic and noradrenergic impairment is the most common adverse effects seen in receptor in balanced and optimum condition.[18] The cancer patients undergoing or after the discontinuation catecholamine transporters located in prefrontal cortex of chemotherapy.[29] inhibit the corticosterone, which result in the increase extracellular catecholamine levels. Thus, the stress- CICI Pathogenesis mediated glucocorticoid release causes stimulation of The exact pathogenesis of chemotherapy-induced both the dopamine 1 (D1) and alpha-1 noradrenergic cognitive function is unknown.[4] The etiology of receptor and causes cognitive impairment. CICI depends on the number of factors that lead to either direct or indirect effects on the central CHEMOTHERAPY-INDUCED nervous system, thus it in turn affects the cognitive STRESS capability of the cancer patients undergoing chemotherapy. The long-term cognitive impairment Experimental results support that anticancer in chemotherapy-treated individuals who have cancer drugs induce a stress response in the tumor is determined by genetic predisposition. The studies

200 Drug Invention Today | Vol 11 • Special Issue 2 • 2019 Sindhu R, et al. have shown that the cancer patients having allele CICI as explained in the pathogenesis. Studies have apolipoprotein e4 (APOEe4) are at the increased risk also shown that the patients who are treated with of developing cognitive dysfunction when compared drugs such as , , and with patients having other APOE alleles.[30] 5- regimen or the bleomycin, , cisplatin scheme, or regimens are at the greatest Some of the commonly used anticancer drugs do not risk of developing CICI.[37] cross the blood–brain barriers in required quantities. The small number of chemotherapy drugs can Several experimental studies are associated with the reach the brain parenchyma by altering the genetic dose, duration, and intensity of treatment which are variability in transporters of the blood–brain barrier.[31] a risk factor for chemotherapy-induced cognitive The previous studies have shown that minimal doses dysfunction. The other studies have shown that the of chemotherapy damage the brain structures which patients receiving a high dose of anticancer drugs are are associated with cognition, including cell death also in risk of developing CICI.[38] The individuals and decreases the cell division.[32] Chemotherapy- with breast cancer undergoing chemotherapy or induced menopause indirectly causes a change have completed the chemotherapy are at the highest in the hormonal level, including the decrease in risk of developing CICI.[39] Demographic details, neuroprotective estrogen hormones which adversely socioeconomic status, age, and gender are also the risk affect the cognitive function. The breast and prostate factors for inducing CICI.[40] cancer patients with hormonal therapy also suffer from cognitive dysfunction due to a reduction in the FACTORS AFFECTING CICI testosterone and estrogen levels. The other effective mechanism for CICI is DNA damage that affects There are various factors which affect the cognitive CNS secondary and caused increased oxidative impairment in patients receiving chemotherapy; some stress.[33] The difference between the secretion of of them are emotional distress, fatigue, and hormonal reactive oxygen, including free radicals and peroxides, therapy where each of them is explained below: causes oxidative stress. The exposure to exogenous Emotional Distress toxins results in the production of free radicals. The endogenous metabolism also produces some free The psychosomatic manifestations in cancer patients radicals to neutralize microorganisms, particularly occur due to emotional distress that is associated viruses and bacteria.[34] The pathogenesis of CICI may with the diagnosis of cancer or also may be due to also be attributed to immune dysregulation, cancer, or chemotherapy treatment. Literature survey has chemotherapy or even with the release of inflammatory demonstrated that cancer patients once they are cytokines such as interleukin (IL)-1, IL-6, and tumor emotionally distressed, particularly with depression, necrosis factor-alpha. These inflammatory cytokines it affects them for a long period of time and the cross the blood–brain barrier.[35] These are seen in complications persist even after the completion of [41] patients undergoing immunotherapy. Considering all, treatment. Many experimental results have proven there is a lack of indication to precisely explain the that prolonged cognitive dysfunction seen in cancer mechanism of CICI. As a result, the pathogenesis of patients was due to anxiety or depression which was CICI remains undefined. Further studies are required done by measuring patient’s quality of life, cognitive to disclose the exact pathogenesis of CICI. dysfunction without any impact on objective testing of cognitive function.[3,28]

RISK FACTORS ASSOCIATED FOR Weakness (Fatigue) CHEMOBRAIN Earlier studies demonstrated that cancer patients who There are several risk factors that increase the are suffering from severe fatigue might also suffer risk of developing CICI. Some of them include: from other problems such as neuropsychological (1) Administration of high doses of drugs due to functioning, cognitive dysfunction, and physical reduce in systemic clearance or due to change in activity which are scored using various questionnaires. pharmacokinetic or pharmacogenetic variation of However, there is no evidence that fatigue is linked drug; (2) additive or synergistic effects of multitherapy; with abnormalities in the objective neuropsychological (3) administration of drugs through intra-arterial route tests, but it is associated with the altered cognitive [3] by disturbing blood–brain barrier; and (4) intrathecal dysfunction. The weakness is linked with daily self- route of administration.[36,37] reported neurophysiological working and not with objective neuropsychological functioning. The other risk factors include epsilon 4 alleles of APOE which may be a potential genetic marker that Hormonal Therapy increases the susceptibility to CICI; the individuals The most significant confounders for CICI are with the with this allele are at the greater risk of developing hormonal therapy drugs such as tamoxifen, aromatase

Drug Invention Today | Vol 11 • Special Issue 2 • 2019 201 Sindhu R, et al. inhibitors, or with androgens. There is strong evidence cancer.[50,51] However, assessing patients for cognitive that hormonal therapy might also induce cognitive impairment are difficult due to the lack of clinically impairment in cancer patients.[42] This cognitive useful instruments. Clinicians are encouraged to carry impairment occurs mainly due to the reduced levels out a combination of assessment to diagnose cognitive of estrogen receptors which are usually found widely impairment in cancer patients. in CNS. Tamoxifen is used as the standard endocrine therapy for breast cancer patients as tamoxifen is an MANAGEMENT OF CICI antagonist for estrogen receptors in breast tissues. The earlier data have shown that this tamoxifen inducing Several efforts have been introduced to improve cognitive dysfunction is contradictory. The study was and test the interventions that may improve, avert conducted by recruiting 1163 patients with breast the expansion of CICI while researchers and cancer in which nearly 710 patients were administered clinicians are still trying to understand and illustrate with tamoxifen.[43] The limitation of this experiment the CICI.[8] For feasibility and preliminary results, was that the cognitive impairment was assessed by cognitive behavioral therapy intervention, memory, sending questionnaire through the mail.[3] There is and attention adaptation training are tested, and the evidence from recent studies that tamoxifen exerts results of this study showed that the results are safe, estrogen-like effect only in the brain. This study feasible, satisfied and improve the working memory concluded that the results from this study reduced the and quality of life.[52] The functioning skills of CICI anxieties about the safety of using tamoxifen to prevent breast cancer patients were improved by cognitive elderly patients with the risk of developing breast training, waiting list trial, which was novel, online, cancer.[44] Further studies on tamoxifen and cognition home-based program targeting function either by are required to elucidate clinical issues regarding the objective or self-report measures.[53] The objective administration of tamoxifen has an adverse effect on and the perceived cognitive function were improved cognitive function. by cognitive training trial, which concentrated on memory and speed of processing training.[54] The DIAGNOSIS OF CICI secondary analysis of a large study on elderly cancer patients who excise became evidence that memory Since cancer survivors report the cognitive problems can be improved by excise when compared to non- during or after the cancer treatment, it has become excise patients.[55] Further, medication errors were important to diagnose the cognitive functions thought proven to be harmful to the patients irrespective of the pre- and post-treatment.[45,46] There is evidence their place of occurrence. Apart from adverse drug that cancer and cancer treatment related to cognitive reaction and adverse drug events, medication errors impairment exist and this can affect the social performance, occupational functioning, and well- are important confounders that need to be evaluated being.[47] Patient’s self-report, clinical evaluation, and before attributing an adverse drug reaction to any [56] neuropsychological tests are some of the tools used drug. It is vital to minimize such confounders before to evaluate the cancer patients who report cognitive attributing to the chemobrain to chemotherapy alone. problems. The concern from patients or caretakers is some of the motivation for fetching the attention to the CONCLUSION further need for evaluation of cognitive impairment. The review is aimed at understanding the concepts Complete clinical evaluation should be carried out to by which treatment using the chemotherapeutic assess the patient’s reports with cognitive problems. The approaches developed stress inside an individual specific cognitive issue and the presenting complaint suffering from cancer. It shows how stress is can be assessed using clarifying questions which developed, leading to a series of conditions resulting include evaluation of difficulty with memory, difficulty in cognitive impairment. The same condition when in word finding, and also multitasking which show an resulting from treatment with chemotherapeutic drugs impact on daily functioning.[48] Assessment of cancer is known as chemobrain. The review ventures through history, comorbidities, and present medications of the individuals helps to determine the reversible factors clinical studies performed worldwide to understand which may cause cognitive impairment. Type of tumor, the prevalence and assessments made to establish staging, and treatment history are some of the important any causal information that was either predicted parameters to determine the history of cancer.[49] or established between chemotherapy, stress, and chemobrain. Studies are required for thorough International cognition and cancer task force analysis and understanding of the mechanism and for clinical trials have recommended the use of assessment of the conditions and their cascade of neuropsychological tests to evaluate cognitive other morbid incidences that might contribute to the functions such as learning and memory, processing development of cognitive impairment, with stress and speed, and executive function in patients with with chemotherapy.

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