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Cancer- and Treatment-Related Cognitive Changes: What Can We Do Now? What Lies Ahead?

September 15, 2014
By Catherine M. Bender, PhD, RN, FAAN
John D. Merriman, PhD, RN, AOCNS
Publication
Article
OncologyOncology Vol 28 No 9
Volume 28
Issue 9

Much of the existing research into the phenomenon commonly referred to as “chemobrain” has been descriptive, and we know enough now to identify some patients at risk for cognitive changes after a diagnosis of cancer.

The common term “chemobrain” belies the complex nature of the problem of changes in cognitive function experienced by patients with cancer.[1] Multiple factors contribute to these cognitive changes. Moreover, some patients have been found to have poorer cognitive function than their healthy counterparts before they began therapy, pointing to the possibility that factors other than treatment are contributing to the problem.[2,3]

In general, whether an individual has cancer or not, more years of education and a higher IQ are related to better cognitive function, while advancing age is related to poorer or declining objectively measured cognitive function.[4] Cognitive function is also interrelated with mood and functional ability. In particular, if someone reports a significant deterioration in cognitive function, they are more likely to also experience worsening mood. Conversely, individuals who are clinically depressed commonly experience poorer attention, learning and memory, and psychomotor slowing.[5,6] Fluctuations in hormone levels that naturally occur over the course of life may also be related to changes in cognitive function. For example, there is evidence that the hormonal fluctuations that occur during a woman’s reproductive cycle and with menopause are related to variations in cognitive function, and particularly to variations in verbal memory.[7,8]

It is important to recognize that some patients with cancer are at greater risk for changes in cognitive function. The stress, anxiety, or depressive symptoms they experience across the trajectory of the cancer experience may influence their cognitive function, although clinically meaningful deterioration in objectively measured cognitive function would not be expected unless a patient were experiencing clinical depression meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. It is more common that patient-reported cognitive problems are associated with changes in mood that do not necessarily meet diagnostic criteria for a mood disorder.[5,6] Self-reported cognitive problems may also be associated with other symptoms, such as fatigue, sleep disturbance, and pain.[9-13] Moreover, poorer cognitive function may be related to medications taken to manage these symptoms (eg, analgesics, antiemetics, hypnotics).[14] Factors that may contribute to poorer pretreatment cognitive function in patients with cancer include lingering effects of anesthesia after breast cancer surgery, disease-related factors, comorbidities (eg, diabetes, heart failure), and the medications used to manage comorbid conditions.[1,2]

Patients who have received cancer treatment in the past are at increased risk for developing cognitive impairments with current treatment, particularly those who experienced cognitive problems with past therapy.[15] Patients receiving higher-dose therapy[16] or a longer duration of therapy, particularly with some biologic agents, such as interferon alfa, are also at increased risk for cognitive impairments.[17-19] Similarly, patients receiving concurrent chemoradiation[20] or therapy delivered directly to the central nervous system are at greater risk.[14] Other factors that increase patients’ risk of cognitive impairments include a history of psychiatric illness, substance abuse, neurological disease, or neurotrauma.[4]

When a patient with cancer complains of cognitive problems, clinicians should keep in mind that these complaints may be associated with mood changes rather than neuropsychological changes. Probing more about depressive symptoms or anxiety may lead to appropriate management strategies. However, when there is concern about clinically significant cognitive impairments, referral for a comprehensive neuropsychological assessment may be warranted.

Building on the progress researchers have made in characterizing this complex phenomenon and identifying risk factors, future research has the potential to improve the identification of patients at different levels of risk for cognitive changes so that targeted interventions may be provided to the patients who need them most. To reach this goal of personalized medicine, we must understand the mechanisms underlying cognitive changes. As noted, while the multiple primary procedures and adjuvant therapies provided to cancer patients could contribute to these changes, at least some of the cognitive changes previously attributed to treatment were evident before adjuvant therapy.[21-23] Subgroups of patients are likely at variable levels of risk due to pretreatment factors (eg, mood changes, cognitive reserve, physical fitness, genomic differences that impact inflammatory processes).[23-26] Moreover, these and other unknown factors may influence trajectories of cognitive changes during treatment.

A powerful tool for uncovering the mechanisms underlying cognitive changes in these subgroups is neuroimaging (eg, functional MRI). Imaging studies have the potential to provide substantial insight by uncovering brain biomarkers associated with cognitive changes in different subgroups. These brain biomarkers may identify novel targets for screening and intervention. High costs, and challenges such as claustrophobia, make the widespread use of neuroimaging for research and clinical screening unlikely in the near future. However, technological advances will likely obviate these difficulties with time, much as they are beginning to do for the use of genetics in oncology practice.[27,28] Once costs come down and other barriers begin to abate, the powerful combination of neuroimaging and genomic techniques has the potential to provide the detailed risk profiling needed to enable clinicians to offer targeted education and interventions before cognitive changes manifest, which may prevent or minimize these potentially detrimental changes.

In summary, much of the existing research into the phenomenon commonly referred to as “chemobrain” has been descriptive, and we know enough now to identify some patients at risk for cognitive changes after a diagnosis of cancer. While we can educate patients about the possibility of these changes, we are just beginning to learn about appropriate interventions that may attenuate changes in cognitive function. Few interventions have been tested, and none have yet shown clear benefits that would warrant their implementation in clinical practice. Studies have explored the efficacy of medications such as psychostimulants and erythropoietin with mixed results.[29,30] Studies using interventions such as cognitive behavioral therapy, cognitive training, and physical exercise are showing initial promise for attenuating changes in cognitive function.[31-34] However, more research is needed to determine the efficacy of these interventions and the optimal doses for the management of changes in cognitive function in patients with cancer.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgment:Dr. Merriman is a Postdoctoral Scholar supported by the National Institute of Nursing Research funded T32 grant titled “Interdisciplinary Training of Nurse Scientists in Cancer Survivorship Research (TNR011972A).”

References:

1. Hurria A, Somio G, Ahles T. Renaming “chemobrain.” Cancer Invest. 2007;25:373-77.

2. Ahles TA, Saykin AJ, McDonald BC, et al. Cognitive function in breast cancer patients prior to adjuvant treatment. Breast Cancer Res Treat. 2008;110:143-52.

3. Wefel JS, Lenzi R, Theriault R, et al. ‘Chemobrain’ in breast carcinoma? A prologue. Cancer. 2004;101:466-75.

4. Lezak MD, Howieson DB, Loring DW, et al. Neuropsychological assessment. 4th ed. New York: Oxford University Press; 2004.

5. Cavanaugh SV, Wettstein RM. The relationship between severity of depression, cognitive dysfunction, and age in medical inpatients. American J Psychiatry. 1983;140:495-96.

6. Grant I, Olshen RA, Atkinson JH, et al. Depressed mood does not explain neuropsychological deficits in HIV-infected persons. Neuropsychology. 1993;7:53-61.

7. Sherwin BB. Estrogen and cognitive functioning in women. Endocrine Rev. 2003;24:133-51.

8. Sherwin BB. Estrogen and cognitive aging in women. Neuroscience. 2006;138:1021-26.

9. Bender CM, Pacella ML, Sereika SM, et al. What do perceived cognitive problems reflect? J Support Oncol. 2008;6:238-42.

10. Cull A, Hay C, Love SB, et al. What do cancer patients mean when they complain of concentration and memory problems? Br J Cancer. 1996;74:1674-79.

11. Kibiger G, Kirsh KL, Wall JR, Passik SD. My mind is as clear as it used to be: a pilot study illustrating the difficulties of employing a single-item subjective screen to detect cognitive impairment in outpatients with cancer. J Pain Sympt Manage. 2003;26:705-15.

12. Klepstad P, Hilton P, Moen J, et al. Self reports are not related to objective assessments of cognitive function and sedation in patients with cancer pain admitted to a palliative care unit. Palliat Med. 2002;16:513-19.

13. Poppelreuter M, Weiss J, Kulz AK, et al. Cognitive dysfunction and subjective complaints of cancer patients: A cross-sectional study in a cancer rehabilitation centre. Eur J Cancer. 2004;40:43-49.

14. Meyers CA. Neurocognitive dysfunction in cancer patients. Oncology (Williston Park). 2000;14:75-9; discussion 79.

15. Wefel JS, Meyers CA. Cancer as a risk factor for dementia: a house built on shifting sand. J Natl Cancer Inst. 2005;97:788-9.

16. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy.[comment]. J Natl Cancer Inst. 1998;90:210-8.

17. Minisini A, Atalay G, Bottomley A, et al. What is the effect of systemic anticancer treatment on cognitive function? Lancet Oncol. 2004;5:273-82.

18. Valentine AD, Meyers CA, Kling MA, et al. Mood and cognitive side effects of interferon-alpha therapy. Sem Oncol. 1998;25:39-47.

19. Hensley M, Peterson B, Silver R, et al. Risk factors for severe neuropsychiatric toxicity in patients receiving interferon alfa-2b and low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer and Leukemia Group B 9013. J Clin Oncol. 2000;18:1301-08.

20. Hui KG, Bernstein LJ, Brown J, et al. Cognitive functioning after radiotherapy or chemoradiotherapy for head-and-neck cancer. Intl J Rad Oncol. 2011;81:126-34.

21. Berman MG, Askren MK, Jung M, et al. Pretreatment worry and neurocognitive responses in women with breast cancer. Health Psychol. 2014;33:222-31.

22. Cimprich B, So H, Ronis DL, Trask C. Pre-treatment factors related to cognitive functioning in women newly diagnosed with breast cancer. Psycho-Oncology. 2005;14:70-8.

23. Ahles TA, Root JC, Ryan EL. Cancer- and cancer treatment-associated cognitive change: an update on the state of the science. J Clin Oncol. 2012;30:3675-86.

24. Merriman JD, Aouizerat BE, Cataldo JK, et al. Association between an interleukin 1 receptor, type I promoter polymorphism and self-reported attentional function in women with breast cancer. Cytokine. 2014;65:192-201.

25. 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. Psycho-Oncology. 2003;12:612-9.

26. Wefel JS, Vardy J, Ahles T, Schagen SB. International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol. 2011;12:703-8.

27. Frank E, Nimgaonkar VL, Phillips ML, Kupfer DJ. All the world’s a (clinical) stage: rethinking bipolar disorder from a longitudinal perspective. Mol Psychiatry. 2014 Jul 22. [Epub ahead of print]

28. Bombard Y, Bach PB, Offit K. Translating genomics in cancer care. J Natl Comp Cancer Netw, 2013;11:1343-53

29. 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;16:577-83.

30. O’Shaughnessy JA. Effects of epoeitin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clin Breast Cancer. 2002;3(suppl):S116-S20.

31. Ferguson RJ, Ahles TA, Saykin AJ, et al. Cognitive-behavioral management of chemotherapy-related cognitive change. Psycho-Oncology. 2007;16:772-7.

32. Mishra SI, Scherer RW, Snyder C, et al. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Library. 2012;2012:1-459.

33. Mishra SI, Scherer RW, Geigle PM, et al. Exercise interventions on health-related quality of life for cancer survivors. Cochrane Library. 2012;2012:1-379.

34. Ferguson RJ, McDonald BC, Rocque MA, et al. Development of CBT for chemoterhapy-related cognitive change: results of a waitlist control trial. Psycho-Oncology. 2012;21:176-86.

Articles in this issue

Waiting for a Miracle
Waiting for a Miracle
Routine Use of Maintenance Therapy in Follicular Lymphoma: The Strategy Is Effective, Raising the Question, ‘What Is the Most Important Measure of Success in the Current Era?’
Routine Use of Maintenance Therapy in Follicular Lymphoma: The Strategy Is Effective, Raising the Question, ‘What Is the Most Important Measure of Success in the Current Era?’
Routine Use of Maintenance Therapy in Follicular Lymphoma: Examine the Rationale for Maintenance Use Before Uniformly Adopting a Strategy
Routine Use of Maintenance Therapy in Follicular Lymphoma: Examine the Rationale for Maintenance Use Before Uniformly Adopting a Strategy
Heterogeneity and Cancer
Heterogeneity and Cancer
Gastrointestinal Neuroendocrine Tumors: Slow but Steady Progress
Neuroendocrine Tumors: Answers-and Questions
An Update on Gastroenteropancreatic Neuroendocrine Tumors
An Update on Gastroenteropancreatic Neuroendocrine Tumors
Tumor Heterogeneity Is Fundamental to the Tumor Ecosystem
Chemobrain: Is It Time to Initiate Guidelines for Assessment and Management?
Cancer Treatment and Cognitive Function: Chemotherapy Is Not the Only Culprit
Cancer- and Treatment-Related Cognitive Changes: What Can We Do Now? What Lies Ahead?
An Overview of Chemotherapy-Related Cognitive Dysfunction, or ‘Chemobrain’
Tumor Heterogeneity: The Lernaean Hydra of Oncology?
Tumor Heterogeneity and Implications for Clinical Practice
What Next? Choosing Second-Line Therapy in Progressive Renal Cell Carcinoma
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