Cognitive changes following chemotherapy were first recognized more than 35 years ago and have been colloquially termed “chemobrain.”1 The most common symptoms of chemobrain are problems with memory and concentration.2 Patients may report forgetting things they usually have no trouble recalling; difficulty concentrating; struggling to remember details such as names, dates, and sometimes larger events; problems multitasking; failure to remember common words or the inability to find the right words to finish a sentence; and taking longer to complete tasks.3 Neuropsychological testing has revealed that working memory, processing speed, and executive function are the most frequently impaired functions in patients reporting such cognitive problems.4
Chemobrain has also been observed after other cancer therapies, and even before any systemic treatment is started. In a breast cancer cohort study (N = 84), 35% of women with breast cancer exhibited cognitive impairment before the start of any treatment.5 The etiology of chemobrain is multifactorial and can be attributed to host-, disease-, and treatment-related factors.5
Host-related factors involve advanced age, genetic vulnerabilities, and nutritional deficits that account for lower cognitive reserve.6 For instance, apolipoprotein E (ApoE) plays a role in neuronal repair and plasticity. It is well known that the APOE4 allele carrier has increased risk for developing Alzheimer’s dementia. The APOE4 allele is also less able to repair neuronal damage from chemotherapy. Patients with the APOE4 allele tested several years after chemotherapy scored lower on visual memory and spatial memory tests.7
Disease-related factors can be complex. It is easy to understand that chemobrain occurs in patients with primary brain tumors or brain metastases. Interestingly, profound chemobrain is often seen in non-central nervous system cancers, such as small-cell carcinoma of the lung and breast cancer.8,9 Debilitating physical symptoms secondary to cancer or cancer treatment can also attribute to chemobrain. For instance, anemia, a common physical symptom of cancer patients, can lead to cerebral hypoxia and fatigue. Data suggest that development of cancer or chemotherapy-related anemia predisposes patients to cognitive dysfunction. In fact, it has been shown that treatment of anemia results in improved cognitive function.10 Depression and anxiety, either pre-existing or following cancer diagnosis, may further confound cognitive difficulties, as the anxiety can decrease cognitive ability in someone with such extant limits.
Treatment-related factors include chemotherapy, radiation therapy, immunotherapy, hormonal therapy, and/or adjuvant medication treatment. Some antineoplastic agents, such as methotrexate, cisplatin, 5-fluorouracil, and cytarabine, can cross the blood-brain barrier and cause direct neurotoxic effects leading to cortical atrophy, demyelination, or microvascular changes.11 Other chemotherapy agents such as paclitaxel, docetaxel, etoposide, and carboplatin may indirectly cause neurotoxicity by activating proinflammatory cytokines interleukin (IL)-1 beta, interferon (IFN) gamma, and tumor necrosis factor alpha.12 Immunotherapy with cytokines shares the same mechanism of neurotoxicity. IFN alpha and IL-2 both have acute and persistent neurotoxic side effects, neither of which is always reversible after treatment cessation.11
Radiation therapy is another major cause of chemobrain, regardless of whether the radiation to brain tissue is direct or indirect. The indirect effect is likely related to activation of proinflammatory cytokines causing systematic toxic side effects.13 Direct cerebral radiation injury could occur acutely or in delayed phases. Chemobrain in acute radiation injury phase is usually self-limited. Late radiation injury to white matter, which occurs anytime between a few months to even 10 or more years after therapy, is irreversible and progressive.14 Clinical presentation of subcortical white matter dysfunction is similar to that seen in subcortical dementia, and vascular damage is often involved.
Another treatment-related factor of chemobrain can be hormonal therapy. It is well known that reproductive hormones, such as estrogen, have neurotrophic and neuroprotective actions. Estrogen has abundant receptors in the brain. The mechanisms of neuroprotective actions of estrogen include increasing cholinergic and serotonergic activities, facilitating memory formation, and relieving oxidative stress.11 Tamoxifen, an antagonist of the estrogen receptor, is associated with significant neurotoxicity leading to chemobrain in a subgroup of women.15,16 Adjuvant medications, such as steroids for cerebral edema, antiepileptic for seizure prophylaxis, narcotics for pain, or benzodiazepines for anxiety, can further add medication-induced cognitive difficulties.
The risk of developing chemobrain increases significantly for patients exposed to high-dose regimens, the additive or synergistic effects of multiagent chemotherapy, concurrent chemo- and radiation therapy, intra-arterial administration with blood-brain barrier disruption, or direct intrathecal administration. The risk then increases exponentially in patients for whom there are interactions between these host-, disease-, and treatment-related factors.
The following case of a recipient of stem cell transplant for myelodysplastic syndrome will demonstrate the clinical presentation of chemobrain and the consequence of nontreatment. This will allow a review of the etiologies of chemobrain in this patient.
Mr. A. is a 55-year-old male who was in good health prior to being diagnosed with myelodysplastic syndrome (MDS). He initially had 12% myeloblasts in his bone marrow, which only dropped to 7% after eight cycles of decitabine. The only curative therapy, as well as preferred treatment option, was allogenic stem cell transplant (SCT) from a well-matched donor. Prior to his SCT, he underwent conditioning with high doses of fludarabine and cyclophosphamide, in addition to myeloablative total body irradiation to provide in vivo T-cell depletion. He also received cyclosporine for graft-versus-host disease prophylaxis and standard herpes prophylaxis with high-dose acyclovir, fungal prophylaxis with voriconazole, pneumocystis pneumonia/toxoplasmosis prophylaxis with sulfamethoxazole and trimethoprim (Bactrim™), and tuberculosis prophylaxis with isoniazid. His myeloablative SCT was complicated with neutropenic fever and acute kidney injury. He was subsequently started on sirolimus, fludarabine, and methylprednisone for pancytopenia and chimerism (the coexistence of donor and recipient cells). Two months after SCT, he was deemed to have engraftment failure.
Psychiatry was consulted for assessment and treatment of his anxiety and depression. Mr. A.’s chief complaints were memory and concentration problems gradually worsening after the initiation of chemotherapy. He was a very productive and hard-working business owner prior to his MDS diagnosis, but he became easily frustrated by his illness and treatment over time. He eventually closed his business because he could no longer perform the various tasks required in his role as owner. While staying at home, he started several home improvement projects but was not able to finish them. He reported difficulty focusing and an inability to sustain attention on the task at hand. He also experienced low energy and a gradual loss of interest in his usual daily activities. Clinical impression at the time was a cognitive disorder secondary to SCT (ie, chemobrain) leading to secondary depressive disorder. A Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnosis would be mild neurocognitive disorder.
Mr. A.’s chemobrain was the result of multiple factors (Table 1). It should be pointed out that stem cell transplant alone poses a high risk of developing chemobrain;17,18 in addition, the conditioning process prior to stem cell transplant in order to provide in vivo T-cell depletion requires high doses of chemotherapy and high doses of total body irradiation, which are separate risk factors for chemobrain.
Etiologies of Chemobrain for Case Patient
The prevalence of chemobrain varies between 17% and 75% depending on studies and co-factors.9 Chemobrain may resolve gradually after treatment, although for a subgroup of patients, chemobrain may persist for years.11 Unfortunately, chemobrain is often not recognized by the medical community. Many women express that they wish they had received some warning before the cancer treatment. The increase of mere awareness of the “chemobrain” concept has been shown to increase reporting of cognitive symptoms.19
Chemobrain is both a clinical diagnosis and a diagnosis of exclusion. Clinical diagnosis is based on a good history of both medical and psychiatric illnesses and treatments. Reversible causes and modifiable factors should be treated, such as thyroid disease, anemia, fatigue, pain, and sleep disturbance. Brian imaging studies are helpful in some cases, but often do not correlate well with clinical presentation.
Chemobrain can be persistent; however, it should not be confused with dementia. Patients with chemobrain have difficulty with memory retrieval, but they do not have actual memory loss. Although chemobrain does affect efficiency, it does not affect intellect, talent, or problem-solving skills.20 Chemobrain patients still function, but with increased effort and time. They are aware of their memory problems and worry about it. Therefore, chemobrain has significant negative influence over quality of life, which is of the utmost importance for long-term cancer survivors.
Because the ability to focus is diminished with chemobrain, duties become more difficult and often take longer to accomplish. This daily extra mental effort will contribute to complaints of fatigue. Memory problems also tend to increase stress, especially in professional environments.19 For instance, a very experienced journalist with metastatic breast cancer complained of becoming afraid of phone conferences because she would randomly have trouble finding words and her mind would go blank (Dong, personal observation). These types of changes lead chemobrain patients to feel scared, dependent, and emotionally drained.19 If chemobrain is not recognized and treated, patients will experience increased anxiety and eventual depressed mood. Depression and anxiety will then further confound cognitive difficulties.
Chemobrain management requires a multidisciplinary approach. Medical teams will not only treat cancer but also comorbid conditions such as anemia, pain, fatigue, and insomnia. Physicians should be mindful of risks of developing chemobrain, use minimal effective doses of cancer therapies, and optimize cognition-impairing medications, such as steroids, narcotics, and benzodiazepines.
No specific recommendations are currently available for psychopharmacological management, but a few agents have been used off label.10 Psychostimulants, such as methylphenidate, may provide short-lived benefit by improving attention and psychomotor speed; side effects are anxiety and high blood pressure. Modafinil improves fatigue and drowsiness and is associated with a paralleled reduction of depression. Donepezil and other cholinergic inhibitors have also been suggested, but there is little clinical evidence to support their use. Antidepressants can certainly help with anxiety and mood symptoms, but it is unclear if selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors have a direct cognitive-enhancing effect. Erythropoietin also plays a role in neuroprotection; erythropoietin and its receptor are expressed in neural cells of the human brain. Ongoing studies are investigating the therapeutic potential of erythropoietin in preventing the development of chemobrain.10 Other studies suggested possible prevention and treatment of chemobrain using hormonal therapy, antioxidants, dopamine agonists, or anti-inflammatory agents. 21
Studies show some behavioral interventions could be more effective in the long term. The American Cancer Society recommends the use of day-to-day coping strategies (Table 2). The concept is to encourage using residual abilities to develop compensatory techniques or alternative means of performing cognitive tasks.10
Day-to-Day Coping Strategies
The prognosis for such cognitive problems known as chemobrain is variable. This can translate into giving patients hope that there is some element of improvement, which can be due to actual modification of the pathophysiology or accommodation to the defects.
“Chemobrain” is somewhat of a misnomer. The etiology of chemobrain is multifactorial, involving host-, disease- and treatment-related factors; and risk factors are additive or synergistic. Ultimately, chemobrain is a complicated interaction between many factors. Chemobrain at its essence is cognitive difficulties, particularly in memory, concentration, and processing speed. It attributes to fatigue and increased distress, and may potentially lead to anxiety, depression, and a loss of overall ability to function. Prolonged, untreated chemobrain can have negative impacts on quality of life; therefore, it is important to recognize chemobrain and treat the reversible or modifiable factors. For long-term cancer survivors with persistent chemobrain, pharmacological and behavioral interventions may help restore some of the lost functions and improve overall quality of life.
- Silberfarb PM. Chemotherapy and cognitive defects in cancer patients. Annu Rev Med. 1983;34:35–46. doi:10.1146/annurev.me.34.020183.000343 [CrossRef]
- Wefel JS, Vardy J, Ahles TA, Schagen SB. International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol. 2011;12:703–708. doi:10.1016/S1470-2045(10)70294-1 [CrossRef]
- Chemo brain. American Cancer Society. http://www.cancer.org/treatment/treatment-sandsideeffects/physicalsideeffects/chemo-therapyeffects/chemo-brain. Revised May 30, 2012. Accessed June 1, 2014.
- Anderson-Hanley C, Sherman ML, Riggs R, Agocha VV, Compas BE. Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc. 2003;9:967–982. doi:10.1017/S1355617703970019 [CrossRef]
- Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA. “Chemobrain” in breast carcinoma? a prologue. Cancer. 2004;101(3):466–475. doi:10.1002/cncr.20393 [CrossRef]
- Ahles TA, Saykin AJ, McDonald BC, et al. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol. 2010;28:4434–4440. doi:10.1200/JCO.2009.27.0827 [CrossRef]
- Ahles TA, Saykin AJ, Noll WW, et al. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology. 2003;12(6):612–619. doi:10.1002/pon.742 [CrossRef]
- Kanard A, Frytak S, Jatoi A. Cognitive dysfunction in patients with small-cell lung cancer: incidence, causes, and suggestions on management. J Support Oncol. 2004;2:127–140.
- Walker CH, Drew BA, Antoon JW, Kalueff AV, Beckman BS. Neurocognitive effects of chemotherapy and endocrine therapies in the treatment of breast cancer: recent perspective. Cancer Invest. 2012;30:135–148. doi:10.3109/07357907.2011.636116 [CrossRef]
- Fardell JE, Vardy J, Johnston IN, Winocur G. Chemotherapy and cognitive impairment: treatment options. Clin Pharmacol Ther. 2011;90(3):366–376. doi:10.1038/clpt.2011.112 [CrossRef]
- Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007;7:192–201. doi:10.1038/nrc2073 [CrossRef]
- Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 2003;97:2919–2925. doi:10.1002/cncr.11382 [CrossRef]
- Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: a review. Front Oncol. 2012;2:1–18. doi:10.3389/fonc.2012.00073 [CrossRef]
- Valk PE, Dillon WP. Radiation injury of the brain. Am J Neuroradiol. 1991;12:45–62.
- Sherwin BB. Estrogen and cognitive function in women. Proc Soc Exper Biol Med. 1998;217:17–22. doi:10.3181/00379727-217-44200 [CrossRef]
- Gao X, Dluzen DE. Tamoxifen abolishes estrogen’s neuroprotective effect upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system. Neuroscience. 2001;103(2):385–394. doi:10.1016/S0306-4522(01)00014-8 [CrossRef]
- Mosher CE, Redd WH, Rini CM, Burkhalter JE, DuHamel KN. Physical, psychological, and social sequelae following hematopoietic stem cell transplantation: a review of the literature. Psychooncology. 2009;18(2):113–127. doi:10.1002/pon.1399 [CrossRef]
- Syrjala KL, Artherholt SB, Kurland BF, et al. Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. J Clin Oncol. 2011;29(17):2397–2404. doi:10.1200/JCO.2010.33.9119 [CrossRef]
- Boykoff N, Moieni M, Subramanian SK. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. J Cancer Surviv. 2009;3:223–232. doi:10.1007/s11764-009-0098-x [CrossRef]
- Meyers CA, Perry JR. Cognition and Cancer. New York, NY: Cambridge University Press; 2008. doi:10.1017/CBO9780511545900 [CrossRef]
Etiologies of Chemobrain for Case Patient
|Host-related factors (genetic vulnerabilities)
Paternal uncle died of lymphoma at age 46 years
Mother had dementia
Myelodysplastic syndrome resistant to chemotherapy
Anemia and neutropenia
Depression and anxiety
Failed eight cycles of chemotherapy over 7 months
Ablative therapy with high dose of chemotherapy (fludarabineand cyclophosphamide) in combination with total body irradiation prior to stem cell transplant
Allogenic stem cell transplant
Cyclosporine and methylprednisone post–stem cell transplant
Day-to-Day Coping Strategies
Use a detailed daily planner.
Exercise your brain.
Get enough rest and sleep.
Exercise your body.
Eat your vegetables
Set up and follow routines.
Don’t try to multitask.
Ask for help when you need it.
Track your memory problems.
Try not to focus on how much these symptoms bother you.
Talk to family, friends, and your health care team about it.