Background: Chemotherapy-related cognitive impairment (CRCI) is a frequent, yet poorly recognized complication of cancer therapy. This Fast Fact reviews the effects, diagnosis, and management of CRCI.
Clinical Significance: Changes in memory, attention, processing speeds, and problem-solving during or after exposure to chemotherapy have been referred to as “chemobrain” or CRCI. CRCI often begins right away with 50-80% noticing cognitive changes during chemotherapy (1,2); others may not notice the changes for a few weeks after chemotherapy exposure. While most CRCI symptoms resolve after chemotherapy is discontinued, 25-35% experience cognitive changes that persist years after treatment completion (3-4). Patients may describe it to their clinicians as a sense of “forgetfulness” or “cloudiness in thinking.” Although the degree of CRCI is usually subtle, even slight changes in cognition can adversely impact decision-making capacity, advanced care planning, treatment adherence, and caregiver burden. One study of breast cancer survivors found only a 10% decrease in standardized cognition scores, but over 45% self-reported these changes as significant to their quality of life (5).
At Risk Patients:
- > 65 years of age, CNS involvement, lower baseline cognitive reserve, social isolation, and depression are the most established risk factors (4,6).
- Genetic factors, including various APOE and COMT genotypes, have been implicated in both resiliency or vulnerability to CRCI depending on the allele (7).
- Leukemia, breast, prostate, ovarian, and CNS cancers (8).
- Although methotrexate, cytarabine, and ifosfamide are known for their central neurotoxic effects, other, more general factors about the chemotherapy may have a larger role than the type of chemotherapy administered, such as: a) high-dose exposure; b) multi-agent therapy; c) concurrent chemotherapy with cerebral radiation; d) intrathecal administration (8,9).
Assessment: Cognition can be affected by many other factors common in cancer patients: depression, anxiety, sleep disturbances, metastases, and medications. A full clinical evaluation should be performed to identify modifiable cognitive risk factors prior to diagnosing CRCI. While short cognitive screening tools often lack adequate sensitivity and specificity to detect the subtle changes of CRCI, they may be the most feasible options to incorporate into clinical practice. Examples include the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) (10), the Montreal Cognitive Assessment (MoCA) (11), the Mini-Mental Status Exam (MMSE) (12), and the Mini-Cog (13). Even these tests can be time-consuming; therefore, many clinicians reserve their use for at-risk and/or symptomatic patients who are not acutely ill or imminently dying, as they are most likely to benefit from the diagnosis and treatment. If the screening tool suggests CRCI, ideally a full neuropsychological evaluation is pursued to confirm the diagnosis, guide rehabilitative efforts, and obtain requisite support such as disability benefits.
Management: Because CRCI often improves weeks to months after chemotherapy exposure, many patients require no intervention. For others with persistent symptoms or for whom discontinuation of the inciting chemotherapy is not a feasible care option, there are several pharmacological agents under investigation for CRCI. However, they are primarily limited to pilot data. As such there are no FDA-approved medications for CRCI.
- Psychostimulants are the most studied medication class for CRCI, yet, most trials look at cognition only as a secondary outcome. Furthermore, the data are mixed: modafinil and methylphenidate have shown mild-moderate cognitive improvement in some studies (14-16) but not others (17-19).
- Donepezil has demonstrated some efficacy in early investigational trials (20,21). Memantine has shown mixed results (22).
- Beyond pharmacologic interventions, the most established efficacy is seen in cognitive rehabilitation approaches like cognitive behavioral therapy (CBT) and a novel therapy called Memory and Attention Adaptation Training which incorporates psychoeducation, stress management, mindfulness, and self-awareness into CBT (23,24). These interventions have been associated with a moderate improvement in FACT-Cog scores that are sustained through a 2-month follow-up (25). A referral to a clinical psychologist is often necessary for this type of cognitive rehabilitation.
Summary: As many patients are not aware of the cognitive side effects of cancer treatment, clinician recognition and psychoeducation about CRCI is likely the most crucial aspect of its management. Some patients may worry that the cognitive changes associated with chemotherapy are a result of an undiagnosed neuro-degenerative disorder like Alzheimer’s disease. Clinician counseling about CRCI’s signs and symptoms, etiology, and prognosis of likely improvement after cessation of chemotherapy exposure can thereby alleviate excessive concern and validate patient experiences.
- Janelsins MC, Kesler SR, Ahles TA, Morrow GR. Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Rev Psychiatry Abingdon Engl. 2014;26(1):102-113. doi:10.3109/09540261.2013.86426
- Janelsins MC, Kohli S, Mohile SG, Usuki K, Ahles TA, Morrow GR. An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Semin Oncol. 2011;38(3):431-438. doi:10.1053/j.seminoncol.2011.03.014.
- Ahles TA, Saykin AJ, Furstenberg CT, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(2):485-493. doi:10.1200/jco.2002.20.2.485.
- Ahles TA, Root JC, Ryan EL. Cancer- and cancer treatment-associated cognitive change: an update on the state of the science. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(30):3675-3686. doi:10.1200/JCO.2012.43.0116.
- Janelsins MM. 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. 2016-12. doi:10.1200/JCO.2016.68.5826.
- Jim HSL, Phillips KM, Chait S, et al. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(29):3578-3587. doi:10.1200/JCO.2011.39.5640.
- Harris SE, Deary IJ. The genetics of cognitive ability and cognitive ageing in healthy older people. Trends Cog Sci. 2011;15:388-394. doi:10.1016/j.tics.2011.07.004
- Wefel JS, Schagen SB. Chemotherapy-related cognitive dysfunction. Curr Neuro and Neurosci Rep. 2012;12(3):267-75.
- Verstappen CC, Heimans JJ, et al. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 2003;63(15):1549-63
- Wagner L, Sweet J, Butt Z, et al: Measuring patient self-reported cognitive function: Development of the Functional Assessment of Cancer Therapy – Cognitive Function instrument. J Support Oncol 7:W32-W39, 2009.
- Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699. doi:10.1111/j.1532-5415.2005.53221.x.
- 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(3):189-19.
- Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog as a screen for dementia: validation in a population-based sample. J Am Geriatr Soc. 2003;51(10):1451-1454.
- Kohli S, Fisher SG, Tra Y, et al. The effect of modafinil on cognitive function in breast cancer survivors. Cancer. 2009;115(12):2605-2616. doi:10.1002/cncr.24287.
- Lundorff L, Jonsson B, Sjogren P. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial. Palliat Med. 2009; 23(8): 731-8. doi:10.1177/0269216309106872
- Gagnon B, Low G, Schreier G. Methylphenidate hydrochloride improves cognitive function in patients with advanced cancer and hypoactive delirium: a prospective clinical study. J Psychiatry Neurosci. 2005; 30(2):100-7.
- Boele FW, Douw L, de Groot M, et al. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial. Neuro-Oncol. 2013;15(10):1420-1428. doi:10.1093/neuonc/not102.
- Blackhall L, Petroni G, Shu J, et al. A pilot study evaluating the safety and efficacy of modafinil for cancer-related fatigue. J Palliat Med. 2009;12(5): 433-439. doi:10.1089/jpm.2008.0230.
- Mar Fan HG, Clemons M, Xu W, et al. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer. 2008;16(6): 577-83. doi:10.1007/s00520-007-0341-9.
- Correa DD, Kryza-Lacombe M, Baser RE, et al. Cognitive effects of donepezil therapy in patients with brain tumors: a pilot study. J Neurooncol. 2016;127(2):313-9.
- Shaw EG, Rosdhal R, D’Agostino RB et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol. 2006; 24(9): 1415-20. doi:10.1200/JCO.2005.03.3001
- Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15(10):1429-1437. doi:10.1093/neuonc/not114.
- Kucherer S, Ferguson RJ. Cognitive behavioral therapy for cancer-related cognitive dysfunction. Curr Opin Support Palliat Care. 2017;11(1):46-51. doi:10.1097/SPC.0000000000000247.
- Ferguson RJ, Ahles TA, Saykin AJ, et al. Cognitive-behavioral management of chemotherapy-related cognitive change. Psychooncology. 2007;16(8):772-777. doi:10.1002/pon.1133.
- Ferguson RJ, Sigmon ST, Pritchard, AJ, LaBrieet al. A randomized trial of videoconference-delivered cognitive behavioral therapy for survivors of breast cancer with self-reported cognitive dysfunction. Cancer. 2016;122: 1782–1791. doi:10.1002/cncr.29891
Authors Affiliations: Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York State Psychiatric Institute.
Conflicts of Interest: none
Version History: Originally edited by Sean Marks MD; first electronically published September 2017
Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.
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