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• W4306774110 abstract "Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction. Patients with cancer may suffer from a decline in their cognitive function after various cancer therapies, including surgery, radiation, and chemotherapy, and in some cases, this decline in cognitive function persists even years after completion of treatment. Chemobrain or chemotherapy-induced cognitive impairment, a well-established clinical syndrome, has become an increasing concern as the number of successfully treated cancer patients has increased significantly. Chemotherapy-induced cognitive impairment can originate from direct neurotoxicity, neuroinflammation, and oxidative stress, resulting in alterations in grey matter volume, white matter integrity, and brain connectivity. Surgery has been associated with exacerbating the inflammatory response associated with chemotherapy and predisposes patients to develop postoperative cognitive dysfunction. As the proportion of patients living longer after these therapies increases, the magnitude of impact and growing concern of post-treatment cognitive dysfunction in these patients has also come to the fore. We review the clinical presentation, potential mechanisms, predisposing factors, diagnostic methods, neuropsychological testing, and imaging findings of chemotherapy-induced cognitive impairment and its intersection with postoperative cognitive dysfunction. Editor's key points•Cognitive impairment after cancer treatments and surgery is widely recognised. However, the current evidence regarding the combined effects of chemotherapy and surgery/anaesthesia on cognition is inadequate.•The authors review the clinical presentation, pathophysiology, diagnostic methods, and imaging findings of the intersection between chemotherapy-induced cognitive impairment and postoperative cognitive dysfunction, identifying risk factors and preventive strategies.•Future studies are needed to define and reduce postoperative cognitive dysfunction in patients with chemotherapy-induced cognitive impairment. •Cognitive impairment after cancer treatments and surgery is widely recognised. However, the current evidence regarding the combined effects of chemotherapy and surgery/anaesthesia on cognition is inadequate.•The authors review the clinical presentation, pathophysiology, diagnostic methods, and imaging findings of the intersection between chemotherapy-induced cognitive impairment and postoperative cognitive dysfunction, identifying risk factors and preventive strategies.•Future studies are needed to define and reduce postoperative cognitive dysfunction in patients with chemotherapy-induced cognitive impairment. Cancer is the second cause of death behind cardiovascular diseases worldwide.1Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2021.CA Cancer J Clin. 2021; 71: 7-33Crossref PubMed Scopus (8520) Google Scholar According to the World Health Organization (WHO), 39.5% of the world's population will be diagnosed with cancer at some point in their lives.2WHO. Health topics, Available from:https://www.who.int/health-topics/cancer#tab=tab_1.Google Scholar More than 19.3 million patients will hear the word cancer next year, and nearly 10 million people will die because of cancer-related complications.3Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (23541) Google Scholar The WHO states that ‘the major goals of cancer treatment are to cure or significantly prolong the lives of patients, and to ensure the greatest possible quality of life for cancer survivors’.4World Health Organization Cancer.https://www.who.int/news-room/fact-sheets/detail/cancerDate: 2022Date accessed: February 28, 2022Google Scholar However, some patients cannot achieve those goals because of cancer progression or the development of complications related to anticancer therapies.5Wu H.S. Harden J.K. Symptom burden and quality of life in survivorship: a review of the literature.Cancer Nurs. 2015; 38: E29-E54Crossref PubMed Scopus (178) Google Scholar Available options for cancer treatment include surgery, endocrine/hormonal therapy, targeted therapies, radiation, chemotherapy, and, more recently, immunotherapy.6Gralow J.R. Burstein H.J. Wood W. et al.Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease.J Clin Oncol. 2008; 26: 814-819Crossref PubMed Scopus (297) Google Scholar Neoadjuvant chemotherapy improves the survival rates for numerous types of cancers.7Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials.Lancet Oncol. 2018; 19: 27-39Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar,8Dehal A. Graff-Baker A.N. Vuong B. et al.Neoadjuvant chemotherapy improves survival in patients with clinical T4b colon cancer.J Gastrointest Surg. 2018; 22: 242-249Crossref PubMed Scopus (45) Google Scholar It remains a frequently preferred option in treating malignancies, including breast and colon cancers.8Dehal A. Graff-Baker A.N. Vuong B. et al.Neoadjuvant chemotherapy improves survival in patients with clinical T4b colon cancer.J Gastrointest Surg. 2018; 22: 242-249Crossref PubMed Scopus (45) Google Scholar,9Masood S. Neoadjuvant chemotherapy in breast cancers.Womens Health (Lond). 2016; 12: 480-491Crossref PubMed Scopus (41) Google Scholar Unfortunately, neurotoxicity such as peripheral neuropathies and chemotherapy-induced cognitive impairment (CICI) are among the most feared complications in patients receiving chemotherapy and immunotherapies.10Nurgali K. Jagoe R.T. Abalo R. Adverse effects of cancer chemotherapy: anything new to improve tolerance and reduce sequelae?.Front Pharmacol. 2018; 9: 245Crossref PubMed Scopus (0) Google Scholar As the life expectancy of patients with cancer is prolonged and the importance of quality of life comes to the fore, there is increasing concern about the long-term neurotoxic adverse effects of systemic anticancer therapies. Patients with cancer may also need surgery to treat their cancer as a part of their treatment regimen.8Dehal A. Graff-Baker A.N. Vuong B. et al.Neoadjuvant chemotherapy improves survival in patients with clinical T4b colon cancer.J Gastrointest Surg. 2018; 22: 242-249Crossref PubMed Scopus (45) Google Scholar Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are two major perioperative neurological complications grouped under perioperative neurocognitive disorders.11Eckenhoff R.G. Maze M. Xie Z. et al.Perioperative neurocognitive disorder: state of the preclinical science.Anesthesiology. 2020; 132: 55-68Crossref PubMed Scopus (69) Google Scholar POD is characterised by a fluctuating disturbance in attention and awareness caused by maladaptation of the brain. At the same time, POCD is defined as ‘new cognitive deficits that appear postoperatively (i.e. memory impairment, ability to multitask, or reduced psychomotor dexterity)’.12Rundshagen I. Postoperative cognitive dysfunction.Dtsch Arzteb Int. 2014; 111: 119PubMed Google Scholar,13Evered L. Silbert B. Knopman D.S. et al.Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery—2018.Br J Anaesth. 2018; 121: 1005-1012Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar POCD is associated with poor postoperative outcomes such as delayed recovery, prolonged length of stay, loss of work, and increased medical expenses.14Steinmetz J. Christensen K.B. Lund T. Lohse N. Rasmussen L.S. ISPOCD GroupLong-term consequences of postoperative cognitive dysfunction.Anesthesiology. 2009; 110: 548-555Crossref PubMed Scopus (706) Google Scholar Strikingly, POCD 3 months after noncardiac surgery is also associated with increased mortality.14Steinmetz J. Christensen K.B. Lund T. Lohse N. Rasmussen L.S. ISPOCD GroupLong-term consequences of postoperative cognitive dysfunction.Anesthesiology. 2009; 110: 548-555Crossref PubMed Scopus (706) Google Scholar General anaesthesia and surgical stress have been proposed as risk factors for POCD.15Hindman B.J. Emboli, inflammation, and CNS impairment: an overview.Heart Surg Forum. 2002; 5: 249-253PubMed Google Scholar Comorbidities such as advanced age, pre-existing cerebral, cardiac, or vascular disease, preoperative mild cognitive impairment, low educational level, and history of alcohol abuse have been described as risk factors for POCD.12Rundshagen I. Postoperative cognitive dysfunction.Dtsch Arzteb Int. 2014; 111: 119PubMed Google Scholar,16Monk T.G. Weldon B.C. Garvan C.W. et al.Predictors of cognitive dysfunction after major noncardiac surgery.Anesthesiology. 2008; 108: 18-30Crossref PubMed Scopus (1027) Google Scholar As the number of patients treated with chemotherapy increases, the rate of subjects presenting to surgery with CICI is expected to increase, thus POCD. This narrative review will summarise the biological and clinical intersection between CICI and POCD. A broad literature survey with no restriction until February 2022 was conducted on the risk factors and interventions regarding CICI and postoperative cognitive impairment. The terms ‘chemotherapy-induced cognitive impairment’, ‘chemobrain’, ‘chemo-fog’, ‘CICI genetic factor’, ‘CICI therapy’, ‘CICI cognitive rehabilitation’, and ‘postoperative cognitive dysfunction’, and ‘perioperative neurological disorders’ were searched using the PubMed database. In humans, the healthy brain is resilient to general anaesthesia and surgery effects.17Mashour G.A. Palanca B.J.A. Basner M. et al.Recovery of consciousness and cognition after general anesthesia in humans.eLife. 2021; 10e59525Crossref PubMed Scopus (21) Google Scholar However, the impact of anaesthetics and surgery on the brain of patients with CICI is poorly understood. Chemobrain, chemo-fog, or CICI refers to short- and long-term deterioration in cognitive function after chemotherapy administration.18Wieneke M.H. Dienst E.R. Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer.Psycho-oncology. 1995; 4: 61-66Crossref Scopus (265) Google Scholar,19Matsuda T. Takayama T. Tashiro M. Nakamura Y. Ohashi Y. Shimozuma K. Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients—evaluation of appropriate research design and methodology to measure symptoms.Breast Cancer. 2005; 12: 279-287Crossref PubMed Scopus (83) Google Scholar CICI was initially described in the 1970s but was not identified until the late 1980s.20Davis B.D. Fernandez F. Adams F. et al.Diagnosis of dementia in cancer patients: cognitive impairment in these patients can go unrecognized.Psychosomatics. 1987; 28: 175-179Crossref PubMed Scopus (0) Google Scholar Its prevalence among cancer survivors ranges from 17% to 75%.21Bender C.M. Sereika S.M. Berga S.L. et al.Cognitive impairment associated with adjuvant therapy in breast cancer.Psychooncology. 2006; 15: 422-430Crossref PubMed Scopus (253) Google Scholar, 22Wefel J.S. Lenzi R. Theriault R.L. Davis R.N. Meyers C.A. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial.Cancer. 2004; 100: 2292-2299Crossref PubMed Scopus (536) Google Scholar, 23Jenkins V. Shilling V. Deutsch G. et al.A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.Br J Cancer. 2006; 94: 828-834Crossref PubMed Scopus (317) Google Scholar Ahles and colleagues24Ahles T.A. Saykin A.J. Furstenberg C.T. et al.Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma.J Clin Oncol. 2002; 20: 485-493Crossref PubMed Scopus (599) Google Scholar reported low neuropsychological performance in 39% of patients who received systemic treatment for breast cancer compared with 14% of those who received local treatment. Ouimet and colleagues25Ouimet L.A. Stewart A. Collins B. Schindler D. Bielajew C. Measuring neuropsychological change following breast cancer treatment: an analysis of statistical models.J Clin Exp Neuropsychol. 2009; 31: 73-89Crossref PubMed Scopus (60) Google Scholar reported that 8% of patients receiving chemotherapy and 2% receiving hormonal therapy had impairment in 35% of 23 major cognitive domains. In a large cohort study, women with breast cancer showed about a 10% decline in cognitive function approximately 6 months after chemotherapy. Although some women recovered, others still showed 5–10% cognitive decline 12 months after therapy.26Janelsins M.C. Heckler C.E. Peppone L.J. et al.Cognitive complaints in survivors of breast cancer after chemotherapy compared with age-matched controls: an analysis from a nationwide, multicenter, prospective longitudinal study.J Clin Oncol. 2017; 35: 506-514Crossref PubMed Scopus (178) Google Scholar However, it is worth mentioning that about a third of the patients with cancer suffer from cognitive decline before receiving chemotherapy.27Ahles T.A. Saykin A.J. McDonald B.C. et al.Cognitive function in breast cancer patients prior to adjuvant treatment.Breast Cancer Res Treat. 2008; 110: 143-152Crossref PubMed Scopus (259) Google Scholar CICI has a known onset, an acute phase, and in some patients, a long resolutive period that can last months to years.28Wefel J.S. Saleeba A.K. Buzdar A.U. Meyers C.A. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer.Cancer. 2010; 116: 3348-3356Crossref PubMed Scopus (369) Google Scholar During that time, transient or permanent chemotherapy-related neurological complications such as acute and chronic encephalopathy, posterior leukoencephalopathy syndrome, cerebellar syndrome, motor impairment, and peripheral neuropathies have been described. They can be responsible for CICI-related symptoms.29Dietrich J. Monje M. Wefel J. Meyers C. Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy.Oncologist. 2008; 13: 1285-1295Crossref PubMed Scopus (258) Google Scholar, 30Videnovic A. Semenov I. Chua-Adajar R. et al.Capecitabine-induced multifocal leukoencephalopathy: a report of five cases.Neurology. 2005; 65: 1792-1794Crossref PubMed Scopus (0) Google Scholar, 31Perry A. Schmidt R.E. Cancer therapy-associated CNS neuropathology: an update and review of the literature.Acta Neuropathol. 2006; 111: 197-212Crossref PubMed Scopus (193) Google Scholar Patients can experience interference with their functional independence, leading to psychological stress and negatively impacting their quality of life.32Wefel J.S. Schagen S.B. Chemotherapy-related cognitive dysfunction.Curr Neurol Neurosci Rep. 2012; 12: 267-275Crossref PubMed Scopus (252) Google Scholar Phrases such as “I can't read technical books anymore. I just do not understand them” frequently describe the interference.33Boykoff N. Moieni M. Subramanian S.K. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response.J Cancer Surviv. 2009; 3: 223-232Crossref PubMed Scopus (333) Google Scholar CICI can also delay the ability of patients to return to work-related activities.19Matsuda T. Takayama T. Tashiro M. Nakamura Y. Ohashi Y. Shimozuma K. Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients—evaluation of appropriate research design and methodology to measure symptoms.Breast Cancer. 2005; 12: 279-287Crossref PubMed Scopus (83) Google Scholar,33Boykoff N. Moieni M. Subramanian S.K. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response.J Cancer Surviv. 2009; 3: 223-232Crossref PubMed Scopus (333) Google Scholar Two studies reported that survivors who returned to work stated that cognitive changes negatively affect staying in employment, the possibility of promotion, and financial stability.33Boykoff N. Moieni M. Subramanian S.K. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response.J Cancer Surviv. 2009; 3: 223-232Crossref PubMed Scopus (333) Google Scholar,34Ottati A. Feuerstein M. Brief self-report measure of work-related cognitive limitations in breast cancer survivors.J Cancer Surviv. 2013; 7: 262-273Crossref PubMed Scopus (0) Google Scholar In one of those studies, fatigue was an independent contributor to work-related difficulties in women with breast cancer who received chemotherapy.34Ottati A. Feuerstein M. Brief self-report measure of work-related cognitive limitations in breast cancer survivors.J Cancer Surviv. 2013; 7: 262-273Crossref PubMed Scopus (0) Google Scholar Up to 35% of clinically cured oncological patients report their persistence for extended periods, even several years after treatment cessation.35Janelsins M.C. Kesler S.R. Ahles T.A. Morrow G.R. Prevalence, mechanisms, and management of cancer-related cognitive impairment.Int Rev Psychiatry. 2014; 26: 102-113Crossref PubMed Scopus (361) Google Scholar Furthermore, a significant proportion of patients who receive long-term evaluation (30–100%) experience late-onset severe neurological sequelae starting several months after chemotherapy completion. In one study, 30% of cancer patients experienced late-onset cognitive deterioration 7.7 months after finishing chemotherapy.28Wefel J.S. Saleeba A.K. Buzdar A.U. Meyers C.A. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer.Cancer. 2010; 116: 3348-3356Crossref PubMed Scopus (369) Google Scholar Similarly, radiotherapy and newer treatments such as immunotherapies have detrimental effects on cognition.36McGinnis G.J. Raber J. CNS side effects of immune checkpoint inhibitors: preclinical models, genetics and multimodality therapy.Immunotherapy. 2017; 9: 929-941Crossref PubMed Scopus (0) Google Scholar,37Greene-Schloesser D. Robbins M.E. Radiation-induced cognitive impairment—from bench to bedside.Neuro Oncol. 2012; 14: 37-44Crossref Scopus (0) Google Scholar Immune-related adverse events (irAEs) include a spectrum of adverse effects related to immunotherapies' mechanism of action, which are considerably different from chemotherapies.38Brahmer J.R. Lacchetti C. Schneider B.J. et al.Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.J Clin Oncol. 2018; 36: 1714-1768Crossref PubMed Scopus (1950) Google Scholar Both central and peripheral neurological toxicities after immune checkpoint inhibitors have been described, including cognitive impairment caused by encephalopathy, aseptic meningitis, meningo-radiculo-neuritis, and Guillain–Barre-like syndromes.39Yang J.C. Hughes M. Kammula U. et al.Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.J Immunother. 2007; 30: 825Crossref PubMed Scopus (587) Google Scholar, 40Bompaire F. Mateus C. Taillia H. et al.Severe meningo-radiculo-neuritis associated with ipilimumab.Invest New Drugs. 2012; 30: 2407-2410Crossref PubMed Scopus (57) Google Scholar, 41Wilgenhof S. Neyns B. Anti-CTLA-4 antibody-induced Guillain–Barré syndrome in a melanoma patient.Ann Oncol. 2011; 22: 991-993Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Like CICI, POCD has an abrupt onset; it usually occurs within the first week after surgery and may last several months.42Abildstrom H. Rasmussen L.S. Rentowl P. et al.Cognitive dysfunction 1–2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction.Acta Anaesthesiol Scand. 2000; 44: 1246-1251Crossref PubMed Scopus (326) Google Scholar Daiello and colleagues43Daiello L.A. Racine A.M. Yun Gou R. et al.Postoperative delirium and postoperative cognitive dysfunction.Anesthesiology. 2019; 131: 477-491Crossref PubMed Scopus (0) Google Scholar reported that 40% of the patients who developed POCD within a month of surgery also exhibited cognitive changes 6 months postoperatively. Age, a higher American Society of Anesthesiologists (ASA) physical status, a longer length of stay, and the presence of delirium during hospitalisation are associated with poor long-term postoperative cognitive outcomes.16Monk T.G. Weldon B.C. Garvan C.W. et al.Predictors of cognitive dysfunction after major noncardiac surgery.Anesthesiology. 2008; 108: 18-30Crossref PubMed Scopus (1027) Google Scholar Contrary to popular belief, Evered and colleagues44Evered L. Scott D.A. Silbert B. Maruff P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic.Anesth Analg. 2011; 112: 1179-1185Crossref PubMed Scopus (291) Google Scholar noted that the incidence of POCD 3 months after surgery was comparable in cardiac and non-cardiac surgery. Sedatives, anxiolytics, anaesthetics, and excessive consumption of long-acting opioids have been implicated in POCD45Starr J.M. Whalley L.J. Drug-induced dementia.Drug Saf. 1994; 11: 310-317Crossref PubMed Scopus (0) Google Scholar,46Wang Y. Sands L.P. Vaurio L. Mullen E.A. Leung J.M. The effects of postoperative pain and its management on postoperative cognitive dysfunction.Am J Geriatr Psychiatry. 2007; 15: 50-59Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar (Fig 1). It has been speculated that POCD incidence might be lessened by performing surgeries under regional anaesthesia.47Silbert B. Evered L. Scott D. Incidence of postoperative cognitive dysfunction after general or spinal anaesthesia for extracorporeal shock wave lithotripsy.Br J Anaesth. 2014; 113: 784-791Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar,48Tzimas P. Samara E. Petrou A. Korompilias A. Chalkias A. Papadopoulos G. The influence of anesthetic techniques on postoperative cognitive function in elderly patients undergoing hip fracture surgery: general vs spinal anesthesia.Injury. 2018; 49: 2221-2226Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar However, a randomised controlled study comparing regional anaesthesia without sedatives to general anaesthesia did not favour regional anaesthesia.47Silbert B. Evered L. Scott D. Incidence of postoperative cognitive dysfunction after general or spinal anaesthesia for extracorporeal shock wave lithotripsy.Br J Anaesth. 2014; 113: 784-791Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Non-anaesthetic drugs affecting the CNS have also been implicated in POCD. Monk and colleagues16Monk T.G. Weldon B.C. 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Studies have demonstrated that older patients with reduced cognitive reserve show poorer results in neuropsychological tests when receiving chemotherapy than healthy individuals or patients with cancer who were not treated with chemotherapy.50Ahles T.A. Saykin A.J. McDonald B.C. et al.Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve.J Clin Oncol. 2010; 28: 4434-4440Crossref PubMed Scopus (378) Google Scholar Interestingly, advanced age, lower education status, and a decline in cognitive function before surgery are also risk factors for POCD.27Ahles T.A. Saykin A.J. McDonald B.C. et al.Cognitive function in breast cancer patients prior to adjuvant treatment.Breast Cancer Res Treat. 2008; 110: 143-152Crossref PubMed Scopus (259) Google Scholar,51Moller J. Cluitmans P. 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However, shared multipronged mechanisms might be involved in both conditions (Fig 2). It has been speculated that blood–brain barrier (BBB) dysfunction is one of those mechanisms. The function of the BBB is to keep cytotoxic substances from indiscriminately entering the brain, including most chemotherapeutic agents. However, antineoplastic drugs can penetrate the CNS after intravenous administration, where they can exert cytotoxic effects by inducing DNA changes, as is the case for methotrexate and 5-fluorouracil.56Choi S.M. Lee S.H. Yang Y.S. Kim B.C. Kim M.K. Cho K.H. 5-fluorouracil-induced leukoencephalopathy in patients with breast cancer.J Kor Med Sci. 2001; 16: 328-334Crossref PubMed Google Scholar, 57Winocur G. Vardy J. Binns M.A. Kerr L. Tannock I. The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice.Pharmacol Biochem Behav. 2006; 85: 66-75Crossref PubMed Scopus (153) Google Scholar, 58Dietrich J. Han R. Yang Y. Mayer-Pröschel M. 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• W4306774110 title "Perioperative considerations in patients with chemotherapy-induced cognitive impairment: a narrative review" @default.
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