Elsevier

Seminars in Oncology

Volume 40, Issue 6, December 2013, Pages 709-725
Seminars in Oncology

Cognitive Effects of Cancer and Its Treatments at the Intersection of Aging: What Do We Know; What Do We Need to Know?

https://doi.org/10.1053/j.seminoncol.2013.09.006Get rights and content

There is a fairly consistent, albeit non-universal body of research documenting cognitive declines after cancer and its treatments. While few of these studies have included subjects aged 65 years and older, it is logical to expect that older patients are at risk of cognitive decline. Here, we use breast cancer as an exemplar disease for inquiry into the intersection of aging and cognitive effects of cancer and its therapies. There are a striking number of common underlying potential biological risks and pathways for the development of cancer, cancer-related cognitive declines, and aging processes, including the development of a frail phenotype. Candidate shared pathways include changes in hormonal milieu, inflammation, oxidative stress, DNA damage and compromised DNA repair, genetic susceptibility, decreased brain blood flow or disruption of the blood-brain barrier, direct neurotoxicity, decreased telomere length, and cell senescence. There also are similar structure and functional changes seen in brain imaging studies of cancer patients and those seen with “normal” aging and Alzheimer’s disease. Disentangling the role of these overlapping processes is difficult since they require aged animal models and large samples of older human subjects. From what we do know, frailty and its low cognitive reserve seem to be a clinically useful marker of risk for cognitive decline after cancer and its treatments. This and other results from this review suggest the value of geriatric assessments to identify older patients at the highest risk of cognitive decline. Further research is needed to understand the interactions between aging, genetic predisposition, lifestyle factors, and frailty phenotypes to best identify the subgroups of older patients at greatest risk for decline and to develop behavioral and pharmacological interventions targeting this group. We recommend that basic science and population trials be developed specifically for older hosts with intermediate endpoints of relevance to this group, including cognitive function and trajectories of frailty. Clinicians and their older patients can advance the field by active encouragement of and participation in research designed to improve the care and outcomes of the growing population of older cancer patients.

Section snippets

Aging, Frailty, and Cognitive Decline

Aging is the net effect of the temporal accumulation of damage to cellular processes and systems, loss of compensatory mechanisms, and increased vulnerability to disease and death. Closely aligned to this definition is the clinical concept of frailty, which can be considered a phenotype of aging. This phenotype is characterized by a diminished biologic reserve and resistance to stressors caused by collective declines across physiologic systems, leading to vulnerability to insult and adverse

Models of aging

The constellation of intersecting factors related to cancer-related cognitive decline, frailty, and aging raises several provocative questions: If cancer therapy impacts cognitive function, does the trajectory of dysfunction parallel that of normal aging (phase shift hypothesis), or is the trajectory of dysfunction accelerated in comparison to normal aging (accelerated aging hypothesis)?5 Is the lowest common denominator a depletion of reserve leading to a frail phenotype (reliability theory of

Measurement Issues

There are many methodological considerations in studying the complex interactions between cancer, cancer therapy and cognitive function. In this section we highlight several concerns specific to evaluations of the role of aging and needs of older patients. For excellent reviews of international consensus panels on methods for studying cancer and cognition the reader is referred to summaries of the International Cognition and Cancer Task Force.35, 142, 151

First, this is a field that will require

Practice Implications

From the preceding review it is apparent that there is a fairly strong body of evidence linking aging processes to cancer-related cognitive declines. But it is also clear that there are many unanswered questions. While the research community grapples with how to provide rigorous empiric evidence for older cancer patients, clinicians are faced every day with caring for the growing number of older cancer patients presenting to their practices. What then are the implications of what we think we

Conclusions

There is a strong albeit non-universal body of literature supporting the phenomenon of cognitive decline after breast cancer and its systemic therapies. This side effect is likely to be only experienced by a sub-group of patients, and while risk factors have been identified, biological mechanisms and pathways have not been fully elucidated. From what we do know, it appears that there are common underlying processes at the intersection of cancer, aging and the frail phenotype. Geriatric

References (177)

  • J.L. Ross et al.

    The Turner syndrome-associated neurocognitive phenotype maps to distal Xp

    Am J Hum Genet

    (2000)
  • B.S. McEwen et al.

    Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain

    Exp Gerontol

    (1994)
  • B.B. Sherwin

    Estrogen and cognitive aging in women

    Neuroscience

    (2006)
  • T.C. Unfer et al.

    Influence of hormone replacement therapy on blood antioxidant enzymes in menopausal women

    Clin Chim Acta

    (2006)
  • V.A. Jenkins et al.

    Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II)

    Lancet Oncol

    (2008)
  • C.M. Bender et al.

    Cognitive function and reproductive hormones in adjuvant therapy for breast cancer: a critical review

    J Pain Symptom Manage

    (2001)
  • V. Shilling et al.

    The effects of oestrogens and anti-oestrogens on cognition

    Breast

    (2001)
  • G. Joshi et al.

    Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug Adriamycin: implications for oxidative stress-mediated chemobrain

    Neuroscience

    (2010)
  • J. Blasiak et al.

    Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer

    Mutat Res

    (2004)
  • L. Migliore et al.

    Chromosome and oxidative damage biomarkers in lymphocytes of Parkinson's disease patients

    Int J Hyg Environ Health

    (2001)
  • L. Migliore et al.

    Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients

    Neurobiol Aging

    (2005)
  • K.W. Caldecott

    DNA single-strand breaks and neurodegeneration

    DNA Repair (Amst)

    (2004)
  • R.L. Rolig et al.

    Linking DNA damage and neurodegeneration

    Trends Neurosci

    (2000)
  • Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality-All COD,...
  • United States Census Bureau, U.S. Department of Commerce, Economics and Statistics Administration. Population by age,...
  • P.M. Silberfarb

    Chemotherapy and cognitive defects in cancer patients

    Annu Rev Med

    (1983)
  • B. Eberhardt et al.

    Short-term monitoring of cognitive functions before and during the first course of treatment

    J Cancer Res Clin Oncol

    (2006)
  • T.A. Ahles et al.

    Cancer- and cancer treatment-associated cognitive change: an update on the state of the science

    J Clin Oncol

    (2012)
  • H.S. Jim et al.

    Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy

    J Clin Oncol

    (2012)
  • T.A. Ahles et al.

    Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve

    J Clin Oncol

    (2010)
  • J. Campisi

    Aging, cellular senescence, and cancer

    Annu Rev Physiol

    (2013)
  • D. Head et al.

    Frontal-hippocampal double dissociation between normal aging and Alzheimer's disease

    Cereb Cortex

    (2005)
  • T. Hedden et al.

    Healthy and pathological processes in adult development: new evidence from neuroimaging of the aging brain

    Curr Opin Neurol

    (2005)
  • A.J. Saykin et al.

    Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives

    Semin Clin Neuropsychiatry

    (2003)
  • S.K. Conroy et al.

    Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage

    Breast Cancer Res Treat

    (2013)
  • R. Siegel et al.

    Cancer statistics,. 2013

    CA Cancer J Clin

    (2013)
  • American Cancer Society. Breast cancer facts & figures. 2011-2012. Atlanta: American Cancer Society, Inc. Assessed May...
  • S.J. Jansen et al.

    Explaining differences in attitude toward adjuvant chemotherapy between experienced and inexperienced breast cancer patients

    J Clin Oncol

    (2005)
  • C. Anderson-Hanley et al.

    Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature

    J Int Neuropsychol Soc

    (2003)
  • D.D. Correa et al.

    Neurocognitive changes in cancer survivors

    Cancer J

    (2008)
  • A. Stewart et al.

    A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer

    Clin Neuropsychol

    (2006)
  • B.J. Small et al.

    Catechol-O-methyltransferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors

    Cancer

    (2011)
  • P.A. Ganz et al.

    Does tumor necrosis factor-alpha (TNF-alpha) play a role in post-chemotherapy cerebral dysfunction?

    Brain Behav Immun

    (2012)
  • T.A. Ahles et al.

    Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma

    J Clin Oncol

    (2002)
  • T.A. Ahles

    Brain vulnerability to chemotherapy toxicities

    Psychooncology

    (2012)
  • V. Koppelmans et al.

    Neuropsychological performance in survivors of breast cancer more than. 20 years after adjuvant chemotherapy

    J Clin Oncol

    (2012)
  • A. Hurria et al.

    Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient's perspective

    Breast Cancer Res Treat

    (2006)
  • R.J. Freilich et al.

    Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients

    Neurology

    (1996)
  • T.H. Yamada et al.

    Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy

    J Neuropsychiatry Clin Neurosci

    (2010)
  • A. Hurria et al.

    Is cognitive dysfunction a complication of adjuvant chemotherapy in the older patient with breast cancer?

    Breast Cancer Res Treat

    (2007)
  • Cited by (0)

    This research was supported by the National Cancer Institute (NCI) at the National Institutes of Health (NIH) grant no. R01CA129769; in part by NCI, NIH grants no. U10 CA 84131, R01CA 127617, and K05CA096940 to J.S.M.; and by NCI, NIH grant no. P30CA51008 to Lombardi Comprehensive Cancer Center (synergy developmental funds to J.S.M. and J.V.M.). The work of A.J.S. and B.C.M. was supported in part by R01 CA101318, P30 CA082709, R25 CA117865, U54 RR025761, C06 RR020128, S10 RR027710, R01 AG019771, P30 AG010133, F30 AG039959, and U24AG021886. The work of R.A.S. was supported by NIH grant no. P30-AG13846 to Boston University Alzheimer’s Disease Center. The work of A.H. was supported in part by NIH grant no. U54 132378 and by the Starr Foundation.

    Financial disclosures: Hurria: Seattle Genetics, Amgen Pharmaceuticals, and Genetech (consultation); Glaxo Smith Kline, Abraxis Bioscience, and Celgene (research support). All remaining authors have declared no conflicts of interest.

    View full text