Cancer Treatment and Cognitive Function: Chemotherapy Is Not the Only Culprit

With the growing number of cancer survivors,[1] there is increased interest in understanding and preventing post-treatment sequelae that may limit full recovery to prediagnosis health. As a result, during the past 2 decades there has been growing interest in the evaluation of patient-reported complaints of persistent post-chemotherapy cognitive changes. Cognitive complaints often co-occur with fatigue and depressive symptoms in cancer patients, making it difficult for clinicians to evaluate whether these difficulties are merely associated with other physical and psychological etiologies, or are separate and distinct-direct side effects of cancer treatment.

As discussed by Moore,[2] the major challenge in evaluation of cognitive complaints following cancer treatment has been the lack of a strong association of the subjective experience of increased cognitive difficulties with standardized neuropsychological (NP) tests, which are considered objective and the gold standard for identifying deficits in cognitive function. However, it should be noted that NP tests were designed for the assessment of patients with major head trauma, vascular insults, psychiatric conditions, and dementias; thus, their sensitivity for the detection of more subtle changes in performance is limited. In addition, the difficulty of simply and efficiently performing objective assessments (NP testing or imaging) concurrently with chemotherapy treatments has made it difficult to monitor the potential toxic impact of chemotherapy on cognitive function. More recent use of neuro-imaging together with subjective reports and NP testing has demonstrated that subjective complaints are, in fact, associated with changes in brain activity.[3-5] These studies are costly and complex, limiting their use to research settings; nevertheless, they provide observational support for the validity of self-reported complaints.

The cognitive complaints implicating chemotherapy exposure that were the subject of early investigations were often reported in women receiving CMF (cyclophosphamide, methotrexate, fluorouracil [5-FU]) adjuvant chemotherapy.[6,7] Both methotrexate and 5-FU cross the blood-brain barrier, so their effect on the CNS was a possible mechanism for the development of cognitive difficulties. Subsequent animal model studies probed these two agents, examining behavioral and pathologic changes in rodents.[8] However, changes in adjuvant chemotherapy regimens for breast cancer, as well as in common treatment regimens for other cancers, resulted in the omission of these two agents, yet patient reports of cognitive difficulties persisted. Thus, other mechanisms have been entertained, including genetic predisposition, changes in the blood-brain barrier, DNA damage with telomere shortening, inflammation, and changes in testosterone and estrogen levels.[9,10]

In our research, we have found significant elevations of the soluble proinflammatory cytokine tumor necrosis factor receptor 2 in association with adjuvant chemotherapy and radiation exposure in a contemporary sample of breast cancer patients.[11] These levels fall during the 12 months after the end of adjuvant chemotherapy, and as systemic levels normalize, there is also normalization of cerebral metabolism on brain imaging.[11] Animal models examining systemic administration of doxorubicin implicate doxorubicin’s generation of reactive oxygen species that then cross the blood-brain barrier and stimulate local production of inflammatory cytokines in the brain, potentially affecting cerebral function-so this can be a secondary mechanism associated with inflammation.[12] Recent work from our laboratory also finds an association of cognitive complaints, specifically those involving deficits in verbal fluency, after initiation of endocrine therapy, independent of recent chemotherapy and radiation exposure.[13] To explain post-treatment cognitive difficulties, it is important to account for the multiple potential exposures that a patient receives while undergoing cancer treatment, and not just chemotherapy.

As noted by Moore, there have been many challenges surrounding the design and conduct of studies to evaluate cognitive function, with those studies that have included testing prior to chemotherapy showing pre-existing NP test deficits in some patients. These evaluations are helpful in that they establish the pre-chemotherapy baseline for individuals; however, they rarely are conducted prior to the surgery and general anesthesia that may precede chemotherapy. Only a few studies have evaluated cognitive function prior to surgery.[14,15] It is likely that patients have variable cognitive reserves at the time of diagnosis,[9] and that the insults of multiple cancer treatments (surgery, chemotherapy, radiation therapy, immunotherapy) can affect subsequent outcomes. Host factors and personal vulnerability may be just as important as the treatment exposures. It is well recognized with other treatments (eg, taxanes) that there is tremendous variability in who develops a specific toxicity and how persistent it will be. In the case of cognitive dysfunction after breast cancer treatments, patients with certain specific single nucleotide polymorphisms in the promoter region of proinflammatory cytokines appear to be at greater risk for cognitive complaints.[16]

In reviewing potential intervention strategies, Moore overlooked a number of more recent reports that have examined other strategies, including some that have used computerized tools,[17,18] and cognitive rehabilitation strategies that have been evaluated.[19-21] We have recently reported on the results of a randomized trial of a 5-week group-based cognitive rehabilitation intervention study in breast cancer survivors that showed improvement in self-reported cognitive complaints, improved NP test performance, and normalization of electroencephalography (EEG) patterns in women in the intervention group as compared with the control group, and these improvements were sustained in the 2 months post-intervention. [22-24] The EEG findings in this study suggest that this may be a useful biomarker of cognitive changes in cancer patients, and as noted by Moore et al,[25] might be integrated into the prospective evaluation of patients receiving chemotherapy. An intervention in older adults that involved computerized training has suggested that EEG findings may reflect brain plasticity[26]-and suggests that such computerized training might be used for the mitigation of cognitive deficits that can occur with cancer treatments. All of these efforts at rehabilitation and “brain training” are in their infancy, but clearly reflect the need and potential opportunities to address this toxicity of cancer treatment.

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

References:

1. de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomark Prev. 2013;22:561-70.

2. Moore HCF. An overview of chemotherapy-related cognitive dysfunction, or ‘chemobrain.’ Oncology (Williston Park). 2014;28:797-804.

3. Ganz PA. “Doctor, will the treatment you are recommending cause chemobrain?” J Clin Oncol. 2012;30:229-31.

4. Pomykala KL, de Ruiter MB, Deprez S, et al. Integrating imaging findings in evaluating the post-chemotherapy brain. Brain Imaging Behav. 2013;7:436-52.

5. Deprez S, Vandenbulcke M, Peeters R, et al. Longitudinal assessment of chemotherapy-induced alterations in brain activation during multitasking and its relation with cognitive complaints. J Clin Oncol. 2014;32:2031-8.

6. Schagen SB, Muller MJ, Boogerd W, et al. Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. Ann Oncol. 2002;13:1387.

7. Schagen SB, van Dam FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer. 1999;85:640-50.

8. Seigers R, Schagen SB, Van TO, Dietrich J. Chemotherapy-related cognitive dysfunction: current animal studies and future directions. Brain Imaging Behav. 2013;7:453-9.

9. Ahles TA. Brain vulnerability to chemotherapy toxicities. Psycho-Oncology. 2012;21:1141-8.

10. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007;7:192-201.

11. Ganz PA, Bower JE, Kwan L, et al. Does tumor necrosis factor-alpha (TNFalpha) play a role in post-chemotherapy cerebral dysfunction? Brain, Behavior, and Immunity. 2013;30, Supplement:S99-S108.

12. Joshi G, Sultana R, Tangpong J, et al. Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain. Free Radical Res. 2005;39:1147-54.

13. Ganz PA, Petersen L, Castellon SA, et al. Cognitive function after the initiation of adjuvant endocrine therapy in early stage breast cancer: an observational cohort study. J Clin Oncol. 2014. In press.

14. Hedayati E, Schedin A, Nyman H, et al. The effects of breast cancer diagnosis and surgery on cognitive functions. Acta Oncologica. 2011;50:1027-36.

15. Hedayati E, Alinaghizadeh H, Schedin A, et al. Effects of adjuvant treatment on cognitive function in women with early breast cancer. Eur J Oncol Nurs. 2012;16:315-22.

16. Bower JE, Ganz PA, Irwin MR, et al. Cytokine genetic variations and fatigue among patients with breast cancer. J Clin Oncol. 2013;31:1656-61.

17. Von Ah D, Carpenter JS, Saykin A, et al. Advanced cognitive training for breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat. 2012;135:799-809.

18. Kesler S, Hadi Hosseini SM, Heckler C, et al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. Clin Breast Cancer. 2013;13:299-306.

19. Ercoli LM, Castellon SA, Hunter AM, et al. Assessment of the feasibility of a rehabilitation intervention program for breast cancer survivors with cognitive complaints. Brain Imaging Behav. 2013;7:543-53.

20. Schuurs A, Green HJ. A feasibility study of group cognitive rehabilitation for cancer survivors: enhancing cognitive function and quality of life. Psycho-Oncology. 2013;22:1043-9.

21. Cherrier MM, Anderson K, David D, et al. A randomized trial of cognitive rehabilitation in cancer survivors. Life Sci. 2013;93:617-22.

22. Ercoli L, Castellon S, Hunter A, et al. Assessment of the feasibility of a rehabilitation intervention program for breast cancer survivors with cognitive complaints. Brain Imag Behav. 2013:1-11.

23. Hunter AM, Kwan L, Ercoli LM, et al. Quantitative electroencephalography biomarkers of cognitive complaints after adjuvant therapy in breast cancer survivors: a pilot study. Psycho-Oncology. 2014;23:713-5.

24. Ercoli LM, Castellon S, Petersen L, et al. Cognitive rehabilitation group intervention for breast cancer survivors: results of a randomized clinical trial. International Cancer and Cognition Task Force Meeting; Seattle, WA 2014.

25. Moore HF, Parsons M, Yue G, et al. Electroencephalogram power changes as a correlate of chemotherapy-associated fatigue and cognitive dysfunction. Support Care Cancer. 2014;22:2127-31.

26. Anguera JA, Boccanfuso J, Rintoul JL, et al. Video game training enhances cognitive control in older adults. Nature. [Letter]. 2013;501:97-101.