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Cancer Related Cognitive Impairment (CRCI): More than cancer and chemo

Michelle Kirschner BSN, ACNP, APRN,BC,  Survivorship

Rhonna Shatz, DO Bob and Sandy Heimann Chair in Alzheimer’s Disease Research and Education, Director of Cognitive Disorders Center

It is well established that one significant side effect of cancer and its treatment is cognitive dysfunction.   Although commonly referred to as “chemo-brain” CRCI research indicates that cancer itself along with therapies such as radiation, hormonal deprivation and chemotherapy depress cognitive function.  The most affected cognitive domains-- attention, short term memory (working memory),  and executive functions--are fundamental for functioning in all other cognitive domains, but the most difficult to detect using office based tools and the ones most likely to be dismissed as depression or stress.  Research has shown that up to 25% of cancer survivors suffer from persistent cognitive symptoms. 1  There is still much to determine about the underlying causes of symptoms,  risks for elevated and prolonged symptoms, along with effective treatment options.           

CRCI occurs in the context of an individual’s cognitive fingerprint shaped by a lifetime of exposures; each individual brings unique mixtures of structural, genetic, and metabolic strengths and vulnerabilities to the specific effects of cancer and its treatment.  The armature of cognition is the network, groups of neurons that wire together and fire together in service of common overall functions, such as sensory processing (default mode network), conceptual and motor tasks (attention and executive network), language, and visual-spatial functions.  Each of the networks have unique vulnerabilities to specific tumor/cancer treatment effects and particular neurodegenerative and medical conditions.  For example the executive network is the one most susceptible to general inflammation induced by tumors, anticholinergic side effects of medications, and to neurodegenerative Parkinson’s-Lewy body disease.   Conceptually, maintenance of cognitive function is the result of resistance and resilience factors in relationship to the specific tumor and cancer treatment effects.  Resistance consists of processes that prevent pathology and resilience relates to the factors that maintain function despite the presence of pathology.  For example, the Klotho gene attenuates microglial activation underlying cognitive impairment in cancer, a resistance function, whereas  aerobic activity buffers the negative effects of cancer related inflammation, a resilience factor.  Cognitive reserve is a term to describe the net effect of resistance and resilience factors.  The most robust factors for high cognitive reserve are genetic (choosing parents wisely) and early education which engineer structural network integrity.  However, cognitive reserve is an active process throughout a lifetime, the result of physical activity, socialization, and exposure to a wide variety of new and different pursuits.  Thus, it provides a pathway for mitigating CRCI through a wide variety of non-medical interventions. 

CRCI, therefore, is beyond cancer and chemotherapy.  Genetic loading for neurodegenerative diseases, aging related changes in genes, psychiatric and autoimmune diseases can lower reserves.  In addition, an individual’s current health status and habits can worsen symptoms.  Psychiatric symptoms such as depression and anxiety, chronic pain, fatigue and anticholinergic medication burden all have cognitive consequences.  Of fundamental importance to both cognitive and systemic health, however, is sleep.  Often dismissed as function that is best bragged about in its absence, sleep is a biological imperative that if prevented leads first to intrusive episodes of sleep during waking times, and if restricted further, death. Since it is conserved across all species, it must serve constituitive functions.  In brainless animals, it regulates  peripheral metabolic and immune functions fundamental to daily life, but in the evolutionarily advanced animals with brains, it has been adapted to serve the greatest survival tool, cognition. 

Healthy sleep is the foundation for cognitive function. Though for adults a total sleep time of 7 hours is necessary, sleep must progress in a series of uninterrupted orderly stages for both adequate processing of memory and elimination of toxic waste generated by memory building and reshaping.  Any disturbance in sleep, whether sleep apnea, pain, or 21st century electronics, will negatively impact cognition and increase the risk for neurodegenerative disease.   It has been demonstrated that cancer also impacts sleep and researchers are now homing in on the role of sleep in cancer related cognitive impairment (CRCI).   “Acupuncture versus cognitive behavioral therapy for insomnia in cancer survivors: A secondary analysis of a randomized clinical trial” explores the use of two nonpharmacologic interventions to improve sleep subsequently cognitive symptoms. 4  A secondary analysis was performed on subgroup of 99 study participants within an original trial completed in 2019 that had received either acupuncture or cognitive behavioral therapy to improve insomnia.  The Brown Attention Deficit Disorder scale was used to access subjective cognitive function and the Buschke Slelctive Reminding Test to determine objective symptoms of attention, learning and memory.  Both interventions demonstrated benefit in improving cognitive function.  The acupuncture patients that had improved insomnia symptoms showed improved attention, learning and memory along with subjective symptoms.  Research subjects that received CBT-I had improvement in subjective cognitive symptoms irrespective of improved insomnia.  The study was not powered to directly compare both interventions.

NCCN guidelines discourages the nonspecific use of medications such as modafinil, mehylphenidate, memantine and donepezil as first line treatment for CRCI.  These treatments have had mixed results in previous research studies and may add to the side effects created by polypharmacy.  They do not address the negative effects of persisting underlying causes of symptoms.  Individuals with CRCI benefit from a comprehensive evaluation of factors contributing to their cognitive symptoms.  Some of the most effective interventions are nonpharmacologic,  to address such issues as anxiety, depression, insomnia,  and sleep apnea.  Moreover, there is importance to viewing CRCI treatment more broadly as brain health:  diet, exercise, socialization, and passionate engagement in a variety of new and different activities..   The cancer cognitive clinic at UC Health developed by Dr. Rhonna Shatz applies these principles.  The goal is to address the full spectrum of health related inputs that are contributing to symptoms, provide supportive tools through cognitive therapy and integrative options, and promotion of brain health.  Studies such as the one explored in this article provides further clarification for the use of potential treatment options.

Read the reviewed research article


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  2. Allen DH, Myers JS, Jansen CE, Merriman JD, Von Ah D. Assessment and Management of Cancer- and Cancer Treatment–Related Cognitive Impairment. Journal for nurse practitioners. 2018;14:217-224.e5
  3. Zeng Y, Dong J, Huang M, et al. Nonpharmacological interventions for cancer-related cognitive impairment in adult cancer patients: A network meta-analysis. International journal of nursing studies. 2020;104:103514-103514.
  4. Liou KT, Root JC, Garland SN, et al. Effects of acupuncture versus cognitive behavioral therapy on cognitive function in cancer survivors with insomnia: A secondary analysis of a randomized clinical trial. Cancer. 2020;126:3042-3052.
  5. National Comprehensive Cancer Network. Survivorship (Version 3.2021). http:
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  7. Salerno EA, Culakova E, Kleckner AS, Heckler CE, Lin PJ, Matthews CE, Conlin A, Weiselberg L, Mitchell J, Mustian KM, Janelsins MC. Physical Activity Patterns and Relationships With Cognitive Function in Patients With Breast Cancer Before, During, and After Chemotherapy in a Prospective, Nationwide Study. J Clin Oncol. 2021 Oct 10;39(29):3283-3292. doi: 10.1200/JCO.20.03514. Epub 2021 Aug 18. PMID: 34406822; PMCID: PMC8500586.
  8. Shahid M, Kim J. Exercise May Affect Metabolism in Cancer-Related Cognitive Impairment. Metabolites. 2020 Sep 20;10(9):377. doi: 10.3390/metabo10090377. PMID: 32962184; PMCID: PMC7570125 (exercise, inflammation, and CRCI)
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