Cognitive Effects of Cancer and Its Treatments at the
Intersection of Aging: What Do We Know; What Do We
Need to Know?
Jeanne S. Mandelblatt,aArti Hurria,bBrenna C. McDonald,cAndrew J. Saykin,dRobert A. Stern,e
John W. VanMeter,fMeghan McGuckin,gTiffani Traina,hNeelima Denduluri,iScott Turner,f
Darlene Howard,jPaul B. Jacobsen,kand Tim Ahles,l,mfor the Thinking and Living With Cancer Study
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
0093-7754/-see front matter
& 2013 Elsevier Inc. All rights reserved.
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.
Address correspondence to Jeanne S. Mandelblatt, MD, MPH, Lombardi Comprehensive Cancer Center, 3300 Whitehaven Blvd, Suite 4100,
Washington, DC 20007. E-mail: email@example.com
aDepartments of Oncology and Population Sciences, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
bDepartment of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA.
cCenter for Neuroimaging, Department of Radiology and Imaging Sciences and the Melvin and Bren Simon Cancer Center, Indiana University School
of Medicine, Indianapolis, IN.
dCenter for Neuroimaging, Department of Radiology and Imaging Sciences and the Melvin and Bren Simon Cancer Center, Indiana University School
of Medicine, Indianapolis, IN.
eDepartments of Neurology and Neurosurgery and Director, Clinical Core, BU Alzheimer’s Disease Center, Boston University School of Medicine,
fDepartment of Neurology, Georgetown University Medical Center, Georgetown University, Washington, DC.
gDepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
hDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
iDepartment of Medicine, Georgetown University; Virginia Cancer Specialists, US Oncology, Arlington, VA.
jDepartment of Psychology, Georgetown University, Washington, DC.
kDivision of Population Science, Moffitt Cancer Center, Tampa, FL.
lDepartment of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY.
mDepartment of Psychiatry, Weill Cornell Medical College, New York, NY.
Seminars in Oncology, Vol 40, No 6, December 2013, pp 709-725
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.
Semin Oncol 40:709-725 & 2013 Elsevier Inc. All rights reserved.
year 2030.2As these individuals develop cancer, they
are at risk of experiencing adverse cognitive effects
of this disease and its local and systemic therapies.
described three decades ago,3and a fairly consistent,
albeit not universal, picture of these deficits has
evolved to the present.4–6There are a striking
number of common underlying biological risks and
pathways for the development of cancer and cancer-
related cognitive declines and aging processes.
These commonalities may have implications for the
clinical care of the growing number of older cancer
Breast cancer is an ideal disease for inquiry into
the intersection of aging and cognitive effects of
cancer and its therapies because it is the second
most common cancer in women,14with more than
50% of new cases occurring among women 65 and
older,1,15and its treatment has historically included
a high rate of use of systemic chemotherapy and/or
hormonal therapy. There is also the largest body of
empiric evidence about the cognitive aspects of
breast cancer and its treatments, compared to other
Most controlled investigations and meta-analyses
of the studies of the effects of breast cancer therapy
on cognitive function report decrements in one or
more domains, including verbal working memory,
visual memory and visual-spatial domains, executive
function (including working memory), and/or proc-
essing speed compared to pretreatment cancer and/
declines have been observed to persist for variable
periods of time from 1 year16,22to as many as 10–20
years post-treatment.23–25Unfortunately, the mean
age in the most recent meta-analysis of the cognitive
effects of breast cancer therapy was 53 years6and
only a few studies have been designed to examine
outcomes for older patients.4,26–29
High rates of objective and subjective cognitive
impairment have been reported in most studies of
ancer is largely a disease of older age.1With
the graying of America, one in five individu-
als will be 65 years or older (“older”) by the
older breast cancer patients.28–30However, variable
rates of cognitive decline have been noted in other
studies that include older cancer patients.4,27,31–34
All of these reports have had small samples of older
patients (n ¼ 13–50),4,27,30some have focused on
patients treated in mid-life and evaluated at age 65 or
older,28and only one was able to examine age
interactions.7In that study, Ahles and colleagues
found that women aged 60–70 years with low base-
line cognitive reserve who underwent chemother-
apy had lower performance on tests of processing
speed compared with those not receiving chemo-
therapy and controls (Figure 1).5,7Thus, it is possible
that only a subgroup of older patients (or patients at
any age) experience cognitive effects after systemic
cancer therapy.6,7,35However, there is only limited
empiric evidence about the risk factors that define
vulnerable groups, and even less for older cancer
Here, we present a framework for considering the
relationships among the key constructs involved in
evaluating the cognitive effects of cancer and its
treatments at the intersection of aging, review some
potential shared biological mechanisms and how
they fit within current theories of aging, discuss
methodological challenges in conducting research
on this topic in the older population, and summarize
the clinical implications of these results for the care
of the growing older population diagnosed with and
surviving with cancer.
AGING, FRAILTY, AND COGNITIVE DECLINE
Aging is the net effect of the temporal accumu-
lation 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 collec-
tive declines across physiologic systems, leading to
vulnerability to insult and adverse outcomes.36
J.S. Mandelblatt et al710
Fried and colleagues initially described the frail
phenotype as having three of five of the following
criteria: weight loss, exhaustion, low physical activ-
ity, slow walking gait, and poor grip strength.36
Although this original phenotype did not include
cognitive function, it is now widely recognized as
one of the key factors involved in the impaired
physiologic pathways leading to frailty.37–40The
converse is also true: individuals with frailty are
more vulnerable to the development of cognitive
disorders (eg, Alzheimer’s disease) and to cognitive
decline after stressors such as cancer therapy
(Figure 2).7,24,41Further, frailty and cognitive deficits
each are independently associated with high risks
of dependence and mortality. For example, selected
measures of cognitive function, such as the Trail
Making Test, have been noted to predict physical
frailty as measured on the Short Physical Perform-
ance Battery, as well as mortality in older individuals
in the general population.42Identifying the biolog-
ical underpinnings of these associations and disen-
tangling their temporal and etiological relationships
is an important research priority and an area of
From what we do know, it seems that there are
several potential common pathways. Observations that
biomarkers of inflammation such as high C-reactive
protein (CRP) and high interleukin-6 (IL-6) are seen in
the frail phenotype,43senescence,9,44,45and cognitive
declines in Alzheimer’s disease46and after cancer
therapy22,47suggest one potential common biolog-
ical pathway. There is also overlap in the genotypes
(eg, apolipoprotein E gene [APOE] polymorphisms)
associated with cancer related cognitive declines,
(a) WRAT belowmedian
Standardized Change in Processing Speed
Chemotherapy ControlChemotherapy Control
(b) WRAT abovemedian
3049 year olds
Figure 1. Pre- to post-treatment change in processing speed by treatment, age groups, and level of cognitive reserve
(assessed by the Wide Range Achievement Test [WRAT]-Reading). Reprinted with permission from Ahles, et al. 2012,
Journal of Clinical Oncology.5
Figure 2. The same change in brain resources can have
a minimal effect on cognitive performance in a young
adult (a), a moderate effect in an older adult with high
cognitive reserve (b) and a greater effect on an older
adult with low cognitive reserve (c). Likewise, the same
change in frailty level will have differential effects on the
individual as a function of overall system reserve.
Adapted and reprinted with permission from Ahles
et al, Psychooncology, 2012.24
Cognitive effects of cancer and its treatments711
Alzheimer’s and their associated frailty pheno-
types.24,48–50Further support of the concept of
common underlying biological processes is based
on the recent body of evidence demonstrating
similar brain structural alterations in aging, cancer-
related cognitive declines, and Alzheimer’s disease,
including decreases in overall brain volume, gray
matter, white matter connectivity and hippocampal
volume.5,13,25,51–54Finally, the observation that can-
cer patients have lower cognitive function than
expected based on age and education even before
any treatment5,55suggests, as depicted in Figure 3,
that there are common underlying risks for cancer
and cognitive decline, and that both are in part age-
related phenomena. In the next section we highlight
some of the research on the potential common
pathways related to the pathogenesis of cognitive
decline, frailty, and aging.
Common Biological Pathways
Most consider that cancer and aging are linked,
although the molecular mechanisms responsible for
the increasing risk of cancer with increasing age and
frailty are not completely understood. Aging is
clearly related to neurodegenerative diseases such
as Alzheimer’s disease. It is also biologically plausible
that cancer and neurodegenerative conditions are
linked, since they have some common pathways
related to the cell cycle (eg, p53 proteins and
the peptidylprolyl cis/trans isomerase 1 [Pin1] pro-
tein), albeit in opposing directions, with cancer
related to proliferation and Alzheimer’s related to
In this broad context, the precise biological
mechanisms and pathways underpinning cognitive
decline after cancer and/or its treatments remain
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 or damage to specific brain
regions, decreased telomere length, and cell senes-
cence (Figure 3).5,8,51,59–62
Hormonal levels decrease over the lifespan and
have been implicated in cognitive function in non-
cancer populations63and hormonal replacement
therapy has been noted to decrease the risk of
Alzheimer’s disease by up to 29%.64–69Breast cancer
hormonal therapies act by blocking or lowering
hormonal levels in individuals with estrogen recep-
tor–positive tumors. Possible mechanisms by which
hormonal treatment could affect cognition include
decreases in cholinergic activity,66,70reduced induc-
tion of serotonin receptors,71direct toxic effects on
changes in lipids.74Since estrogen also has anti-
oxidant effects75,76and maintains telomere length,77
breast cancer hormonal therapies that block estro-
gen also may exert their negative effects on cogni-
tion via accelerating aging.
The role of hormonal change is supported by the
body of research demonstrating decrements in cog-
nitive function among women receiving systemic
hormonal therapy, either alone or with chemother-
apy.78–83However, effects are not universal and may
not be observed with all hormonal therapies. For
example, a recent clinical trial reported by Schilder
et al noted cognitive declines in verbal memory and
executive function among women treated with
tamoxifen but not exemestane.79This result is bio-
logically plausible since estrogen can be neuropro-
tective, and estrogen receptors, the targets of
tamoxifen and other drugs in its class, are found in
large numbers in the frontal lobe and hippocam-
pus84–87; these same areas have been noted to have
abnormalities on imaging studies.53,88In contrast,
exemestane, one type of aromatase inhibitor, blocks
conversion of androgens into estrogens, and its
metabolites have mild androgenic properties. Since
androgens can enhance cognition, this may be one
explanation for the relative lack of impairment due
to this particular hormonal regimen. However,
results for the effect of other hormonal therapies
on cognition have been inconsistent.79–81One intri-
guing finding of the Schilder trial comparing hormo-
nal therapies was a preliminary result which showed
that tamoxifen had larger effect sizes and affected
a greater number of cognitive domains in women 65
Figure 3. Postulated common underlying aging pro-
cesses associated with frailty, cancer, and cancer sys-
temic therapy and their impact on cognitive outcomes.
J.S. Mandelblatt et al712
and older compared to women less than 65 years of
age.79It will be important to replicate this finding
and to examine the role of different types of estro-
gen receptors in brain tissue, especially if hormonal
therapies will be recommended for longer periods of
Inflammatory responses involved in aging, cancer,
and/or generated by cancer-directed agents have
been suggested as one pathway for cognitive
declines via triggering of neurotoxic cytokines.89A
study by Ganz and colleagues examined several pro-
inflammatory cytokines in breast cancer patients.
They found that soluble tumor necrosis factor-alpha
receptor II (sTNF-RII) levels were significantly higher
in those who received chemotherapy compared to
those who did not, but that levels declined over
time. Of note, the higher sTNF-RII levels were
associated with self-reported memory complaints
and decreased brain metabolism in frontal regions
on positron emission tomography (PET) scans, and
subjective cognitive function improved as sTNF-RII
levels declined over the 1-year follow-up.22Other
inflammatory cytokines were not associated with
neurocognition and the relationships were not sig-
nificant after controlling for fatigue levels, suggesting
that fatigue and cognitive declines both might share
a common inflammatory etiology. Unfortunately,
assessments occurred after initial therapy, so that
the separate effects of having cancer could not be
assessed; the study also lacked a control group and
was focused on the effects of menopause and
hormonal therapy in younger women, so it may
not be generalizable to pathways related to aging.
Also, since aging is associated with the accumulation
of multi-morbidities that affect or are the result of
inflammatory pathways (eg, diabetes, heart dis-
ease),90it will require careful sampling and sub-
inflammation related to cancer in studying cognitive
outcomes and to control for fatigue components
of frailty phenotypes. This will be an important area
for future research.
DNA Damage and Repair
Oxidative DNA damage, as measured in lympho-
cytes, has been noted in breast cancer patients both
before any systemic therapy and after chemother-
apy.13,91,92Conroy and colleagues recently con-
ducted an innovative study with breast cancer
survivors and matched non-cancer controls. The
sample ranged in age from 41 to 79 years; the cancer
patients were 3–10 years post-treatment. They found
that oxidative DNA damage was higher in patients
than controls and that DNA damage was correlated
with self-reported cognitive problems, lower cogni-
tive function, and less frontal gray matter density and
brain activation on functional magnetic resonance
imaging (fMRI).13While only a small number of
patients was assessed (n ¼ 48), the result is interest-
ing because oxidative DNA damage and diminished
DNA repair mechanisms are also markers of senes-
cence,44and are seen in age-related diseases includ-
ing Parkinson’s disease, mild cognitive impairment,
and Alzheimer’s disease.93,94Hormonal therapies
also may be associated with increased DNA dam-
whereby DNA damage leads to cognitive decline is
unclear, but it is postulated to be related to either
production of defective proteins that lead to neuro-
nal apoptosis96or to problems in transcription that
cause the loss of required gene protein products.97
It also should be noted that DNA damage can trigger
cytokine release, which in turn increases oxidative
stress and further DNA damage.98,99How these
processes are affected by age-related DNA damage
or chronic inflammation related to other non-cancer
comorbidities is unclear and will need to be disen-
tangled to understand fully the mechanisms of
cognitive decline in older cancer patients.
There is considerable variability across individuals
in presence and extent of cognitive changes associ-
ated with cancer and cancer treatment. The obser-
differentially affected strongly suggests that genetic
influences may modulate the influence of exposure
to cancer pathophysiology or treatment.12,51,100
studied for associations with cognitive changes after
cancer treatment21,24but numerous other candidate
genes may play a role.51,100Many of these genes
have a role in age-related cognitive decline.
APOE is located on chromosome 19 and was first
identified as a risk for Alzheimer’s disease in the early
1990s.101It remains the leading known genetic risk
for this disease. It codes for ApoE, a complex
lipoprotein known to play a role in lipid transport
and regulation of inflammatory immune activity,
among other biological functions. In the central
nervous system, ApoE is also involved in amyloid
beta metabolism, a key substrate of Alzheimer’s, as
well as neural repair processes after brain injury and
brain plasticity. APOE has three alleles (ε2, ε3, and
ε4 variants), which are, in turn, determined by two
single-nucleotide polymorphisms (SNPs), rs7412 and
rs429358. APOE ε4 is the adverse risk allele that
confers risk of Alzheimer’s102and is associated with
poor recovery after stroke and trauma.103,104
Cognitive effects of cancer and its treatments713
Ahles and colleagues noted that breast cancer
survivors who received chemotherapy and were APOE
ε4–positive had greater cognitive decline in the visual-
spatial and visual memory domains compared to
ε4-negative survivors receiving this treatment (average
age, 56 years).24However, the relationship between
APOE and cognitive outcomes has not been consistent
in the few other studies to examine this question
among breast cancer patients,54although they often
were not designed to have power to detect genetic
influences. APOE also has been noted to be a risk
factor for the development of breast cancer105or
a moderator of fat and obesity risks of breast cancer.106
If APOE polymorphisms are linked to risk of disease,
especially more aggressive types of disease or larger
tumors (seen in obese women), and women with
these tumors are differentially more likely to receive
chemotherapy, then APOE–post-treatment relation-
ships may be confounded.
Adding to the complexity are the observations
that polymorphisms of estrogen receptors also influ-
ence ApoE synthesis107,108and interact with ApoE in
risk for Alzheimer’s,109so there may be treatment–
gene interactions in producing cognitive decline.
This idea is supported by one study of non-cancer
patients where hormone replacement therapy was
only protective of cognitive decline among women
without an ApoE ε4 allele.110It will be important to
test these hypotheses directly in future studies of
cognitive outcomes in older breast cancer patients
receiving different types of hormonal therapy, espe-
cially as recommendations for this modality are
extended from 5 to 10 years of treatment.111,112
The other gene studied specifically in cancer
patients with regard to cognitive outcomes is
COMT, located on chromosome 22q11. COMT
codes for catechol-O-methyltransferase, an enzyme
that metabolizes catecholamine neurotransmitters
including dopamine, epinephrine, and norepinephr-
ine; the Val158Met SNP (rs4680) in COMT (sub-
stitution of methionine
dopamine break down and decreases synaptic neuro-
transmitter levels. COMT plays an important role in
dopamine regulation in the frontal lobes and has
been shown to be associated with executive func-
tion in normal controls. In a study of cancer and
cognition by Small and colleagues, breast cancer
patients treated with chemotherapy who were
COMT-valine carriers performed worse on measures
of attention compared to COMT-methionine homo-
zygotes, although the average age of these women
was 51 years.21Of note, Lindenberger et al have
found an age interaction with the COMT gene.113
Brain-derived neurotrophic factor (BDNF) is
another gene involved in neuron growth and repair
and is found primarily in the prefrontal cortex and
hippocampus.114,115A functional polymorphism of
BDNF has been associated with lower memory and
executive function in non-cancer populations.116–118
Lindenberger and colleagues observed interactions
between BDNF, COMT, and age.
underscores the complex interplay between aging,
declining reserve, and genetic factors. Overall, the
role of BDNF and other neural and glial growth
factors appears promising for investigation in cancer
Some other SNPs also have been implicated in
cognitive decline among cancer patients. In a pre-
liminary report, Ganz reported that the TNF-alpha-
308 promoter SNP was associated with the level of
self-reported memory problems after cancer treat-
ment,119,120consistent with the posited role of an
inflammatory mechanism in the etiology of this
Variations in genes that affect blood-brain barrier
transporters also could be involved in mediating the
direct neurotoxicity of some chemotherapeutic
agents, since in animal models, only small doses
are needed to produce neuronal cell death.51,61,121
For example, the multidrug resistance 1 (MDR1)
gene encodes the protein P-glycoprotein (P-gp); P-gp
influences the level of a chemotherapeutic agent in
the brain.51,122Polymorphisms of the MDR1 gene
(eg, C3435T in exon 26)123could influence P-gp
function such that a sufficient amount of drug
reaches neuronal cells to directly cause toxicity.
An emerging area of genetic investigation is
related to microRNAs (miRNA). miRNAs are very
small non-coding RNAs that are becoming increas-
ingly recognized as playing a major role in regulating
gene expression and cell metabolism in cancer and
examined the relationship between the functional
roles of miRNAs in cancer and Alzheimer’s disease as
two age-associated disorders.48Numerous other can-
didate genes and pathways are thought to potentially
may play a role in cognitive changes associated with
Alterations in Blood-Brain Barrier and Other
Many systemic chemotherapies including anthra-
cyclines do not appear to cross the blood-brain
barrier. Exceptions may include those included in
the cyclophosphamide, methotrexate, and fluorour-
acil (CMF) regimen.89,124Since older patients may
remain more likely to get CMF regimens due to the
higher cardiac and other toxicity profiles seen with
anthracycline regimens, older breast cancer patients
may be at higher risk for direct neurotoxicity, under-
scoring the need to carefully consider specific agents
when studying outcomes among older patients.
J.S. Mandelblatt et al714
Other factors that affect vascular function125have
been implicated in aging and cognitive performance,
such as smoking and low levels of high-density
lipoproteins (HDL).100,126,127Interestingly, nicotine
and statin medications seem to be protective of
cognitive decline, so that these relationships are
not straightforward.125,128Similar to observations
in cancer patients, there also appear to be interac-
tions between cerebrovascular disease or diabetes
and the ApoE ε4 allele in producing memory impair-
ments.17,18,129These observations could help to
identify subgroups of older cancer patients at risk
for cognitive declines related to vascular factors.
Structural and Functional Brain Changes on
To the extent that cancer treatments may accel-
erate or mimic the effects of aging, some overlap in
brain structures affected by cancer treatments and
aging is expected. Imaging studies have demon-
strated that total gray matter volume reliably
decreases with advancing age, with regional changes
exhibited mainly in the frontal cortex and in regions
around the central sulcus, including the hippocam-
pus.130Lower hippocampal volume is related to
memory functioning and has been observed in breast
cancer patients after treatment.131White matter also
diminishes with increasing age.130,132Reduction in
volume of frontal brain structures and changes in the
integrity of white matter tracts have been reported
after chemotherapy, as have alterations in brain
activation on functional neuroimaging.12,13,25,133–139
Of note, there appear to be pretreatment cancer
effects as well, with altered frontal cortex activation
noted with fMRI during tasks in breast cancer
patients relative to healthy controls.140,141Similar
abnormalities related to breast cancer treatment
have been observed using functional positron emis-
sion tomography (PET) and electro-physiological
methods.142There are also differences in resting
state between breast cancer patients and controls.143
However, all of these imaging studies have been
among breast cancer patients under age 65 years.
Imaging studies in older patients will be critical to
confirming the brain structural links between cancer
Over the life course, telomeres shorten with each
cell replication, ultimately leading to cell senescence
(see below) and apoptosis, so that leukocyte telo-
mere length has been used an a marker of cellular
age with shorter length indicating a greater degree of
senescence. As such, telomere health has been
linked to aging, Alzheimer’s disease severity, cancer
risk, and mortality rates.144For example, patients
with Alzheimer’s have been observed to have shorter
telomeres than controls, and shorter length also has
been associated with greater disease severity.144
Cancer chemotherapy also has effects on telomere
length, and this could be another common pathway
between aging and cancer-related cognitive decline
via effects on replicating cells.62,145–147
Senescence refers to the state of cells that are
metabolically active but can no longer replicate.
Many of the same factors that we have been discus-
sing as common potential causal pathways to aging
and to cognitive decline after cancer and cancer
therapy have been implicated as stressors that can
lead to cell senescence.8,148Senescent cells evoke
inflammatory responses and accumulate at sites of
pathology, including Alzheimer’s plaques.8,148Sen-
escent cells also can be considered a biomarker of
the frailty phenotype9that places cancer patients at
risk for cognitive declines. The targets for cancer
treatments could potentially negatively affect bio-
logic markers of aging such as senescence, since
there is a reciprocal relationship between tumor
suppression and senescence in healthy cells. For
example, increases in tumor-suppressor mechanisms
through p53/p21 and p16INK4a/pRB and other path-
ways are under investigation as leverage points for
cancer treatment but also are associated with
increased cell senescence, and could therefore accel-
erate aging and increase risk for cognitive toxic-
ity.8,148Thus, it will be important to consider
senescence and the translation of the basic science
of aging into clinical studies of the impact of cancer
and new systemic cancer therapies on cognitive
outcomes in older patients.
Taken together, this body of mechanistic research
suggests that biologic processes underlying cancer,
the impact of cancer treatments, aging, and cogni-
tive decline are linked, and that cancer treatments
may actually accelerate the aging process.62As with
most conditions, not all breast cancer patients
develop cognitive effects related to their cancer or
its treatments, underscoring the need to identify the
subgroup with the highest risk of cognitive decline.
Overall, age-related phenotypes such as frailty and
diminished cognitive and overall reserve and bio-
markers reflecting senescence and aging processes
are logical candidates for identifying patients at high
risk of cognitive decline.5
MODELS OF AGING
The constellation of intersecting factors related to
cancer-related cognitive decline, frailty, and aging
raises several provocative questions: If cancer
Cognitive effects of cancer and its treatments 715
therapy impacts cognitive function, does the trajec-
tory 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)?5Is the lowest
common denominator a depletion of reserve leading
to a frail phenotype (reliability theory of aging)?
As depicted on Figure 4, the phase shift theory
postulates that cancer patients experience decre-
ments in cognitive function compared to their non-
cancer counterparts, and those decrements remain
constant over time. Alternatively, if cancer and its
treatment are actually accelerating aging processes,
we would expect that the slope of decline in
cognitive function would be steeper for patients
relative to their non-cancer cohorts. The relativity
theory of aging149further posits that declines in
cognitive function are a function of overall system
redundancy and repair (ie, net reserve), so that
patients who are frail would be expected to show
the steepest decline and those with less frailty (and
greater reserve) would decline at a slower rate.
These differences would not be appreciated by only
examining the average trajectory (see also Figure 2).
Beyond cancer and cancer therapies, access to
healthcare and management of chronic disease and
lifestyle factors such as exercise or smoking would
affect reserve and system failures. In the reliability
theory, frailty would be considered as the failures of
An important strength of the reliability theory for
studying cognitive effects of cancer and its treat-
ments in older patients is that it does not depend on
a given treatment affecting a specific biologic path-
way.5As noted by Ahles and colleagues, different
patterns of failure across various biologic systems
may confer more or less risk of specific treatments
for each patient: one patient may be vulnerable to
DNA damaging effects of a particular chemotherapy
regimen, whereas another patient may be suscepti-
ble to the impact on the hormonal milieu of endo-
crine treatments. Implicit in this conceptualization is
the idea that the trajectories of cognitive decline are
dependent on pre-morbid cognitive and other sys-
tem reserve. One practical implication for future
research is the need for pretreatment assessments
and evaluation of self-reported function prior to
cancer diagnosis. Viewed through the lens of aging
theories, researchers also may want to specifically
investigate discrete trajectories, rather than group
averages when assessing temporal trends in cogni-
There are many methodological considerations in
studying the complex interactions between cancer,
cancer therapy and cognitive function. In this sec-
tion we highlight several concerns specific to eval-
uations of the role of aging and needs of older
patients. For excellent reviews of international con-
sensus panels on methods for studying cancer
and cognition the reader is referred to summaries
of the International Cognition and Cancer Task
First, this is a field that will require transdiscipli-
nary collaboration between basic scientists and
clinical researchers, including gerontologists and
geriatricians. One obvious methodological basic sci-
ence issue is the need to use older animals or
Figure 4. Trajectories of cognitive decline based on theories of aging and frailty phenotype. Adapted with permission
from Ahles, et al, 2012, Journal of Clinical Oncology.5
J.S. Mandelblatt et al716
systems that mimic aging systems, since the aging
tissue microenvironment can have important effects
on age-related chronic disease phenotypes and cog-
nitive processes.9Kirkland has suggested use of
chronologically aged mouse chronic disease models,
progeroid-bred with chronic disease mouse models,
or chronic disease mouse models treated with “age-
accelerating” interventions such as high-fat diets.9
Likewise, in human studies, the greatest challenge
to understanding the complex interplay of cancer
and its therapy against the backdrop of aging proc-
esses is the lack of inclusion of the older age group
in many research studies and clinical trials. As noted
in the preceding sections, it will be important to
include sufficient numbers of older patients to
capture variability in reserve and frailty, effects of
different classes of therapeutic agents, and the
impact of other chronic diseases and biological
To fully understand the trajectory of cognitive
declines, it is also essential to assess baseline func-
tion and follow patients longitudinally. A well-
matched non-cancer control group is also essential
to valid inference but can be difficult in older
populations given the high rates of cognitive disor-
ders and other chronic diseases and medications that
affect cognition. Thus, well-specified inclusion cri-
teria and matching based on multi-morbidities
should be considered. Care must be taken to use
instruments that are validated in the target popula-
tion. Moreover, issues of “cognitive reserve”7,152
must be taken into account through appropriate
control for estimated premorbid ability, educational
attainment, and other proxy measures of this
construct. Although many investigators strive for
patients, in part because of the need to avoid
potential fatigue effects from longer test batteries,
it is critical that the brevity is balanced by an
hypothesized to be impacted by treatment (Table 1).
Recruiting older participants also requires sensi-
tivity to needs of this group, including the need for
larger fonts, hearing and ambulatory assistance,
pacing of testing sessions, and having protocols to
address research-detected cognitive decline.
To the extent feasible, studies should include
frailty measures and other markers of age-related
processes and biospecimens for correlative science
analyses to elucidate biologically plausible mecha-
nisms specific to older hosts (eg, markers of cell
Analyses of data from older patients could con-
sider use of trajectory analysis153in addition to use
of group means and changes in group means.
Informative missing data on covariates and cognitive
outcomes as well as the impact of practice effects
will be especially important to consider when fol-
lowing older age groups longitudinally. As in other
observational research, the analysts will need to
consider the role of confounding due to the com-
mon factors affecting systemic treatment selection
and those placing older women at risk for cognitive
Across a variety of cancers and types of treatment,
the magnitude of cognitive effect tends to vary by
choice of control group; this has not been empiri-
cally evaluated in older patients but should be even
Table 1. Domains of Cognitive Function Frequently Affected by Cancer and Cancer Systemic
Therapy and Their Implications for Daily Activities in Older Cancer Patients
DomainCommon TestsExamples of Impact on Functioning
Trailmaking Parts A & B, Digit Symbol,
Controlled Oral Word Association
Test (COWAT), NAB Driving Scenes,
Timed Instrumental Activities of Daily
Living (TIADL), NAB Figure Drawing
NAB Digits Forward, NAB Digits
Ability to organize activities, arrive on
time, make plans and decisions,
correct errors and conceptualize.
Attention Ability to pay attention to new
information and process the
Learning and Memory Logical Memory I and II Wechsler
Memory Scale (WMS-4), NAB List
Visual spatial NAB Figure Drawing Copy Subscale
Boston Naming Test, Category Fluency Ability to fluently bring words to mind.
Ability to learn or recall new
Ability to integrate visual information
with motor activities.
Cognitive effects of cancer and its treatments717
more important than in studies of younger patients.
For example, in several meta-analyses, the largest
effects (medium to large effects based on standard
deviation effect sizes) were noted when cancer
patients were compared to population normative
values; moderate changes were seen when patients
were compared to healthy non-cancer controls
matched on age and education.17,18,20,154,155In
studies of younger breast cancer patients, effects
appear to be the smallest when patients are com-
pared to their own baseline, pretreatment func-
tion,154although practice effects may account for
some of the lack of effect if alternative forms of tests
are not employed. As suggested by Ahles, Wefel, and
others, these average effects may mask meaningful
declines among subgroups. As they note, when
declines in performance are combined with improved
performance as a result of practice for the majority of
patients, the effect of chemotherapy on cognitive
declines may be underestimated.34,156
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 know about
cancer-related cognitive decline for the care of older
breast (and other) cancer patients?
The obvious implication for oncology training is
that it includes education on geriatric assessment
and that geriatric assessments should be part of
routine care since they can provide information on
frailty phenotypes and reserve.157The results of
geriatric assessment could be used as a tool for
identifying subgroups of older patients who are
likely to be at highest risk for cognitive decline after
systemic therapy. This information could be used
together with clinical data and results of tumor
multi-gene profiles in discussions with patients
about the balance of benefits and harms of systemic
therapy. Geriatric assessment data could change
treatment recommendations, especially when indi-
cations for systemic therapy are equivocal, since
cognitive changes are among the symptoms most
feared by older adults.158–161
Geriatric assessment also could be used to identify
the population of “pre-frail” older cancer patients
that might need close monitoring and intervention
during and after cancer systemic therapy. In addi-
tion, our review suggests that interventions that
prevent frailty and maintain function could be useful
in preventing or ameliorating cognitive decline
among cancer patients.
There is a relative paucity of human studies
designed to evaluate interventions to treat cancer-
related cognitive changes compared to the large
body of literature describing the phenomenon,
although there are data from animal models that
are informing new approaches. Unfortunately, most
studies in humans and animals generally have not
included or have not been focused on older patients
(or animals).162However, there are studies in Alz-
heimer’s disease with older patients that may have
relevance to the cancer setting, including behavioral
and pharmacological interventions. Existing inter-
ventions have been reviewed elsewhere,163and are
summarized briefly here.
One prominent behavioral approach is cognitive
training. In younger cancer patients, cognitive ther-
apy, including rehearsing compensatory strategies,
was noted to improve cognitive function,164but this
effect was not noted in other studies.165Similar
interventions also have been successful in older
Alzheimer’s patients.166A review of factors associ-
ated with prevention of age-related cognitive decline
reported evidence that physical exercise and possi-
bly diet could be efficacious behavioral interven-
tions.166Exercise has been protective of decline
after chemotherapy in rodents.167Increasing antiox-
idants via dietary change has been shown to be
protective of cognitive decline in animal models.60
Interestingly, in preliminary trials with non-smoking,
non-cancer patients with mild cognitive impairment,
transdermal nicotine was safe and improved cogni-
tive function, possibly via stimulation of nicotinic
acetylcholine receptors.168These data suggest the
value of conducting trials to provide evidence to
support incorporation of some of these approaches
in to clinical care to preserve cognitive function in
older cancer survivors.
There are several promising pharmacological
interventions that have been tested largely in animal
models.163Fluoxetine has been shown in animal
models to prevent behavioral and hippocampal
approaches have not been replicated yet in older
animals, translated to clinical settings with humans,
or tested for safety or interactions with chemo-
therapy efficacy. It will be important to include
sufficient numbers of older patients when these
studies are conducted. In human research, two
studies have demonstrated the efficacy of modafinil,
a psycho-stimulant, in improving memory and atten-
tion and reducing fatigue in cancer patients.171,172
Herbal compounds such as Gingko biloba are under
J.S. Mandelblatt et al 718
Alzheimer’s treatment drugs have been examined in
patients undergoing brain irradiation.
Given the parallels between aging, frailty and
cognitive decline in cancer patients, it is also logical
that interventions that prevent frailty could be useful
as targets for older cancer survivors. These “anti-
aging” models have been examined largely in animal
models and include caloric restriction, rapamycin,
protein aggregation inhibitors, and removal of sen-
As the validity of personalized medicine becomes
more established, understanding the genetic profiles
of older patients at the greatest risk for cognitive
decline also could be useful in clinical decision-
making about systemic therapy and risk of cognitive
decline. These data also could contribute to the next
generation of pharmacogenetic studies that investi-
gate which medications best prevent cognitive
effects in vulnerable women and which systemic
therapies are most and least likely to lead to cogni-
tive toxicity in older women.173,174
There is a strong albeit non-universal body of
literature supporting the phenomenon of cognitive
decline after breast cancer and its systemic thera-
pies. 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 assessment
could be a useful tool to aid in treatment decision-
making and identify the subgroups most vulnerable
to adverse cognitive outcomes.
Given the demographic imperative of a rapidly
growing older population, increasing cancer inci-
dence with advancing age and the increasingly
chronic nature of breast cancer, research in older
cancer patients and survivors will be critical to
providing the evidence for practice guidelines.
Thus, we recommend that designing and conduct-
ing basic science and population trials specifically
for older cancer patients should receive high prior-
ity. These studies should include intermediate end-
points of relevance to this group, including cognitive
function and trajectories of frailty.175–177Clinicians
and their older patients can advance the field by
research designed to improve the care and outcomes
of older cancer patients.
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