Cognitive Dysfunction Secondary to Cancer Therapy
Background
Cognitive changes that negatively affect thinking—including memory, concentration, and behavior—are known as cognitive dysfunction (CD). CD is also referred to as cognitive impairment, cognitive changes, central neurotoxicity, cognitive impairment, or neurocognitive dysfunction1 and is commonly referred to by cancer patients and survivors as “chemo brain” or “chemo fog.” CD has been widely reported in the professional and patient literature, yet its exact etiology in cancer patients remains unknown2 and there is no consensus on its precise definition. Similar changes have been reported in patients with HIV, chronic fatigue syndrome, hepatitis C, and acquired brain injury.
Patients with CD often complain of memory disturbance. When tested with quick assessment in clinic, memory disturbance may not be clinically obvious but become evident in neuropsychological testing, particularly in relation to the individual’s pre-illness level of function. Additional common symptoms of CD in cancer patients include periodic lapses of attention, distractibility, and slowed cognitive processing speed. In general, reasoning and intellectual functions are not affected, but patients often have difficulty performing their normal work because of cognitive inefficiencies.
The effect of these symptoms on daily life can be quite profound, depending on the demands in the individual’s work and home life. Many patients observe that they can no longer multi-task and that they may become overwhelmed when too much is happening at once. They tend to be easily distracted and may go from project to project without completing them.
More than 11 million Americans are cancer survivors.3 Some are actively undergoing treatment and others have put treatment behind them. Treatment with chemotherapy or radiation can contribute to CD, although the extent of the contribution of cancer treatment versus stress or effects of cancer itself is still unknown. CD is more prevalent in cancer patients on active therapy but may persist long after treatment has been discontinued, thus negatively affecting quality of life throughout the cancer trajectory.
Cancer- and cancer treatment–related cognitive changes have been studied most widely in women undergoing treatment for breast cancer, with 17% to 75% reporting symptoms.4 Among patients with all cancers, studies have shown that cognitive difficulties affect 25%–33% of all patients undergoing systemic chemotherapy.5 Although the causes and existence of cancer treatment-related CD have been a subject of debate, recent studies have confirmed that cancer treatment-related CD is a real, measurable side-effect of chemotherapy that appears in some patients. The study of cancer-related CD is relatively new and lacks large phase 3 clinical studies to support evidence-based assessment and interventions.6-7 As a result, neither the National Cancer Institute (NCI) nor the National Comprehensive Cancer Network (NCCN) has yet established guidelines for the care of patients experiencing CD symptoms.
Studies Suggesting Developmental Differences in Cancer-Related CD
Cognitive impairments have been well documented in children who received cancer treatment, some deficits being more noticeable 5 to 11 years after diagnosis.1 Buckwalter et al,1 comparing 541 elderly female cancer survivors with a control group of 3,123 women, found no association between a history of cancer and poorer cognitive function or delayed verbal memory. This study suggests that since all respondents had developed their cancer after age 18, perhaps the adult brain and developing brain have different responses to cancer and treatment.1
Adult Studies Suggesting Cancer-Related Differences in CD
Silverman et al8 examined physical changes in the brain that occur with CD symptoms, which include memory loss, depression, inability to concentrate, and fatigue. Women with breast cancer treated with adjuvant chemotherapy were evaluated 5 to 10 years after their chemotherapy treatments and compared with a control group. On a delayed recall test, the women who received chemotherapy scored an average of 3.2 points lower than the control group. Positron emission tomographic (PET) scans of the treated women revealed changes in cerebral blood flow in regions of the frontal cortex and cerebellum, with the most significant change noted in the inferior frontal gyrus.8 Certain neurocognitive impairments can be traced to specific sites within the brain (Table 1).
Table 1. Neurocognitive Impairments Related to Location In Brain
Site
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Common Deficits
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Left hemisphere
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Language
Verbal memory & reasoning
Right-sided strength & dexterity
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Right hemisphere
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Visual perception & construction
Left hemispatial inattention
Left-sided strength & dexterity
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Frontal lobe
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Executive functions
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Adapted from Baumgartner.2
Cognitive Dysfunction Risk Factors
Predicting which patients will experience CD, to what extent, or for how long is difficult. Medical oncologists, radiologists, and psychologists who participated in a workshop on CD concluded that cognitive changes may be subtle, durable, and possibly disabling.9 Risk factors for CD have not been well defined. Figure 1 lists several presumed CD risk factors.
• Central nervous system involvement from tumor
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• Presence of the apolipoprotein (APOE) e4 allele genetic mutation10
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• Increasing age
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• Estrogen deficiency
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• High-dose or long-term chemotherapy
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• Certain types of chemotherapy
· Cyclophosphamide
· Methotrexate
· 5-Fluorouracil
· Cytarabine
· Procarbazine
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• Hormonal therapy
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• Interleukin 2 or interferon
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• Glucocorticosteroids
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Aside from the cancer and treatment, other factors may contribute to cognitive problems:
Strees
Poor diet
Pain10
Sleep disturbances
Menopause
Anemia4,11,12
Many patients find that CD resolves over time (months to years). A study evaluating brain matter in breast cancer survivors following adjuvant chemotherapy showed that although smaller gray matter was demonstrated within one year, comparisons with healthy controls showed no significant differences after three years.13 The National Coalition for Cancer Survivorship suggests that new research may reveal CD as a lingering side effect for some patients.11
Assessment
Objective testing of memory generally demonstrates a restriction of working memory capacity (e.g., the person is able to learn less information, and learning may be less efficient) and inefficient memory retrieval (e.g., spontaneous recall may be somewhat spotty). However, the ability to store new information is generally intact, meaning that the memory disturbance in cancer patients is vastly different from that in neurodegenerative disorders such as Alzheimer’s disease.
The first indication of CD is the patient’s own report.2 In addition to patient-provided subjective information, it is critical that nurses document objective observations of memory deficits, confusion, or altered functioning in the medical record. The Folstein Mini Mental State Examination (MMSE) http://www.hospitalmedicine.org/geriresource/toolbox/folstein_mini-mental.htm can be administered in 10 minutes in any clinical setting to establish a baseline or document changes.14,15 If the symptoms of CD are distressing to the patient, consider referral to a neuropsychologist for further objective testing of cognitive and executive function. A full battery of neuropsychological tests may range in length from four to seven hours; the burden of testing may add further stress to a patient undergoing therapy and experiencing fatigue.16
Interventions
The most important intervention during patients’ reporting of CD symptoms is listening carefully to their complaints and concerns. Patients and caregivers need education before treatment begins regarding the potential for CD. Educational materials shared with patients should include CD as a potential side effect. Sample available here. Patients must understand the importance of reporting cognitive impairment and offered options for dealing with it. Complaints of cognitive difficulty must be taken seriously and given consideration by the healthcare team.17
Other nonpharmacologic interventions may be helpful, although few have been tested in randomized, controlled clinical trials. (Table 2). It’s best to initiate one or two interventions at a time and evaluate for efficacy before adding others. Changes in cognitive function occur slowly.7
Table 2. Nonpharmacologic Interventions for CD
Intervention
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Rationale
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Acupuncture
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Dilates cerebral blood vessels, improving blood flow and oxygenation
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Antioxidant foods
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High in vitamin C and E; may mediate the effects of oxidative stress
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Increasing fluid intake
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Prevents dehydration
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Informing family and friends
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Decreases stress and increases support
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Mental exercises
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Games, crossword puzzles increases brain activity
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Physical exercise
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Increases blood flow; sense of wellbeing
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Relaxation exercises
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Decreases stress
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Maintain a normal routine
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Make lists for shopping, tasks; use a personal planner for daily schedules; keep frequently used items (keys, cell phone, eyeglasses) in one place
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Ensure adequate sleep
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Based on information from Baumgartner2, Nelson et al7, Evens17, Chemocare18
No specific pharmacologic agents have been approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer-related CD. Some medications such as methylphenidate (a psychostimulant) and donepezil (an acetylcholinesterase inhibitor) are under study for the treatment of CD.
Guidelines and Patient Resources
There are no evidence-based guidelines for the assessment or management of cognitive dysfunction.
References
- Buckwalter J, Crooks V, Petitti D. Cognitive performance of older women who have survived cancer. Intern J Neurosci. 2005;115:1307-1314. doi: 10.1080/00207450590934534
- Baumgartner K. Neurocognitive changes in cancer patients. Semin Oncol Nurs. 2004; 20:284-290. doi:10.1016/j.soncn.2004.07.008
- American Cancer Society. Cancer facts and figures 2009. Available at: http://www.cancer.org/downloads/STT/500809web.pdf Retrieved March 17, 2010.
- O’Shaughnessy J. Chemotherapy-related cognitive dysfunction in breast cancer. Semin Oncol Nurs. 2003;19(suppl 2):17-24. doi:10.1053/j.soncn.2003.09.002
- Coyne BM, Leslie ML. Chemo’s toll on memory. RNWeb. 2004. Available at http://rnweb.mediwire.com/main/Default.aspx?P=Content&ArticleID=102473 Retrieved March 17, 2010.
- Hede K. Chemobrain is real but may need new name. J Natl Cancer Inst. 2008. 100: 162-163, 169. doi:10.1093/jnci/djn007.
- Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions. Palliat Support Care. 2007. 5: 273–280. doi:10.1017/S1478951507000442
- Silverman DHS, Dy C, Castellon SA, et al. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5-10 years after chemotherapy. Breast Cancer Res Treat. 2007;103:303-311. doi: 10.1007/s10549-006-9380-z
- Tannock I, Ahles T, Ganz P, van Dam F. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol. 2004;22:223-2239. doi: 10.1200/JCO.2004.08.094
- Staat K, Segatore M. The phenomenon of chemo brain. Clin J Oncol Nurs. 2005;9:713-721. doi: 10.1188/05.CJON.713-721
- National Coalition for Cancer Survivorship. Cognitive Issues. Available at: http://www.canceradvocacy.org/resources/treatment-issues/side-effects/cognitive.html Accessed March 17, 2010.
- O’ Shaughnessy J. Chemotherapy-induced cognitive dysfunction: a clearer picture. Breast Cancer. 2003;4(suppl 2):S89-S94. doi:10.3816/CBC.2003.s.021
- Inagaki M, Yoshikawa E, Matsuoka Y et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007;110:224-225. doi: 10.1002/cncr.22368
- Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
- Psychological Assessment Resources, Inc. Mini-Mental State Examination. Available at: http://www.minimental.com/. Accessed March 17, 2010.
- Myers JS. Chemotherapy-related cognitive impairment: Neuroimaging, neuropsychological testing, and the neuropsychologist. Clin J Oncol Nurs. 2009;13:413-421. doi:10.1188/09.CJON.413-421
- Evens K, Eschiti VS. Cognitive effects of cancer treatment: “Chemo brain” explained. Clin J Oncol Nurs. 2009;13: 661-666. doi: 10.1188/09.CJON.661-666.
- Chemocare.com. Chemo Brain. (n.d.) Available at: http://www.chemocare.com/managing/chemobrain__how_to_identify_and.asp. Retreived March 17, 2010.
Key Definitions
cerebellum—a large dorsally projecting part of the brain concerned especially with the coordination of muscles and the maintenance of bodily equilibrium; it is situated between the brain stem and back of the cerebrum and formed (in humans) of 2 lateral lobes and a median lobe
delayed recall test—assessment of the ability to verbally repeat a short list or story after a defined period of time
e4 allele—a germline mutation that has been associated with Alzheimer’s disease
executive functions a cluster of high-order capacities, which include selective attention, behavioral planning and response inhibition, and the manipulation of information in problem-solving tasks
frontal cortex—the portion of the brain involved with reasoning, planning, abstract thought, and other complex cognitive functions in addition to motor function
frontal gyrus—any of the convolutions of the outer surface of the frontal lobe of the brain
glucocorticosteroids—any of the group of corticosteroids predominantly involved in carbohydrate fat and protein metabolism, alteration of connective tissue response to injury, and inhibition of inflammatory and allergic reactions. In humans, the most important glucocorticosteroids are cortisol (hydrocortisone) and cortisone
gray matter—the cortex of the brain containing nerve cell bodies, in contrast to the white matter, the part of the brain that contains myelinated nerve fibers
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