Chemo brain: myth or clinical reality? Literature review and clinical case

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BACKGROUND

The World Health Organization reports that cancer is one of the leading causes of mortality worldwide, accounting for nearly 10 million deaths in 2020. The global structure of cancer by localization is as follows: breast cancer (2.26 million cases), lung cancer (2.20 million cases), colorectal cancer (1.93 million cases), prostate cancer (1.41 million cases), skin cancer (1.20 million cases), and stomach cancer (1.09 million cases) [1]. According to the Russian Ministry of Health, in Russia there are 3.94 million patients with cancer, with about 600,000 cases of newly diagnosed cancer annually and 278,000 of cancer deaths in 2021 [2].

Current cancer screening and early diagnosis programs increase the likelihood of a good response to treatment, reduce the severity of the disease, allow the use of less expensive therapies, and increase the chances of survival and life expectancy of patients. In addition, advances in modern therapies for cancer patients have resulted in a steadily increasing number of cancer survivors. Globally, the median 5-year survival rate for breast cancer increased from 75% in the 1975 to 1977 cohort to 91% in the 2008 to 2014 cohort [3]. The American Cancer Society reports that by 2026, the number of cancer survivors in the United States will exceed 20 million, nearly doubling from 2012 [4, 5]. As of 2023, cancer mortality rate in the Russian population has decreased by almost 6% compared to 2018 [2]. This has increased interest in assessing the health-related quality of life in patients with cancer, as well as the psychosocial consequences associated with cancer and its treatment.

This review collected data describing changes in cognitive function and the brain after chemotherapy. Although the negative cognitive effects following localized therapy, particularly cranial irradiation (radiation therapy), have long been evaluated, more than 60% of patients receiving systemic chemotherapy also develop cognitive impairment that significantly affects their daily life, performance and social relationships, and the long-term effects may persist for many years after discontinuation of therapy [6].

CHEMO BRAIN

Cognitive changes associated with chemotherapy have been mentioned since 1978, when concerns were raised about the impact of chemotherapy on the emotional and cognitive status of cancer patients [7]. However, no due scientific attention was paid to this topic until the mid-1990s [8]. The combination of pathological phenomena in patients who have undergone chemotherapy includes disorders of cognitive functions from minimal impairments of short-term memory and reaction time to altered mental status. In world literature the disorders are united by the terms chemo brain, chemo fog [9], and post-chemotherapy cognitive impairment (PCCI) [10]. In literature in Russian, the terms chemo brain and chemo fog are quite rare, while the terms post-chemotherapy neurotoxicity [11], post-chemotherapy encephalopathy [12], and toxic encephalopathy [13] are used more often in the context of neurologic complications. Even though the symptoms of chemo brain are largely represented by disorders of various spheres of mental activity, we could not find the point of view of the Russian-speaking psychiatric community regarding this problem.

CLINICAL FEATURES

Most cancer treatments, including traditional chemotherapy, are associated with severe, sometimes prolonged and irreversible side effects. Patients often experience altered mental status during and after treatment with various anticancer agents. Other treatments, including hormonal and targeted therapies, may also contribute to cognitive impairment [14]. In such cases, the most common complaints are fatigue, emotional lability, low mood, anxiety, memory impairment (up to small memory lapses), difficulty concentrating, and episodes of disorientation in time and space [12]. In addition, cognitive impairment is characterized by difficulties in memorization, term selection, information processing, and multitasking. Critical and strategic thinking, creativity, learning, and establishing connections between objects and phenomena are affected. It is worth noting that the severity of deficits varies significantly with personal experience and attitude toward the condition [15]. Overall, different researchers estimated the number of patients experiencing chemo brain after chemotherapy to be as high as 15%–30% of cases. Of these, up to 75% of patients experience symptoms while undergoing treatment, and 35% report behavioral and cognitive symptoms only after treatment has ended [16]. Most patients reported starting chemotherapy unaware of chemo brain as a potential side effect of the treatment. This initial unawareness often led to shock and panic, with many patients mentioning they learned of chemo brain almost by chance. The lack of an accepted concept of the chemo brain syndrome has hindered the adaptation of many patients, with the disorder often having to be hidden from others, causing the feeling of isolation with the problem and the anxiety associated with it to become personal, preventing patients from seeking support. Initial anxiety 2–6 years after treatment is replaced by frustration and acceptance with further diminishing hope of returning to the pre-chemotherapy state. Some studies have shown that cognitive deficits persist for 10 years after treatment, while others have found a significant improvement after 3 years [15].

ETIOLOGY AND MECHANISMS OF DEVELOPMENT

Cognitive impairment associated with chemotherapy develops through several potential mechanisms including damage to the blood–brain barrier, increased oxidative stress and inflammation in the brain, and impaired neurogenesis, each leading to neuronal dysfunction [17]. Other potential mechanisms have been suggested, including inhibition of hippocampal neurogenesis and direct neuronal damage, as well as activation of secondary glial cells, i.e. microglia and astrocytes, production of proinflammatory cytokines, and defects in myelin-producing cells (oligodendrocyte lineage) [18]. A model of abnormalities in the brain default mode network as a potential biomarker of chemotherapy-induced damage is of interest. This system is believed to be responsible for such processes as implicit learning, autobiographical memory, prediction, analysis of what is happening at the moment, creativity, and self-reflection. A decrease in the level of activity of the default mode network explains the cognitive disorders in this group of patients [19]. Changes in brain activity (signals, cerebral blood flow) in patients with cancer have been observed in all functional networks, including prefrontal, parietal, occipital, temporal, and cerebellar regions. In addition to changes in brain activity, neuroimaging methods reveal decreased gray matter density in frontal, parietal, and temporal regions, and diffusion-weighted MRI data suggest decreased white matter integrity affecting the superior longitudinal fasciculus, corpus callosum, great forceps, and corona radiata, as well as altered structural connectivity throughout the brain network [20]. One study demonstrated evidence of a dramatic reduction in cortical thickness, along with an acceleration of predicted brain age from before treatment and 1 month after chemotherapy in breast cancer patients compared to controls. These results suggest that accelerated aging is one of the underlying mechanisms of chemo brain. These findings are particularly relevant because increasing brain age is associated with an increased risk of developing Alzheimer’s disease in individuals with mild cognitive impairment. Notably, cancer survivors diagnosed with chemo brain tend to have a negative correlation of symptoms with time after treatment, suggesting that some recovery does occur. Nevertheless, deficits can be detected up to 10 years after treatment, suggesting permanent cognitive deficits in some of the cases [21].

MEDICINES COMMONLY ASSOCIATED WITH THE CHEMO BRAIN SYNDROME

Here we discuss the drugs most frequently used in cancer treatment protocols, some of which were used as chemotherapeutic treatment in our patient from the case report that we present below.

Platinum-based products (e.g., cisplatin, oxaliplatin) are widely used for chemotherapy. Prolonged treatment with cisplatin leads to neuronal mitochondrial dysfunction, which affects patients’ cognitive functions. Multiple neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, and post-chemotherapy cognitive impairment are associated with neuronal mitochondrial dysfunction [22–28]. Cisplatin penetrates the blood–brain barrier at levels sufficient to cause damage to hippocampal neurons and neural stem cells [29]. Astrocytes can respond to the “help” signal from damaged neurons, resulting in the transfer of mitochondria to them. Here a paradox arises: if astrocytic mitochondrial transfer leads to neuronal recovery, why do patients undergoing chemotherapy still experience neurotoxicity leading to cognitive impairment? One answer may be the fact that the regenerative capacity of astrocytes becomes deficient when patients are treated for long periods of time, which is characteristic of cisplatin chemotherapy [30]. Indeed, the risk of developing a chemo brain increases with the duration of treatment [31–34]. Exposure of mice to a single course of cisplatin treatment did not cause any cognitive deficits, whereas two courses of treatment caused a significant decrease in performance in cognitive function tests.

The use of doxorubicin in the treatment of various types of cancer [35] is associated with decreased long-term hippocampal potentiation, increased lipid peroxidation, and apoptosis [36]. Moreover, despite the low ability of doxorubicin to penetrate the blood–brain barrier, even its short-term administration has been shown to adversely affect hippocampal cell proliferation [37]. In addition, it has been reported that the combination of doxorubicin and cisplatin impairs cognitive function by increasing phosphorylation of proteins of extracellular signal-regulated kinase 1/2 (Erk1/2) and contributes to inflammation [38], production of reactive oxygen species, and further oxidative stress [39].

The primary mechanism of action of 5-fluorouracil (5-FU, capecitabine, etc.) is inhibition of thymidine synthesis and blocking DNA replication. 5-FU penetrates the blood–brain barrier and directly affects mitotic activity in the brain. It is one of the most common chemotherapeutic agents with long-lasting neurotoxicity. Early studies showed that three systemic injections of 5-FU (40 mg/kg) over five days impaired long-term survival of mature neurons for up to six months after 5-FU treatment in young adult mice. This suggests that slower hippocampal cell proliferation rate may not be evident immediately after 5-FU treatment, whereas long-term neuronal survival is affected [40].

Methotrexate is a dihydrofolate reductase inhibitor used for the treatment of leukemia, lymphoma, choriocarcinoma, breast and lung cancer, and other malignant neoplasms [41]. Methotrexate was found to cause depletion of the cellular potential of oligodendrocytes in human and murine white matter, leading to microglia activation [42]. Activated microglia induce a state of neurotoxic reactivity in astrocytes and disrupt oligodendroglial lineage dynamics and myelin plasticity, ultimately leading to abnormal myelination and cognitive impairment. The major delayed complication of methotrexate therapy is leukoencephalopathy [43]. Although this syndrome can be caused by intrathecal or high-dose systemic methotrexate alone, it is exacerbated by radiotherapy, especially if radiotherapy is administered before or during methotrexate treatment. Symptoms of developing cognitive impairment appear months or years after the treatment. The clinical presentation ranges from mild cognitive impairment to severe progressive dementia [44]. Over time, many patients stabilize or improve after discontinuation of methotrexate, but in some patients the disease may progress and lead to death [45]. Such a diverse course with variants of increased neurotoxicity may be explained by genetic polymorphism, i.e. individual characteristics of methionine metabolism necessary for myelination in a particular patient [44].

One of the main manifestations of paclitaxel-induced neurotoxicity is the phenomenon of endoplasmic reticulum stress [46]. Neurotoxicity is characterized by predominantly symmetrical sensory axonal neuropathy affecting both large and small nerve fibers. Symptoms usually develop 1–3 weeks after treatment initiation [47].

THERAPEUTIC STRATEGIES TO PREVENT OR ALLEVIATE CHEMO BRAIN SYMPTOMS

Inaccurate diagnostic criteria and heterogeneous molecular mechanisms of brain alterations that are not fully understood have hindered effective research into the prevention and treatment of chemo brain. The typical patient receives a “cocktail” of drugs during chemotherapy. In this case, the molecular mechanisms of the chemo brain are a combination of the therapeutic effect and side effects of each drug and their synergism [48].

Inflammatory markers found in patients with Alzheimer’s disease and vascular dementia, characterized by cognitive impairment, have prompted the inflammatory hypothesis and attempts to use aspirin in the treatment of the chemo brain syndrome. The anti-inflammatory drug aspirin was previously reported to prevent tumor-induced cognitive impairment in a murine model of metastatic breast cancer not treated with chemotherapy [49], but a similar study in paclitaxel-treated mice showed that aspirin was not effective in preventing or treating post-chemotherapy cognitive impairment [50].

Several epidemiologic studies and a case–control study have shown that diabetic patients receiving metformin may have a lower risk of developing cancer compared to those using other sugar-lowering medications. The reasons for this finding remain unclear and the results require confirmation in controlled studies [51]. This study inspired another one, on the effect of metformin on mice with doxorubicin-induced memory impairment, where no improvement was observed [52].

Research on the microbiota of patients with cancer is promising and represents a new field that is gradually coming to the forefront of clinical research in oncology from different perspectives [53]. A recent microbiological analysis of over 1,500 tumor and adjacent healthy tissue samples from breast, lung, ovarian, pancreatic, bone and brain cancers and melanoma revealed the presence of intracellular bacteria in both cancerous and immune cells. Importantly, each tumor type was characterized by a different composition of the intratumor microbiota [54]. Growing evidence from animal models and clinical trials emphasizes the significant impact of the gut microbiota on the efficacy of cancer therapy, mainly immuno- and chemotherapy. Restoration of microbiota with probiotics and prebiotics or fecal microbiota transplant may represent a new treatment modality for cancer survivors [55].

Fluvoxamine, a selective serotonin reuptake inhibitor widely used in clinical practice as an antidepressant, improves symptoms of depression resulting from an imbalance between pro- and anti-inflammatory cytokines [56], in addition to alleviating endoplasmic reticulum stress response in vitro and in animal models. In particular, fluvoxamine mitigates paclitaxel-induced neurotoxicity, partly through induction of Sig-1R in cell models, and reduces the infarction size after focal cerebral ischemia in mice [57].

In general, MAO inhibitor antidepressants have been shown to have anti-inflammatory effects [58], with the evidence of inhibition of anti-inflammatory cytokines and lymphocytes. Thus, antidepressants may have beneficial effects on chemotherapy-induced inflammation and post-chemotherapy cognitive impairment by restoring the balance of cytokines. In addition, the pro-cognitive effects of some antidepressants justify their use in patients with chemo brain [59].

Lithium is a drug that has been used for decades to treat psychiatric disorders, but evidence has recently emerged that it may have neuroprotective effects and is associated with less cognitive deficit in various models of brain injury, including after cranial irradiation [60, 61]. Whole brain radiotherapy in mice reduced neuronal proliferation in the subgranular zone of the dentate gyrus, which led to a long-term reduction in neurogenesis [62]. Lithium was found to protect irradiated hippocampal neurons in mice from apoptosis, which improved learning and memory function [61].

The growing popularity of phytotherapy, despite the great success in the development of synthetic drugs, is also reflected in research papers. Mohamed et al. found that epicatechin, a polyphenolic molecule derived from green tea, has a pronounced neuroprotective effect before doxorubicin injection and then during doxorubicin injections for another two weeks [63]. A similar neuroprotective effect was demonstrated for the pulp of mango fruit (Mangifera indica), turmeric rhizome (Curcuma longa), and Indian pennywort (Centella asiatica) [64]. Resveratrol, a natural nonflavonoid polyphenol present in various plant species including grapes, peanuts, berries, and red wine, exhibits anticancer activity against a wide range of cancers (prostate, skin, liver, ovarian, and lung cancers). An in vivo study showed that oral administration of resveratrol for three weeks, starting one week before treatment with docetaxel, adriamycin, and cyclophosphamide, improved cognitive impairment caused by these drugs in mice [65]. In search of a potential phytochemical for the treatment of chemo brain, acetylcholinesterase inhibitors, such as donepezil and rivastigmine, actively used for cognitive impairment in dementia, were studied [66]. Therapy with doxorubicin in combination with donepezil fully restored cognitive function, mitigating the pathologic effects caused by doxorubicin without deteriorating the cytostatic effect [67]. The combined use of doxorubicin with galantamine only resulted in improved memory performance in mice [68].

CASE REPORT

Patient G., 74 years old; has a higher education. In 2018, she was diagnosed with de novo cancer of the sigmoid colon and underwent resection of the sigmoid colon. However, despite the surgical intervention, disease progression with metastases to the left lung occurred. The patient underwent resection of the left lung in 2020, followed by 6 courses of palliative chemotherapy (PCT) with XELOX (capecitabine and oxaliplatin) regimen. In January 2022, the patient underwent resection of liver metastases with additional 4 courses of PCT with XELIRI regimen (capecitabine and irinotecan). In May 2022, during the 3rd course of PCT, no evidence of progression of the primary tumor and metastases were revealed. However, in December 2022 negative dynamics in the lungs and liver was observed. From January to February 2023, two courses of immunotherapy with monoclonal antibody nivolumab were administered, with a positive effect. In June 2023, the 4th line of PCT was started (irinotecan and cetuximab). Final diagnosis: cancer of the sigmoid colon (pT4aN0M0; stage IIb, eligible for radical treatment); disease progression; metastases to the lungs and liver. Concurrent diagnoses: type II diabetes mellitus, subcompensated; hypertension, stage II, risk group 4; congestive heart failure, stage C, functional class II; systemic atherosclerosis. A total of 11 courses of chemotherapy with two courses of immunotherapy were performed during the treatment period.

After the next course of chemotherapy in August 2023, the patient developed an acute memory loss, self-care problems, and free movement deficits. She presented to the Internal Diseases Department with these complaints. The results of the brain MRI showed moderate external hydrocephalus ex vacuo and atrophic changes in the brain matter (cortical atrophy). Mental status at the time of examination: the patient is slow and confused, looks around, gives one-word answers to some questions (e.g., “what is your name?”). Disoriented in time and place. Motor coordination is disturbed; after sitting up with the help of doctors she remained in a sitting position for some time, but after a few minutes she asked to lie down. Muscle tone is weakened. Conclusion: chemo brain syndrome with severe cognitive impairment and an episode of confusion. The following treatment was recommended: dimethyloxobutylphosphonyl dimethylate solution (2 g IV), memantine hydrochloride (10 mg/day), fluvoxamine (100 mg/day), ethylmethylhydroxypyridine succinate solution (10 mL per 200 mL of 0.9 % NaCl solution IV). After several injections of dimethyloxobutylphosphonyl dimethylate, followed by ethylmethylhydroxypyridine succinate, she slept through the night. In the morning, the patient awoke, productive contact appeared, and orientation in time and space was restored. Purposeful movements were not recovered. The patient said that the previous night (before the administration of therapy) she thought she was in Israel, recognized the doctor, but could not understand why he was there and what he was doing. During the next four weeks, positive dynamics was noted in both cognitive and motor functions of the upper and lower extremities.

The presented case report shows how long the patient journey can be. The patient received a “cocktail” of chemotherapeutics and underwent several surgical procedures over 3 years. She presented to the Internal Diseases Department with acute memory loss, puzzling the doctors with the symptoms. It is worth mentioning the patient’s comorbidity in this case. Despite the differences in the point of view of psychiatrists, who emphasize cognitive disorders in chemo brain, and neurologists, who mainly focus on accompanying motor disorders, our patient was prescribed practically the same treatment after appointments with these specialists, which highlights the importance of a multidisciplinary approach. The patient’s rapid recovery from cognitive decline was also surprising for us, because the drugs prescribed (fluvoxamine, dimethyloxobutylphosphonyl dimethylate solution) were used off-label, i.e. they are not indicated for the treatment of the chemo brain syndrome, which requires further experimental and clinical research. As the review shows, there is no unified approach to the treatment of chemo brain. However, rapid recovery of cognitive functions was accompanied by a rather long and difficult process of returning to the previous level of motor activity, which was not described previously in this group of patients, and this is what we would like to point out to specialists.

ADDITIONAL INFORMATION

Funding source. This study was not supported by any external sources of funding.

Competing interests. The authors declare that there are no potential conflicts of interest that require disclosure in this article.

Authors’ contribution. All authors confirm that their authorship complies with the international ICMJE criteria (all authors have made a significant contribution in the preparation of the article, as well as read and approved the final version before its publication). K.K. Yakhin — consulted the patient and prescribed treatment, assessed the patient’s condition over time, literature review, writing the main part of the text; D.T. Zagretdinova, K.S. Sergienko — case analysis, literature review, writing the main part of the text.

Consent for publication. Written consent was obtained from the patient for publication of relevant medical information within the manuscript.

About the authors

Kausar K. Yakhin

Kazan State Medical University

Email: yakhinkk@gmail.com
ORCID iD: 0000-0001-5958-5355
SPIN-code: 6275-6051

MD, Dr. Sci. (Medicine)

 

Russian Federation, Kazan

Dina T. Zagretdinova

Kazan State Medical University

Email: dinakadirleeva99@gmail.com
ORCID iD: 0009-0002-9961-6245
SPIN-code: 6894-1320

Resident

Russian Federation, Kazan

Konstantin S. Sergienko

Kazan State Medical University

Author for correspondence.
Email: kostya_s99@mail.ru
ORCID iD: 0000-0002-2942-6174
SPIN-code: 7792-3042

Resident

Russian Federation, Kazan

References

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