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Chemotherapy and Cognitive Impairment:
Treatment Options
JE Fardell1,2, J Vardy2,3,4, IN Johnston1 and G Winocur5,6,7,8
Chemotherapy has improved survival rates in patients with many of the common cancers. However, there is reliable
evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for
many years after the completion of chemotherapy. The etiology of this phenomenon is largely unknown, and currently
there are no proven treatments. This article explores the clinical and preclinical literature on potential therapies for
chemotherapy-induced cognitive impairments. Emerging results suggest that both pharmacological and behavioral
approaches may offer patients some benefits. However, research in this area has been limited and is sometimes fraught
with methodological flaws. As a result, it is difficult to draw definite conclusions regarding treatment efficacy. These
issues, along with predictors of cognitive decline, are discussed in the light of possible interventions.
The effect of anticancer treatments on cognition is receiving
increasing attention from researchers because some patients
report cognitive difficulties long after anticancer treatment has
been completed. However, there are no proven treatments or
preventive measures for this side effect, and oncology serv­
ice providers may not consider themselves sufficiently know­
ledgeable or well equipped to deal with the cognitive changes
that patients may experience.1 In a qualitative study, Munir
et al.1 found that the majority of the breast cancer survivors
interviewed reported memory loss and attention problems,
yet less than one-third of this survey population had received
any information about the possible effects of chemotherapy on
cognition or any advice about methods of coping with these
problems. Although cognitive impairment in such patients is
generally subtle, even a small degree of difficulty in everyday
functioning can have a significant impact on quality of life.2 In
view of this, the International Cognition and Cancer Taskforce
has identified a need for well-validated treatments and inter­
ventions.3 The purpose of this article is to review the litera­
ture on treatment options for chemotherapy-induced cognitive
deficits. (A recent review by Joly et al.4 discusses therapies
for cognitive difficulties experienced as a result of childhood
malignancies and anticancer treatments and therefore are not
discussed here.)
Chemotherapy-Induced Cognitive Impairment:
Presentation and Incidence
Improvements in treatments for many cancers have led to longer
survival times for patients, and researchers have moved toward
investigating and improving quality of life for survivors. During
and shortly after chemotherapy for cancer, many patients report
attention deficits, memory loss, and confused thought processes.
Up to 70% of patients with cancer report that these cognitive dif­
ficulties persist well beyond the duration of treatment,3,5,6 and
for some the impact on daily functioning is the most trouble­
some survivorship issue that they face.2 Focus-group research
and qualitative interviews with breast cancer survivors have
found that many of these women are no longer able to perform
at their previous levels of competence and frequently do not
feel confident about returning to their jobs.1 Also, survivors fre­
quently describe social situations as daunting, and interpersonal
relationships may suffer as a result.2 Clearly, cognitive problems
resulting from chemotherapy are related to a significant decline
in quality of life.
Studies that have measured cognitive function using stand­
ardized neuropsychological assessments have found mild to
moderate effects of chemotherapy on cognitive performance in
15–50% of the survivors after treatment.4,7 Longitudinal studies
have shown that, in a subset of survivors, cognitive difficulties
1School of Psychology, The University of Sydney, Sydney, New South Wales, Australia; 2Cancer Institute New South Wales, Eveleigh, New South Wales, Australia;
3Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia; 4Sydney Cancer Centre, The University of Sydney, Sydney, New South Wales,
Australia; 5Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada; 6Department of Psychology, University of Toronto, Toronto, Ontario, Canada;
7Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; 8Department of Psychology, Trent University, Peterborough, Ontario, Canada.
Correspondence: G Winocur ([email protected])
Received 25 March 2011; accepted 19 April 2011; advance online publication 3 August 2011. doi:10.1038/clpt.2011.112
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can persist for between 1 and 2 years after the completion of
chemotherapy,8,9 and cross-sectional studies have found cogni­
tive impairments lasting between 4 and 10 years after chemo­
therapy.10,11 Although most of the studies evaluated cognitive
function in breast cancer survivors, more recent work has shown
that similar effects also occur in patients with other types of
cancer. For example, Vardy et al.12 found that patients treated
for colorectal cancer experience cognitive impairment up to 6
months after the completion of treatment.
When cognitive impairments occur, they are typically seen
in processing speed, attention/concentration, and executive
functioning—all of which are widely associated with the func­
tion of the frontal lobes of the brain—and in visual and verbal
memory, which are believed to be under the control of the hip­
pocampus (for a review, see ref. 7). In support of this pattern
of cognitive impairment, several brain-imaging studies found
chemotherapy-related decreases in the integrity of white matter
in the brain area associated with changes in processing speed,13
and others reported changes in electrophysiological indexes
of processing speed (e.g., ref. 11). Inagaki et al.14 discovered
structural brain changes in cancer survivors 4 months after the
completion of chemotherapy treatment, with reduced superior
frontal gyri and parahippocampal gyrus volume being correlated
with poor attention/concentration and impaired memory per­
formance, respectively. Corresponding functional brain changes
have also been reported; de Ruiter et al.10 found hyporesponsive­
ness in both the prefrontal cortex and parahippocampal gyrus
during executive functioning and episodic memory tasks in can­
cer survivors who had received chemotherapy almost 10 years
previously. Overall, imaging studies have found both structural
and functional changes in brain regions that are believed to be
involved in the cognitive deficits experienced by cancer survi­
vors who received chemotherapy.
Complicating the issue somewhat, recent prospective studies
show that ~20% of cancer patients experience cognitive dys­
function even before commencement of chemotherapy (e.g.,
refs. 15,16). This suggests that the cancer itself and/or the can­
cer diagnosis may have an impact on cognition. Indeed, can­
cer induces systemic changes that may influence cognition. For
example, patients with cancer exhibit increased circulating levels
of cytokines; in both preclinical and clinical studies, increased
levels of cytokines and inflammation have been shown to be
associated with impairment of cognition.17 Although receiving a
diagnosis of cancer is associated with increased stress, depression,
and anxiety, the studies that evaluated cognitive function before
chemotherapy did not find an association between depression/
anxiety and objectively measured cognitive impairment (e.g.,
refs. 9,15). Similarly, research has consistently demonstrated that
there is only a weak relationship between self-reported cognitive
impairment and cognitive performance as assessed by formal
neuropsychological testing (e.g., ref. 5). However, self-reported
cognitive symptoms appear to be associated with increased anxi­
ety and depression (e.g., refs. 5,6) and may reflect, at least in part,
the stress of cancer diagnosis and treatment.
Chemotherapy agents that are commonly used in clinical
practice produce significant cognitive impairment in laboratory
art
animals that are free from cancer as well as from other treat­
ment- and diagnosis-related factors. The pattern of cognitive
deficits observed in rodents in these studies is virtually identi­
cal to that experienced by human patients after chemotherapy.
Research studies in animals have shed considerable light on
the potential underlying neurobiological mechanisms linking
chemotherapy with cognitive impairment (Figure 1; for reviews,
see refs. 18,19). Healthy rodents that are given chemotherapy
show increase in cell death in the central nervous system,20
increase in oxidative stress,20,21 increase in microglia activity,22
suppression of hippocampal neurogenesis,23 decreases in levels
of neurotrophic factors,24 and decreases in levels of hippocam­
pal catecholamines,25 as compared to baseline values. Taken
together, this evidence strongly indicates that, although can­
cer and/or a cancer diagnosis may affect cognition in human
patients, chemotherapy induces both central nervous system
changes and measurable cognitive impairments in rodents and
humans. There is a clear need to develop effective interventions
that target the cognitive domains affected and their underlying
neurobiological causes.
Pharmacological Interventions
Erythropoietin
Several studies have investigated the therapeutic potential of
the glycoprotein erythropoietin (EPO) in preventing chemo­
therapy-induced cognitive deficits. EPO stimulates the produc­
tion of red blood cells, and, in anemic patients, EPO treatment
increases hemoglobin levels and reduces the need for blood
transfusions, thereby contributing to better quality-of-life
outcomes.26 However, the relationship between cognition and
hemoglobin levels is not clear-cut; Vearncombe et al.27 reported
that reduced hemoglobin levels, together with increased anxi­
ety, predict a decline on measures of cognitive function. Massa
et al.28 evaluated EPO therapy in 10 elderly cancer patients
who had hemoglobin levels between 10 and 12 g/dl during the
period of chemotherapy. Each of the patients received 10,000 U
twice a day, 6 days a week, for 2 weeks, followed by 10,000 U
three times a week for the following 10 weeks of chemother­
apy treatment. After 4 weeks of treatment, 9 of the 10 patients
demonstrated cognitive improvements from baseline, as meas­
ured by the Mini-Mental State Examination (MMSE), and the
improvements in hemoglobin levels in these patients showed
significant correlation with the improvements in cognition. In
a larger study of 50 anemic cancer patients, Iconomou et al.29
found small but statistically significant improvements in cogni­
tion, as measured by the MMSE, after 12 weeks of combined
chemotherapy and EPO. Interestingly, Iconomou et al.29 failed
to find a relationship between hemoglobin levels and cognition,
despite a significant positive association between hemoglobin
levels and quality of life.
Two studies have examined the effect of EPO treatment
(given during chemotherapy) on long-term cognitive out­
comes. O’Shaughnessy et al.30 conducted a double-blind, pla­
cebo-controlled, pilot trial in which 100 patients with breast
cancer were randomized to receive EPO (40,000 U subcuta­
neously) or placebo once a week throughout the duration of
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Treatment
CNS effects
Neurocognitive effects
Oxidative
stress
Hippocampal
function
Inflammation
Learning and
memory
Chemotherapy
Brain
vascularization
Frontal
cortex
fuction
Neurogenesis
and growth
factors
Executive
function
(planning and
decision making)
Catecholamines
Figure 1 A schematic representation of the putative pathology underlying chemotherapy-induced cognitive impairment associated with hippocampal and
frontal-lobe dysfunction. Chemotherapy may have both direct and indirect effects on the central nervous system (CNS), affecting cognition.
doxorubicin/cyclophosphamide treatment. At the beginning of
the study, hemoglobin levels in EPO and control groups were
between 12 g/dl and 14 g/dl. The study was not powered to find
statistical differences between treatment and control groups;
however, in agreement with the findings of Massa et al.28 and
Iconomou et al.,29 executive functioning, as measured by the
Executive Interview prior to cycle 4 of chemotherapy, improved
in EPO-treated patients relative to placebo patients. Similarly,
hemoglobin levels increased in EPO patients and decreased
in placebo patients, but the association between hemoglobin
changes and cognition was not directly tested. At the 6-month
follow-up, executive functioning scores were similar in the
two groups; however, patients receiving EPO appeared to have
lower levels of fatigue and better quality of life. Mar Fan et al.31
assessed cognition in breast cancer survivors with hemoglobin
<12 g/l who had received (neo)-adjuvant chemotherapy with or
without weekly EPO (40,000 U) by comparing their cognition
scores with those of patients who had received standard care
without EPO. Cognitive function was assessed at a single time
point, 12–30 months after completion of chemotherapy, using
the MMSE and High Sensitivity Cognitive Screen. Patients who
had received EPO during chemotherapy reported better quality
of life than those who had received standard care. Mar Fan et al.
tested the subjects 2 years after completion of chemotherapy.
In agreement with the results of the study by O’Shaughnessy
et al.,30 Mar Fan et al.31 also did not find any difference in
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cognitive function between patients who had received EPO
and those who had not.
Taken together, the available results provide some evidence
that EPO may be effective in improving cognition in the short
term.28–30 However, several methodological issues are worth
noting. In particular, two of the studies that offer support28,29
to this hypothesis employed only brief cognitive screening tests,
which are probably inappropriate for detecting the subtle impair­
ments generally found in cancer survivors.32 In addition, three
of the four studies reported here assessed pretreatment cogni­
tive function28–30 and short-term cognitive outcomes, whereas
Mar Fan et al.31 assessed cognition at 2 years after the conclusion
of the treatment. It is unclear whether EPO treatment during
chemotherapy confers longer-term protection of cognitive func­
tion after chemotherapy. Finally, the studies conducted to date
have been underpowered and/or lacking appropriate control
groups (e.g., ref. 28) and have therefore been unable to establish
whether EPO treatment during chemotherapy has any effect on
cognition. From the available research, it is still not clear what
impact changes in systemic hemoglobin levels have on cogni­
tion in patients after chemotherapy. Indeed, research suggests
that EPO treatment may be beneficial and neuroprotective only
in patients in whom local brain damage is present, for instance,
because of hypoxia or ischemia.26 Therefore, testing the efficacy
of EPO treatment in a sample with heterogeneous cognitive
capacity seems unlikely to yield definitive answers.
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Methylphenidate
The stimulant methylphenidate (MPH) is typically used to
treat attention-deficit/hyperactivity disorder and may also
mitigate cancer-related fatigue.33 MPH acts by modulating
catecholaminergic tone in the prefrontal cortex and striatum
and increases dopamine signaling through multiple pathways
(for a review, see ref. 34). By contrast, methotrexate (MTX)
chemotherapy has been shown to decrease hippocampal cat­
echolamine levels in healthy rats.25 In humans, MPH treatment
has been shown to enhance memory in healthy individuals35
and overall cognitive function in patients with primary brain
tumors.36 Gagnon et al.37 found that treatment with 20–30 mg
MPH per day improved psychomotor, language, and atten­
tion deficit in patients with advanced cancer who had cogni­
tive deficits and associated hypoactive delirium. However, two
recent randomized, placebo-controlled studies failed to find a
clear benefit of MPH on cognition in cancer patients receiving
chemotherapy.38,39
Mar Fan et al.39 conducted a double-blind, placebo-control­
led trial of d-methylphenidate (dMPH) in women with breast
cancer receiving adjuvant chemotherapy. All the participants
received a placebo for one cycle of chemotherapy and were
then randomized to receive 5 mg of dMPH (n = 29) or placebo
(n = 28) twice a day. If this dose was well tolerated, after 1 week
the dMPH dose was increased to 10 mg twice a day, until the
completion of chemotherapy. Cognitive function was assessed
using the High Sensitivity Cognitive Screen and the Revised
Hopkins Verbal Learning Test prior to randomization, at the
end of chemotherapy and 4–6 months thereafter. There were no
significant differences between the dMPH and control groups
with respect to either of the cognitive measures at any of the
time points; however, the results may have been confounded
by a trend that showed more cognitive impairment at base­
line in placebo-receiving patients than those receiving dMPH.
Unfortunately, because of poor accrual, the study closed early;
as a result, conclusions from these results must be regarded as
tentative. Lower et al.38 also found little benefit of dMPH on
cognition in patients with sustained cancer-related fatigue. In
this study, patients had completed four cycles of chemotherapy
25 months previously (on average) and had received dMPH for
8 weeks. Fatigue and cognitive function were assessed prior to
starting and at completion of dMPH treatment. Fatigue, which
was the primary end point, was reduced after dMPH treatment,
but there was no effect on cognition.
Neither of these studies was sufficiently powered to detect a
difference, and it therefore remains unclear what effect continu­
ing MPH treatment beyond chemotherapy completion would
have on late cognitive outcomes. It is possible that treatment
benefits may accrue with time and continued use and may there­
fore not be apparent in the time frames assessed here. However,
a recent review found little evidence to support continued use
of MPH in patients with Alzheimer’s disease, vascular dementia,
or frontotemporal dementia in an attempt to improve cognitive
function.40 The available evidence does not indicate that MPH is
useful for the prevention or treatment of chemotherapy-induced
cognitive deficits. However, until sufficiently powered trials are
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completed with appropriate sample populations, this conclusion
is tentative.
Modafinil
Modafinil is commonly used to treat narcolepsy and shiftwork sleep disorders. Like MPH, it is a central nervous system
stimulant that appears to exert its effects through the release
of the catecholamines norepinephrine and dopamine, and his­
tamine.41 In healthy adults, modafinil acts as an enhancer of
cognition, primarily improving attention;35 in cancer patients,
it has been shown to reduce fatigue.33 Two studies have inves­
tigated the effect of modafinil on cognition in cancer patients.
Lundorff et al.42 examined 28 patients with advanced cancer in
a double-blind, single-dose, crossover trial. The patients were
randomly assigned to receive 200 mg oral modafinil on day 1
and placebo on day 4, or the reverse of that order. On both days,
they were tested with the Finger Tapping Test for psychomotor
speed and Trail Making Test B for visual information processing
and mental flexibility, before and at 4.5 h after drug administra­
tion. Performance on both tests was significantly improved after
modafinil treatment as compared with placebo, and there was a
parallel reduction in depression and drowsiness. In a secondary
analysis, Kohli et al.43 examined the effects on cognition after
4 and 8 weeks of modafinil treatment in patients with breast
cancer (n = 82) who were continuing to experience fatigue
after completing chemotherapy 22 months (on average) earlier.
Participants receiving modafinil demonstrated improved speed
and quality of episodic memory on the computerized Cognitive
Drug Research assessment. These preliminary results are promis­
ing; however, larger longitudinal, randomized, controlled studies
are needed to confirm short- and long-term efficacy, the dura­
tion for which improvement persists, and whether any benefit
is seen in patients who do not have ongoing fatigue.
Donepezil
Donepezil is a cholinesterase inhibitor that is widely used to treat
cognitive impairment in populations free of cancer. It has been
shown to slow the progression of dementia and act as a neuro­
protectant through a number of different mechanisms, including
reduction of inflammation, regulation of catecholamines, and
enhancement of neuroplastic activity.44 Interestingly, preclinical
studies have shown that chemotherapy affects these same path­
ways in healthy laboratory rodents.22,23,25 Winocur et al.45 inves­
tigated the cognition-enhancing effects of donepezil in mice that
had received a combination of the anticancer drugs MTX and
5-fluorouracil (5-FU). Groups of donepezil-treated and control
mice (receiving saline) were administered a series of cognitive
tests that assessed various aspects of learning and memory. Mice
that had received only chemotherapy showed impairment on
tests of hippocampus-dependent memory (e.g., spatial memory)
and a test of nonmatching-to-sample rule learning, known to
be sensitive to frontal lobe impairment. The cognitive deficits
were significantly reduced when mice receiving the anticancer
drugs were treated with donepezil during chemotherapy/con­
trol treatment and throughout the experiment. On some meas­
ures, the performance of the chemotherapy + donepezil group
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matched that of the control groups receiving saline. Although
these results need to be replicated in future studies, they clearly
point to the potential usefulness of donepezil as a treatment for
chemotherapy-induced cognitive impairment.
Only one study has attempted to examine the effect of
donepezil on cognitive function in patients with cancer. Jatoi
et al.46 administered donepezil in combination with vitamin
E to patients with small-cell lung cancer who had previously
received chemotherapy and prophylactic radiation. Cognition
was assessed using the MMSE and the Blessed Dementia Scale,
with testing being carried out at study entry, 1 month later, and
every 3 months thereafter. The trial was closed early because of
poor accrual (n = 9), and the results remain inconclusive.
Fluoxetine
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI)
that is used primarily in the treatment of depression. It
increases extracellular levels of serotonin within the brain
by inhibiting its reuptake by serotonin transporters and
is reported to improve memory function in patients with
depression, as well as in patients with neurodegenerative con­
ditions.47 In addition, preclinical studies have found that treat­
ment with fluoxetine upregulates brain-derived neurotrophic
factor and increases the rate of neurogenesis (for a review, see
ref. 47). Studies in rodents have shown that both these mecha­
nisms are impaired by chemotherapy.23,24 The findings from
preclinical studies by Wigmore and colleagues48,49 suggest
that SSRIs such as fluoxetine may be beneficial in mitigating
chemotherapy-induced cognitive impairments. Specifically,
healthy rats that were administered fluoxetine (10 mg/kg/
day in drinking water) prior to and throughout treatment
with 5-FU chemotherapy showed improved performance on
object location recognition relative to rats treated with 5-FU
alone.48 Similar effects were observed in animals treated with
MTX chemotherapy.49 Interestingly, in these same animals,
decreases in proliferation and survival of neuronal cells in
the hippocampus resulting from chemotherapy were reversed
with fluoxetine treatment.48,49
Although these results are promising, they should be inter­
preted with caution. First, the dose employed in these animal
studies may be far higher than the dose normally employed in
the clinic.47 Second, the use of SSRIs including fluoxetine dur­
ing chemotherapy may not be desirable, given the side effects
of this class of drugs. A preclinical pilot study investigating the
neuroprotective effects of 5 mg/kg/day paroxetine, an SSRI, on
MTX-induced cognitive impairments in our laboratory had to
be aborted because of excessive weight loss and diarrhea in a sig­
nificant number of the animals (Fardell et al., unpublished data).
Indeed, weight loss due to fluoxetine treatment was significant in
both the study by ElBeltagy et al. and the work of Lyons et al.48,49
Taken together, the results of these preclinical studies suggest
that fluoxetine may protect against chemotherapy-induced
cognitive deficits. However, the findings need to be replicated
in cancer patients so as to validate the efficacy and safety of
fluoxetine and other SSRIs in preventing cognitive impairments
caused by chemotherapy.
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Antioxidants and diet
Preclinical studies have shown that several commonly used
chemotherapy agents can induce central oxidative stress in
healthy rodents (for a review, see ref. 19). By contrast, consump­
tion of foods high in antioxidants and antioxidant supplemen­
tation appear to slow the rate of cognitive decline associated
with aging and disease in humans and rodents.50 Little clini­
cal work has been conducted on the usefulness of antioxidants
and supplements in treating chemotherapy-induced cognitive
impairments. However, several preclinical studies have shown
that antioxidant treatment prevents chemotherapy-induced
oxidative stress and cognitive deficits when administered
prior to and during chemotherapy. For example, Joshi et al.21
found that, in healthy mice, systemic treatment with γ-glutamyl
cysteine ethyl ester prior to doxorubicin treatment significantly
decreased markers of oxidative stress, namely, protein oxidiza­
tion and lipid peroxidization. However, because behavior was
not assessed, it is unclear whether these changes in the brain
were associated with concomitant changes in cognition in the
treated mice.
Two studies have assessed the cognitive-behavioral outcomes
of pretreatment with an antioxidant and found protective effects
against chemotherapy-induced cognitive deficits. Helal et al.51
found that prior intracerebroventricular treatment with the
antioxidant zinc sulfate (ZnSO4) prevented short-term mem­
ory impairments induced by systemic carmustine (BCNU)
treatment. Specifically, BCNU treatment caused rats to make
more errors during learning and recall of the radial arm maze,
whereas treatment with ZnSO4 prior to BCNU prevented these
deficits in learning and memory. In addition, hippocampal cell
death and inflammation induced by BCNU treatment were pre­
vented in rats pretreated with ZnSO4. Konat et al.52 investigated
the impact of 4 weeks of cyclophosphamide and doxorubicin
treatment on memory in rats, using the passive avoidance test.
They found that cyclophosphamide + doxorubicin treatment
impaired memory function. However, when rats were treated
with the antioxidant N-acetyl cysteine during chemotherapy,
there was no short-term memory impairment.
Taken together, the results of these preclinical studies suggest
that treatment with antioxidants prior to and during chemo­
therapy prevents the occurrence of cognitive deficits shortly
after chemotherapy. However, the usefulness of antioxidants
in preventing cognitive impairments needs to be evaluated in
cancer patients receiving chemotherapy. Furthermore, it is pos­
sible that overall diet is more important than antioxidant sup­
plementation alone. It is well established that dietary patterns
can have a direct impact on cognitive function in animals and
humans. Diets that are low in calories and saturated fat are
associated with better cognition in old age, particularly when
this is coupled with consumption of foods high in antioxidants,
such as berries and walnuts.50 In rodents, the consumption of
foods (rather than supplements) high in antioxidants increases
hippocampal neurogenesis and neurotrophic factors such as
insulin growth factor 1 and concomitantly improves perform­
ance on measures of learning and memory.53 Conversely, diets
that are high in saturated or hydrogenated fats adversely affect
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both brain function and cognitive performance in rodents and
elderly humans.54 For example, consumption of a high-fat diet
by rodents was shown to induce inflammation, decrease neuro­
genesis and brain-derived neurotrophic factor levels, and cause
poor maze performance.55 In the absence of reliable data, it is
not possible to predict the effect of an improved diet on cogni­
tive outcome in patients with cancer receiving chemotherapy;
however, it is likely to be positive in terms of overall health
benefits.
Herbal supplements
The Chinese herb Ginkgo biloba is commonly used in the com­
munity for treatment of dementia, memory, and difficulties in
concentrating. Constituents of a standardized extract of Ginkgo
biloba, EGb761, have demonstrated neuroprotective effects in
several in vitro and in vivo models. EGb761 appears to have a
mode of action similar to that of antioxidants; it protects brain
tissue from damage by oxidative stress, reduces apoptosis, regu­
lates cerebral blood flow, and interacts with catecholaminergic
neurotransmitters implicated in cognition.56 A recent review of
29 placebo-controlled randomized control trials comparing psy­
chometric tests by cognitive domain confirmed that the greatest
benefits of Ginkgo biloba were found in executive functioning,
selective attention, and memory for both verbal and nonverbal
material, all of which are neuropsychological domains in which
cancer survivors have deficits.56 These findings make Ginkgo
biloba a compound of interest in the prevention and/or alle­
viation of cancer-related cognitive impairment. The results of a
randomized controlled study to evaluate its efficacy is currently
under way in Sydney, Australia, and should provide important
insight.
Behavioral Interventions
Cognitive rehabilitation
Cognitive rehabilitation refers to behavior-oriented inter­
ventions in which individuals receive noninvasive training
designed to improve performance in a range of cognitive and
functional domains. Traditional models of cognitive rehabili­
tation emphasize any of the following approaches: (i) retrain­
ing to retrieve apparently lost cognitive abilities; (ii) teaching
compensatory techniques that encourage the use of residual
abilities to develop alternative ways of performing cognitive
tasks; and (iii) holistic methods that take a broader approach
and address social, emotional, and functional issues related to
cognitive impairment.57
Rehabilitation scientists have also developed programs that
focus on strategic processing and attempt to improve the use
of strategies that are most effective in responding to cognitive
challenges. Participants are not taught new strategies; rather,
they are guided in the use of previously formed strategies. The
assumption is that many well-established strategies survive brain
impairment but that the individuals require instruction and
support in consciously applying them in an effective manner.
There is evidence that such programs can improve memory58
and overall cognitive function59 in elderly adults who experience
significant cognitive decline. In general, programs that take a
art
strategic approach to cognitive rehabilitation are designed for
individuals with frontal-lobe impairment that affects execu­
tive functioning and related cognitive processes (e.g., attention,
conscious recollection). Consequently, this approach may be
particularly well suited to patients who have received chemo­
therapy, whose cognitive deficits are typically in the mild-tomoderate range, and who are sufficiently functional to fulfill
the program’s requirements and apply the strategic training to
real-world demands.
Although cognitive rehabilitation, in one form or another,
is extensively used in many clinical populations that experi­
ence cognitive impairment, its use in cancer patients has been
extremely limited. In one of the few examples, Ferguson and
colleagues60,61 developed a cognitive training program, Memory
and Attention Adaption Training (MAAT), which focuses on
helping participants to develop compensatory strategies for
everyday activities. During the course of four individual faceto-face visits, either once a month59 or once every 2 weeks,61
MAAT covers four key cognitive-behavioral components in
which participants (i) are educated on the effects of chemo­
therapy on cognition; (ii) learn self-awareness, and also how to
self-monitor and identify “at-risk” situations in which cognitive
failures are likely to occur; (iii) learn self-regulation through
relaxation training; and (iv) learn and rehearse cognitive com­
pensatory strategies. In a single-arm pilot study of 29 women
who had received chemotherapy 8 years earlier for breast can­
cer, Ferguson et al.60 found improvements in quality of life,
self-reported cognitive function, and performance on standard
neuropsychological tests, for up to 6 months after undergoing
the MAAT program. Similar results were found in a waitlist
control trial; at a 2-month follow-up, patients participating in
MAAT had significant improvements on the spiritual subscale
of the quality-of-life measure and on verbal memory, relative
to controls; however, there were no differences in self-reported
cognitive function.61
Poppelreuter et al.62 compared the effects of group-based
cognitive training and individualized training on cognitive
impairment in breast cancer patients who had received adju­
vant chemotherapy. Neither form of training resulted in cogni­
tive improvements over and above those observed over time
in a nontreatment control group. Several factors may have
contributed to the null results. Patients were recruited shortly
after they had completed chemotherapy, which is when spon­
taneous recovery of cognitive function is most likely to occur.
By contrast, Ferguson et al.60 evaluated participants who had
completed chemotherapy at least 18 months61 or 3 years60 pre­
viously. Poppelreuter et al.62 concluded that, during this nar­
row time frame immediately after chemotherapy, interventions
aimed at improving cognitive outcomes may not be effective or
necessary. Immediately after completion of treatment, patients
are likely to be dealing with many other important issues, and
confronting cognitive deficits at this time may be psychologi­
cally disturbing.
Clearly, the limited evidence precludes a conclusive statement
about cognitive rehabilitation as a treatment for chemotherapyinduced cognitive impairment; however, the experience with
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these approaches has been very encouraging in other clinical
populations with similar cognitive deficits, and there is no a
priori reason that patients who have undergone chemotherapy
for cancer would not benefit from such intervention.
Physical activity
Physical-activity programs and interventions have been suc­
cessful at mitigating fatigue in cancer survivors.63 Interestingly,
programs that call for increased physical activity have been
effective at improving cognitive function in both healthy indi­
viduals and in those with acquired cognitive dysfunction (e.g.,
patients with depression or Alzheimer’s disease).64 Similar
results have been obtained in preclinical studies in animals.65
In a case series, Galantino et al.66 found that an 8-week yoga
intervention improved performance on measures of cognition
and perceived cognitive function in three breast cancer survivors
who had completed chemotherapy less than 6 months earlier.
Recently, Fardell et al.67 found a significant association between
physical activity and cognition after chemotherapy in rodents.
Rats treated with 5-FU plus oxaliplatin displayed impairments
in object recognition and spatial reference memory. However,
when the animals were given access to running wheels for 4
weeks after 5-FU-plus-oxaliplatin treatment, these deficits in
object recognition and spatial reference memory were prevented.
Physical exercise acts on a number of neurological mechanisms
that contribute toward maintaining cognitive function. Research
in animals has found that physical activity increases levels of
neurotrophic factors such as brain-derived neurotrophic factor,
enhances the proliferation and survival of neural cells in the hip­
pocampus, and decreases central nervous system inflammation
and oxidative stress, while concurrently improving performance
on measures of learning and memory (for a review, see ref. 65).
Many of these factors have been shown to be affected in rodents
treated with chemotherapy.19
From the viewpoint of prevention, individuals with high life­
time levels of physical activity have slower cognitive decline in
old age and a reduced likelihood of developing dementias later
in life, as well as better overall quality of life.64,65 Importantly,
aerobic exercise in elderly persons has been shown to improve
executive functioning and memory,64 which are the cognitive
domains affected by chemotherapy. The beneficial effects of exer­
cise on cognition are associated with concomitant improvements
in markers of brain health. For instance, individuals with higher
levels of physical activity have larger hippocampal volume in
later life.68 By contrast, individuals with low levels of activity
have greater levels of systemic inflammation.65 The impact of
lifetime levels of physical activity on chemotherapy-induced
cognitive impairments has yet to be investigated. However, like
good diet, higher levels of physical activity may be neuroprotec­
tive and lessen the impact of chemotherapy on cognition.
Predictors of Chemotherapy-Induced
Cognitive Deficits
Treatment factors
To identify those who will benefit from interventions in order to
reverse or reduce chemotherapy-induced cognitive deficits, one
372
should be able to identify those who are most likely to develop
these impairments. Several treatment-related factors may
increase the likelihood of cognitive impairment (for a review,
see ref. 7), although the results at this stage are not conclusive.
Two studies have reported that high-dose chemotherapy is
associated with worse cognitive outcomes.6,9 In a longitudinal
study, Schagen et al.9 found that breast cancer patients who had
received high-dose chemotherapy experienced greater cogni­
tive decline over time. A cross-sectional study conducted by
Scherwath et al.69 failed to support these results. In fact, they
found that, at 5 years after completion of treatment, patients who
had received high-dose chemotherapy were less likely to experi­
ence cognitive impairments than those who had received stand­
ard-dose chemotherapy.69 Wieneke et al.70 found that treatment
duration was associated with degree of cognitive decline; those
receiving longer courses of chemotherapy displayed more cog­
nitive impairment. Several studies have reported that adjuvant
hormonal treatment may increase the likelihood of cognitive
impairment after chemotherapy (e.g., refs. 5,8). Finally, the regi­
men of cyclophosphamide, MTX, and 5-FU (CMF) may increase
the likelihood of chemotherapy-induced cognitive deficits,4,7
with MTX in particular contributing to neurotoxicity.
Individual characteristics
Some individual differences appear to increase the likelihood of
chemotherapy-induced cognitive impairments. The presence of
the APOE e4 allele71 and low levels of pretreatment cognitive
reserve8 have been associated with worse cognitive outcomes
after chemotherapy. In the general population, aging is associ­
ated with declines in processing speed,72 and increased age at
diagnosis may increase the impact of chemotherapy on cogni­
tion. In their longitudinal study on patients with breast cancer,
Ahles et al.,8 found an interaction between age and pretreat­
ment cognitive reserve; older patients with less cognitive reserve
showed poorer performance on measures of processing speed
as compared with younger patients with higher levels of pre­
treatment cognitive reserve. Eberhardt et al.73 found that older
patients with hematologic disease or cancer of the intestinal
tract had greater memory impairments shortly after the start of
chemotherapy but that these impairments resolved by 6 months
after completion of treatment.74 Adams-Price and colleagues75
found that older survivors of breast cancer who had received
chemotherapy between 3 and 45 months prior to the evaluation
showed greater impairments in a test of processing speed than
younger survivors and age-matched healthy controls. These pre­
liminary results need to be expanded on with further research to
investigate other cognitive domains that are commonly affected
by chemotherapy over the long term.
The overwhelming majority of the studies have failed to find
any association between psychological well-being and chemo­
therapy-induced cognitive impairments as measured by tra­
ditional neuropsychological assessment. In their 2007 review,
Vardy et al.7 report that only 1 of the 15 studies that they reviewed
reported a positive relationship between affective stress and cog­
nitive performance and that this finding too could be attribut­
able to statistical chance alone. In contrast, Vearncombe et al.27
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found that, together with declines in hemoglobin levels, increased
anxiety predicted impairment on two or more cognitive tests in
women with breast cancer who had received chemotherapy an
average of 6 weeks earlier. This study also found that baseline
fatigue, depression, and functional well-being were significantly
associated with executive functioning and attention. Although
these results warrant further investigation, they should be inter­
preted with caution. Cognitive ability in these patients was
assessed shortly after the completion of chemotherapy treatment,
and the results may not be sustained, particularly because the
cognitive difficulties experienced may spontaneously resolve.
Lifestyle factors
In other at-risk populations, cognitive competency has been
related to various lifestyle factors. These factors have not
been investigated in cancer patients, but they merit attention
because they may similarly affect the degree to which cogni­
tive performance is affected by chemotherapy. On the basis of
the evidence described earlier, we may expect that individuals
with high levels of physical activity, and who have diets that
are low in fat and calories and high in antioxidants, may be
protected against the cognition-related detrimental effects of
chemotherapy to a greater extent than those who are inactive
and have poor dietary habits. Psychosocial factors should also
be taken into consideration; research has shown that elderly
patients and brain-damaged patients perform much better on
neuropsychological tests of cognition and enjoy a higher quality
of life when surrounded by caring family members and caregiv­
ers.76 A positive environment, in itself, may not be sufficient to
prevent chemotherapy-related cognitive deficits, but it could
help in minimizing the impairments. Effective management of
psychosocial issues could also render the patient more respon­
sive to counseling and cognitive rehabilitation programs.
Future Directions and Some Considerations
Two cognition-related syndromes: acute or long-term effects
of chemotherapy on cognition?
As noted early in this article, although changes in cognitive
capacity are commonly experienced during chemotherapy, a
subset of patients experience cognitive impairment lasting sev­
eral years after the completion of treatment. It is unclear from
the available research whether these represent different temporal
aspects of the same underlying condition or whether they are
two separate phenomena. Therefore, interventions that target
cognitive impairments during or shortly after chemotherapy
may not be as effective in those with sustained impairment. For
example, the studies reviewed here suggest that, although EPO
may be effective at improving cognitive function during and
shortly after chemotherapy, there is little evidence to suggest that
EPO protects or improves cognitive function for up to 2 years
after completion of the treatment (O’Shaughnessy et al.30 and
Mar Fan et al.31). The reverse was true of cognitive rehabilita­
tion; Poppelreuter et al.62 found little evidence that cognitive
rehabilitation was beneficial shortly after completion of chemo­
therapy, and Ferguson et al.60,61 found positive effects of MAAT
on longer-term cognitive impairment.
art
Timing and duration of intervention: prevention or treatment
If an intervention is designed to prevent cognitive impairment,
it needs to occur before and/or during chemotherapy. However,
patients are understandably reluctant to take additional medica­
tions during chemotherapy because of potential side effects and
the risk of interactions with their anticancer treatments.39 In addi­
tion, prevention may not be the most efficient approach, given
that only a subset of patients receiving chemotherapy will go on
to develop sustained problems with cognition, and one cannot
accurately predict which patients will belong to this subset. Careful
examination of a broad range of cancer patients receiving chemo­
therapy in preventive drug trials may help to explain why some
studies failed to find positive effects of various interventions.29,38,39
From the results of preclinical studies, donepezil,45 fluoxetine,48,49
and antioxidants21,51,52 are potential interventions to prevent, and
possibly treat, chemotherapy-induced cognitive deficits.
For survivors who have completed their chemotherapy and
have ongoing cognitive impairment, appropriate treatments
need to be identified. Based on the results of the clinical studies
reviewed here, there appears to be tentative evidence for the
positive effects of modafinil42,43 and cognitive rehabilitation60,61
in ameliorating cognitive deficits experienced long after the
completion of chemotherapy, and preclinical research suggests
that increased physical activity after chemotherapy may be effec­
tive.67 However, it is not clear, from either clinical or preclinical
research, whether treatment needs to be ongoing for any cogni­
tive improvements to be maintained.
Methodological considerations
One of the factors that precludes strong conclusions being drawn
on the basis of the research conducted so far in this area is the
choice of study populations and control groups. Studies that
recruited patients with cognitive deficits as identified by either
standard neuropsychological testing28,42 or self-report60,61 found
that their interventions had successful outcomes. Those that
recruited participants regardless of their cognitive status, failed
to find positive effects of the intervention (e.g., refs. 29,38,39).
If patients are not recruited on the basis of cognitive criteria,
particularly for prevention approaches, the sample size needs
to be sufficiently large. This is because only the patients who go
on to develop cognitive difficulties after chemotherapy would
potentially benefit from the intervention. The smallness of the
samples may also explain why several of the trials failed to find
a positive intervention effect.39,42 Furthermore, the side effects
of some of the pharmacological interventions can be bother­
some, and this aspect needs to be considered before deciding to
give all the patients additional medication during chemotherapy,
particularly because sustained cognitive impairment will affect
only a subset of these patients. As mentioned, several studies
assessed cognitive function using brief screening tests (e.g., the
MMSE) that are unlikely to detect cognitive impairment effi­
ciently. Although these tests are quick and easy to administer,
they are generally inappropriate for this setting.3,32
In addition, the positive results of preclinical studies need rep­
lication in both animal cancer models and clinical study sam­
ples. As highlighted above, it is sustained cognitive impairment
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Table 1 Summary of potential treatments for chemotherapy-induced cognitive deficits and central nervous system effects
Balance of evidence of treatment
on chemotherapy-induced
cognitive deficits
Treatment
Potential central nervous system neuroprotective effects
Erythropoietin (EPO)
EPO has many central nervous system effects that may confer neuroprotection;26
the most relevant, given the current research, on underlying mechanisms associated
with chemotherapy-induced cognitive loss are presented here:
• Increased expression of enzymes protecting against oxidative stress and decreases
in levels of nitric oxide–mediated free radicals
• Modification of neurotransmission
• Increase in neoangiogenesis/normalization of cerebral blood flow
Three studies found positive effects of
EPO treatment during chemotherapy on
cognition shortly after the completion of
treatment28–30
Two randomized control studies
evaluated longer-term cognitive
outcomes. Neither found any effect of
EPO treatment on cognition at
6 months30 and 2 years31
Methylphenidate (MPH) Influences the catecholaminergic system—inhibits the DA transporter34:
• May protect against the formation of DA-associated reactive oxygen species (as
occurs in Parkinson’s disease and methamphetamine-induced neurotoxicity) by
attenuating or preventing abnormal accumulation of cytoplasmic DA
• Increases extracellular levels of DA in the prefrontal cortex and striatum and
modulates catecholaminergic tone
Two randomized control trials failed
to find any positive effects of MPH on
cognition in breast cancer survivors38,39
Modafinil
Modafinil is a psychostimulant that inhibits both the DA transporter and the
norepinephrine transporter; its primary effects appear to be through the
catecholaminergic system41
• It significantly increases extracellular levels of DA, norepinephrine, serotonin,
glutamate, and histamine and decreases levels of γ-amino-butyric acid
Two randomized control trials found
positive effects of modafinil on
cognition.42,43 Positive effects were
seen in quality of episodic memory,43
processing speed,42,43 and visual
processing and mental flexibility42
Donepezil
Donepezil is a cholinesterase inhibitor that has many neuroprotective actions
in animal models of Alzheimer’s disease;44 the most relevant, given the current
research on underlying mechanisms associated with chemotherapy-induced
cognitive decline, are presented here:
• Mitigates the effects of oxidative stress
• Modulates neurotransmission
• Improves cerebral blood flow and activity coupling
• Enhances neuroplasticity
• Reduces levels of pro-inflammatory cytokines
One preclinical study showed that
mice treated with donepezil during
chemotherapy displayed improved
spatial memory and rule learning45
Fluoxetine
Fluoxetine is a selective serotonin reuptake inhibitor that increases extracellular
serotonin and appears to modulate important cellular functions that are thought
to be important for neuronal cell survival and neuroplasticity47
• Regulation of the transcription factor cAMP-responsive element binding protein
• Production of neurotrophic factors (e.g., BDNF)
• Regulation of neuronal energy supply
Two preclinical studies found that
administration of fluoxetine during
chemotherapy prevented object location
recognition memory deficits and
prevented suppression of neurogenesis
due to either 5-fluorouracil or
methotrexate48,49
Antioxidants
The primary mode of action of antioxidants is through their ability to prevent the
formation of reactive oxygen species and/or scavenge reactive oxygen species.
Foods containing antioxidants, such as blueberries, have additional neuroprotective
effects 50
• Activate cAMP-responsive element binding protein
• Increase levels of BDNF in the hippocampus
• Reduce central nervous system levels of pro-inflammatory cytokines and cell death
Three preclinical studies showed that
antioxidant administration during
chemotherapy reduces markers of
oxidative stress;21,51,52 two found
concomitant protection of cognitive
function in animals co-treated with
antioxidants and chemotherapy51,52
Physical activity
Exercise has many central nervous system effects,65 the few most relevant given the
current research on underlying mechanisms associated with chemotherapy-induced
cognitive decline are presented here:
• Decreases inflammation
• Increases levels of neurotrophic factors (BDNF, insulin growth factor 1, vascular
endothelial growth factor)
• Increases neuronal cell proliferation and survival
One preclinical study found that physical
activity after chemotherapy prevented
the occurrence of spatial reference
memory impairments and recognition
memory impairments caused by
chemotherapy67
BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; DA, dopamine.
that is most problematic for cancer survivors, and yet the major­
ity of rodent studies have assessed the efficacy of interventions
only immediately after completion of chemotherapy and over
relatively short periods of time. It is not clear whether any of
the candidate interventions offer long-term protection from
cognitive problems experienced as a result of chemotherapy.
This issue, as well as appropriate dose, duration, and timing of
374
the intervention, warrant careful examination because all these
factors are likely to influence the efficacy of the treatment.
Conclusion
Ferguson et al.61 suggest that low-risk treatments (such as
cognitive-behavioral interventions) that emphasize functional
improvements in both cognition and quality of life may provide
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the most benefit for patients with cognitive impairment after
cancer treatment. The etiology of chemotherapy-induced cog­
nitive impairments is likely to be multifactorial, and more than
one treatment modality may be required. Patients with cog­
nitive impairments may benefit from the administration of a
cognition-enhancing drug to aid their ability to both encode
and recall cognitive compensatory strategies learned during
rehabilitation training.
In summary, emerging pharmacological and behavioral ther­
apies offer some hope for cancer survivors who are experienc­
ing chemotherapy-induced cognitive impairments (Table 1).
However, although progress is being made, insufficient data and
methodological limitations in some of the trials reported here
make it difficult to arrive at solid conclusions and recommenda­
tions. More research is clearly required; studies must be adequately
powered to detect an effect and should specify a priori the aims of
the intervention and recruit a sample accordingly. Therapies that
have broad neurobiological and psychological effects, and that
have been shown to be beneficial in other populations with cogni­
tive impairments similar to those reported after chemotherapy,
may offer the best hope for cancer survivors in this regard.
Conflict of Interest
The authors declared no conflict of interest.
© 2011 American Society for Clinical Pharmacology and Therapeutics
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