1. health and fitness
2. disease
3. cancer

School of Health Professions
University of Missouri
Breast Cancer and “Chemobrain”:
The Consequences of Cognitive Difficulties
Following Chemotherapy and the Potential for Recovery
by Stephanie A. Reid-Arndt, PhD, ABPP
Because cancer and its
treatments can cause
cognitive difficulties,
emotional distress, and
physical symptoms,
interventions can improve
functioning in each of
these areas.
Stephanie A. Reid-Arndt, PhD, ABPP, is
Assistant Professor at the University
of Missouri-Columbia School of Health
Professions in the Department of
Health Psychology.
Contact: [email protected]
Abstract
Up to one-third of women
breast cancer survivors report
difficulties with concentration,
multi-tasking, and memory.
Research in the University
of Missouri, Department of
Health Psychology, suggests that
these cognitive difficulties are
associated with poorer quality
of life among breast cancer
survivors after treatment. This
article discusses this treatment
side effect and its consequences
for daily functioning, highlights
ongoing research on the potential
role of stress in the development
of cognitive difficulties, and
reviews treatment options.
Introduction
The Department of Health
Psychology (DHP) at University
of Missouri is comprised of
psychologist practitioners and
researchers who are board certified in
rehabilitation psychology and clinical
neuropsychology. Our department
goals include offering the highest
quality clinical services, conducting
innovative research on behavioral
issues with medical populations, and
providing clinical and research training
to future doctoral-level psychologists.
Clinical services (including cognitive
assessment and psychotherapy) are
provided to individuals who are
referred from providers across the
state and who have chronic medical
conditions (e.g., multiple sclerosis,
epilepsy) as well as acquired medical
issues that can result in cognitive and
physical disabilities (e.g., traumatic
brain injury, stroke, spinal cord
injury). Complementing these
clinical services are the DHP research
programs, which similarly strive to
address neuropsychosocial issues faced
by a range of medical populations.
One such line of research, the DHP
Cancer Outcomes Research Program,
is focused on evaluating and addressing
factors that impact quality of life
among cancer survivors, with a current
emphasis on the relationship between
cognitive deficits and functional
outcomes among breast cancer
survivors.
“Chemobrain” Prevalence
and Characteristics
Breast cancer is the most
prevalent malignancy affecting
women; with a current survival rate
across stages at approximately 88%
there are over 2.1 million breast
cancer survivors living today. With
improvements in mortality rates,
medical and behavioral health care
providers alike are increasingly attuned
106:2 Missouri Medicine w March/April 2009 w 127
Table 1
to the needs of
Average Cognitive Test Scores Over Time
cancer survivors
following treatment
1.6
completion.
1.4
Research on quality
1.2
of life after treatment
1
for cancer abounds1
0.8
and efforts are
0.6
underway to identify
0.4
factors that lessen
0.2
the quality of life
0
experienced by
Time 1
Time 2
-0.2
cancer survivors so
-0.4
that treatments to
-0.6
address these factors
can be developed.
ImmMem
DelMem
Attn
ExecFx
One issue
receiving increased
research has found that cognitive
attention in survivorship research
impairments may diminish over
is the impact of treatments of nontime. One series of studies indicated
neurological cancers on cognitive
that initial cognitive impairments
functioning. Labeled “chemobrain” by noted at two years post-treatment7
cancer survivors, cognitive difficulties
were no longer present at four
have long been reported by patients,
years post-treatment9. Another
particularly breast cancer survivors,
study followed 18 women treated
following chemotherapy. Indeed,
for breast cancer and found that
a growing literature suggests that
approximately 45% evidenced
chemotherapy is associated with a
improved cognitive functioning by one
decline in cognitive functioning among year post-chemotherapy10. Finally,
a subset of women treated for breast
cross-sectional study findings indicate
cancer2 with prevalence estimates
that cognitive functioning improves
ranging from 17-35%3. Deficits have
over time after chemotherapy, but
specifically been noted in memory4, 5,
that individuals with a history of
executive functioning6, and attention/
chemotherapy continue to perform
concentration7. Several meta-analyses
more poorly than healthy controls
have revealed small to medium effect
even several years after treatment
sizes across each of these cognitive
completion5. In aggregate, these
domains, with the largest effects for
data provide evidence that the
executive functioning and verbal
decline in cognitive functioning
memory8.
post-chemotherapy may resolve over
While a preponderance of
time among a portion of affected
evidence suggests that cognitive
individuals, while some will continue
changes can occur after chemotherapy, to demonstrate long term deficits.
the duration of these observed changes
remains in question. Some studies
“Chemobrain” and
document long-term deficits, with
Quality of Life
evidence of cognitive complaints
While progress has been
among 5-10 year cancer survivors4.
made in identifying the type of
Importantly however, longitudinal
neuropsychological deficits cancer
128 w March/April 2009 w 106:2 Missouri Medicine
survivors may
experience, studies of
the effects that these
difficulties may have
on quality of life are
few. Recent qualitative
research has revealed
that women cancer
survivors perceive
they are experiencing
difficulties
with memory,
Time 3
concentration and
planning that affect
their productivity at
home and at work11.
VerbFl
Additionally, research
in the DHP Cancer
Outcomes Research Program has
revealed that cognitive deficits, present
up to one year following treatment
completion, negatively affect quality of
life among breast cancer survivors12.
For this work, women diagnosed
with Stage I–III breast cancer were
recruited through three cancer
treatment facilities in Columbia,
Missouri, and they were evaluated
at three time points: one month,
six months and 12 months postchemotherapy. Of the 46 women
who participated in the one month
post-chemotherapy appointment,
39 completed the six month followup and 33 remained for the one
year follow-up session. During
each of these appointments,
women underwent standard
neuropsychological (cognitive)
testing, which included assessment of
memory, attention/concentration and
executive functioning. Additionally,
they were asked to complete
questionnaires documenting their
cognitive complaints, level of fatigue,
psychological functioning, and quality
of life.
Analyses of group means revealed
deficits in executive functioning (e.g.,
multi-tasking, word finding) at one
month and six months following
chemotherapy, but not at 12 months
post-treatment. See Table 1. However,
some individuals continued to
experience ongoing neuropsychological
difficulties at 12 months posttreatment, which had adverse effects
on important functional outcomes.
(Reid-Arndt, S.A., Hsieh, C., Perry,
M.C. Neuropsychological Functioning
and Quality of Life During the First
Year after Completing Chemotherapy
for Breast Cancer - under review.)
Specifically, analyses revealed
that at six and 12 months postchemotherapy, breast cancer survivors
with poorer executive functioning
were reporting lower overall quality
of life. Conversely, individuals with
better executive functioning were
reporting greater satisfaction in their
relationship with their doctors. These
data provided further evidence that
many women experience a resolution
of neuropsychological difficulties over
time following treatment for breast
cancer. However, the findings also
highlighted the direct impact that
executive dysfunction can have on
important aspects of quality of life
among a portion of breast cancer
survivors.
Possible Etiologies of
“Chemobrain”
Initially it was believed that
cognitive changes following cancer
treatment were symptoms of
depression rather than neurologicallybased cognitive decline. However, a
growing body of research has indicated
that cognitive deficits occur following
treatment in the absence of symptoms
of depression7,9. In considering other
possible etiologies, it has generally
been hypothesized that cognitive
deficits result specifically from
chemotherapy medications, which
may contribute to physiologic changes
such as fatigue, hormonal alterations,
and direct neurotoxic effects13,14.
Additionally, one study has pointed to
the possibility that some individuals
may be genetically predisposed
to experience cognitive deficits
following cancer treatment15. There
is evidence that neuroanatomical
changes may be associated with
treatment-related cognitive decline
based on structural and functional
neuroimaging research13, as alterations
in the hippocampus and frontal
lobes have been noted among breast
cancer survivors with a history of
chemotherapy.
Interestingly, one study of women
prior to and following surgery for
breast cancer revealed that cognitive
deficits may be present in the absence
of chemotherapy16, indicating that
factors other than chemotherapy may
be affecting cognitive functioning
among cancer survivors. Recognizing
this possibility, the DHP Cancer
Outcomes Research Program is
currently evaluating the proposition
that physiologic changes associated
with the stress response may underlie
cognitive impairments associated
with cancer treatment. Briefly, the
potential role of stress in cognitive
decline associated with cancer is
suggested by animal and human studies
identifying a relationship between
neuroendocrine system functioning
and memory abilities. Specifically,
the hypothalamic-pituitary-adrenal
(HPA) axis is the neuroendocrine
system responsible for producing
glucocorticoid and, ultimately, cortisol;
research has documented that chronic
stress leads to hyperactivation of this
system, resulting in the overproduction
of glucocorticoid/cortisol. This
has led to the “glucocorticoid
cascade hypothesis”, which posits a
relationship between chronic high
levels of glucocorticoids, atrophy of
a neural structure associated with
memory (hippocampus), and impaired
memory17.
Supporting this hypothesis are
findings of decreased hippocampal
volume and memory deficits among
elderly individuals who show increases
in cortisol levels over a three to six
year period18. Data from other noncancer populations also support the
relationship of stress, glucocorticoids
and cognitive deficits. For example,
cognitive impairment associated with
depression may be secondary to HPA
axis dysfunction19. Moreover, HPA
axis hyperactivation has been linked
to cognitive decline in individuals with
multiple sclerosis20, who have a high
incidence of depression.
To begin to clarify potential
associations between glucocorticoid
production and cognitive impairment
in cancer survivors, and to help
determine if cognitive deficits may
precede chemotherapy secondary to
stress, we are currently conducting a
study with women who have recently
undergone surgery for tumor resection
and are subsequently diagnosed with
either a benign mass or cancer. Data
are collected regarding women’s
cognitive functioning, stress levels
(via self-report questionnaires and
salivary cortisol), coping styles and
quality of life during this period
after diagnosis and before adjuvant
treatment. Comparisons will be made
between women with benign masses
and women with cancer in order to
document group differences in stress
levels and cognitive functioning.
Additionally, analyses will be
conducted to assess the relationships
between coping styles, stress levels
and cognitive functioning across the
two groups. The primary hypothesis
is that increased stress levels will
be associated with greater cognitive
106:2 Missouri Medicine w March/April 2009 w 129
dysfunction and
poorer quality of
life. Moreover, we
predict that coping
styles may moderate
this effect, such that
individuals using
active coping styles
will evidence lowered
stress levels and less
decline in cognitive
functioning and
quality of life.
improved self-reported
cognitive functioning,
enhanced quality of
life, and gains on
neuropsychological
tests of verbal
memory and executive
functioning. While
one might argue
that test score
improvements resulted
from practice effects,
it is noteworthy that
the goals of improving
survivors’ coping with
cognitive problems and
quality of life were met.
Finally, because cancer and
associated treatments can cause
cognitive difficulties as well as
emotional distress and physical
symptoms (e.g., fatigue and balance
difficulties), interventions that have
the potential to improve functioning
in each of these domains may be
particularly valuable. Recognizing
this, there is a growing interest in
alternative interventions that are
designed to simultaneously improve
both physical and mental functioning,
such as yoga and Tai Chi. The DHP
Cancer Outcomes Research Program
is particularly interested in Tai Chi
and the potential health benefits it
may offer cancer survivors, and a pilot
study of this intervention is currently
underway.
Briefly, Tai Chi is a Chinese
martial art that has long been
practiced for health promotion and
maintenance. Training in Tai Chi
involves practicing forms (slow motion
routines) and is based on a number
of guiding principles, including
mindfulness, breath awareness, active
relaxation, and slow movement. See
Figure 1. Research with non-cancer
populations suggests that Tai Chi may
have beneficial effects on physical
Figure 1. Preliminary evidence exists that practice of Tai Chi results in
changes in the physiological stress response.
Treatment
Options for
“Chemobrain”
While there is much to learn
regarding the mechanisms that
contribute to cognitive decline
following cancer treatment, research
and clinical experience confirm that
cancer survivors are concerned about
the potential impact that cognitive
difficulties may have on quality of
life and daily functioning11, thereby
supporting the value of efforts to
examine intervention possibilities.
Both medical and behavioral
interventions have been identified as
potential avenues for addressing these
difficulties.
One medication that has
received some empirical support
for use in treatment of cognitive
difficulties following treatment
is methylphenidate. Research
with children having a history of
cancer has found that use of this
medication results in improved
cognitive functioning, and particularly
attention21. Additionally, a clinical
trial of dexmethylphenidate for
fatigue in breast cancer survivors
has been conducted; preliminary
findings reported in 2005 at American
Society of Clinical Oncology meeting
suggested this medication resulted
in improvements in fatigue and in
130 w March/April 2009 w 106:2 Missouri Medicine
memory22. However, to date these
medications have not been specifically
approved for the management of
cognitive issues following cancer
treatment.
In terms of behavioral
interventions, general guidelines for
cognitive rehabilitation interventions
can be considered a starting point.
Typically, these interventions focus on
metacognitive strategies (i.e., using
compensatory strategies), which
patients can learn in rehabilitationfocused therapy offered by a
rehabilitation psychologist or speech
language pathologist. There have
been some studies of this strategy with
survivors of childhood cancers and
positive effects are generally found.
Additionally, a rehabilitation-based
model for treated cognitive deficits
among adult cancer survivors was used
in a pilot study23 with positive results.
This intervention focused on
1. education regarding cognitive
functioning;
2. self-awareness training;
3. self-regulation (e.g.,
relaxation training, activity
scheduling and pacing); and
4. cognitive compensatory
strategies training.
At six months after the
intervention, participants evidenced
functioning, emotional well being,
and cognitive functioning. In terms
of physical functioning, Tai Chi
interventions have been shown to
positively effect cardiovascular health,
respiratory functioning, balance,
flexibility and strength24. Positive
effects on emotional functioning have
been suggested by research revealing
that Tai Chi interventions reduce
tension, depression, anger, confusion
and mood disturbance25.
Importantly, preliminary evidence
exists that practice of Tai Chi results
in changes in the physiological stress
response (involving the HPA axis)
described above25. As noted above,
converging lines of evidence indicate
that stress is associated with alterations
in HPA axis functioning, which has
been linked to cognitive deficits in
non-cancer populations. Therefore,
our pilot study will assess whether
practice in a 10-week Tai Chi class
is associated with improvements in
cognitive, emotional and physical
functioning among women cancer
survivors. Measures of cognitive
functioning, physical functioning, and
self-reported stress levels/emotional
functioning are being acquired one
to four weeks prior to treatment,
which involves a 10-week session of
Tai Chi (2 classes/week) and one to
four weeks post-treatment. Our first
session is currently underway, and a
second session is scheduled to begin
in late 2008. With this pilot project
we hope to determine the feasibility
of providing a Tai Chi class to cancer
survivors, and to obtain preliminary
information regarding the potential
benefits to physical, emotional and
cognitive functioning for these
individuals.
Conclusion
As these studies demonstrate,
the DHP Cancer Outcomes Research
Program has three goals with regards
to cognitive deficits following cancer
treatments: understanding the
implications of these difficulties in
terms of daily functioning and quality
of life, contributing to research
considering possible etiologies, and
identifying and evaluating treatments
to improve the lives of individuals
with a history of cancer. While this
program of research focuses on a
specific medical population, these
identified goals mirror those of other
research programs in the Department
of Health Psychology and contribute to
the department’s general mission. Not
only do we strive to address patients’
needs in our region with our clinical
services, but through our research
we also aim to improve the lives of
Missourians and all individuals dealing
with a variety of chronic medical
issues.
References
1. Carver CS, Smith RG, Petronis VM, Antoni
MH. Quality of life among long-term survivors of
breast cancer: different types of antecedents predict
different classes of outcomes. Psycho-Oncology
2006; 15(9): 749-758.
2. Tannock IF, Ahles TA, Ganz PA, Van Dam FS.
Cognitive impairment associated with chemotherapy
for cancer: report of a workshop. Journal of Clinical
Oncology 2004; 22(11): 2233-2239.
3. Ahles TA, Saykin A. Cognitive Effects of
Standard-Dose Chemotherapy in Patients with
Cancer. Cancer Investigation 2001; 19: 812-820.
4. Ahles TA, Saykin A, Furstenberg CT, Cole B,
Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell
T, Greenberg ER, Silberfarb PM. Neuropsychologic
Impact of Standard-Dose Systemic Chemotherapy
in Long-Term Survivors of Breast Cancer and
Lymphoma. Journal of Clinical Oncology 2002; 20:
485-493.
5. Brezden CB, Phillips K, Abdolell M, Bunston
T, Tannock IF. Cognitive Function in Breast Cancer
Patients Receiving Adjuvant Chemotherapy. Journal
of Clinical Oncology 2000; 18: 2695-2701.
6. Jansen CE, Miaskowski C, Dodd M, Dowling
G, Kramer J. A metaanalysis of studies of the effects
of cancer chemotherapy on various domains of
cognitive function. Cancer 2005; 104(10): 2222-2233.
7. Schagen SB, van Dam FSAM, Muller MJ,
Boogerd W, Lindeboom J, Bruning PF. Cognitive
Deficits after Postoperative Adjuvant Chemotherapy
for Breast Carcinoma. Cancer 1999; 85: 640-650.
8. Anderson-Hanley C, Sherman ML, Riggs
R, Agocha VB, Compas BE. Neuropsychological
effects of treatments for adults with cancer: a metaanalysis and review of the literature. Journal of the
International Neuropsychological Society 2003; 9(7):
967-982.
9. Schagen SB, Muller MJ, Boogerd W,
Rosenbrand RM, van Rhijn D, Rodenhuis S, van Dam
FSAM. Late effects of adjuvant chemotherapy on
cognitive function: a follow up study in breast cancer
patients. Annals of Oncology 2002; 13; 1387-1397.
10. Wefel JS, Lenzi R, Theriault RL, Davis RN,
Meyers CA. The cognitive sequelae of standarddose adjuvant chemotherapy in women with breast
carcinoma. Cancer 2004; 100(11): 2292-2299.
11. Downie FP, Mar Fan HG, Houédé-Tchen N,
Yi Q, Tannock IF. Cognitive Function, Fatigue, and
Menopausal Symptoms in Breast Cancer Patients
Receiving Adjuvant Chemotherapy: Evaluation with
Patient Interview after Formal Assessment. PsychoOncology 2006; 15(10): 921-930.
12. Reid-Arndt SA, Hsieh C, Perry MC. Executive
Dysfunction is Associated with Poorer Quality of
Life One Year after Completing Chemotherapy for
Breast Cancer. Accepted for publication in Journal of
Psychosocial Oncology.
13. Saykin AJ, Ahles TA, McDonald BC.
Mechanisms of chemotherapy-induced cognitive
disorders: neuropsychological, pathophysiological,
and neuroimaging perspectives. Seminars in Clinical
Neuropsychiatry 2003 ; 8(4): 201-216.
14. Reid-Arndt SA. The Potential For
Neuropsychology To Inform Functional Outcomes
Research With Breast Cancer Survivors.
NeuroRehabilitation 2006; 21(1): 51-64.
15. Ahles TA, Saykin AJ, Noll WW, Furstenberg
CT, Guerin S, Cole B, Mott LA. The relationship of
APOE genotype to neuropsychological performance
in long-term cancer survivors treated with standard
dose chemotherapy. Psycho-Oncology 2004 ; 12(6):
612-619.
16. Cimprich B, Ronis DL. Attention and
Symptom Distress in Women with and Without
Breast Cancer. Nursing Research 2001; 50(2): 86-94.
17. Sapolsky RM, Krey LC, McEwen BS. The
neuroendocrinology of stress and aging: the
glucocorticoid cascade hypothesis. Endocrine Review
1986; 7: 284-301.
18. Lupien SJ, Lecours AR, Schwartz G, et
al. Longitudinal study of basal cortisol levels in
healthy elderly subjects: evidence for subgroups.
Neurobiology of Aging 1995 ; 17: 95-105.
19. Mitchell AJ, Dening TR. Depressionrelated cognitive impairment: possibilities for its
pharmacological treatment. Journal of Affective
Disorders 1996; 36(3-4): 79-87.
20. Heesen C, Gold SM, Raji A, et al. Cognitive
impairment correlates with hypothalamo-pituitaryadrenal axis dysregulation in multiple sclerosis.
Psychoneuroendocrinology 2002; 27(4): 505-517.
21. Thompson SJ, Leigh L, Christensen R,
Xiong X, Kun LE, Heideman RL, Reddick WE,
Gajjar A, Merchant T, Pui C, Hudson MM,
Mulhern RK. Immediate Neurocognitive Effects of
Methylphenidate on Learning-Impaired Survivors
of Childhood Cancer. Journal of Clinical Oncology
2001; 19(6): 1802-1808.
22. Lower ES, Fleishman AC, Zeldis J, Faleck
H, Manning D. A phase III, randomized placebocontrolled trial of the safety and efficacy of d-MPH as
new treatment of fatigue and “chemobrain” in adult
cancer patients. Journal of Clinical Oncology 2005;
23(16S): 8000.
23. Ferguson RJ, Ahles TA, Saykin AJ, McDonald BC,
Furstenberg CT, Cole BF, Mott LA. Cognitive-behavioral
management of chemotherapy-related cognitive change.
Psycho-Oncology 2007; 16(8): 772-777.
24. Wang C, Collet JP, Lau J. The Effect of Tai
Chi on Health Outcomes in Patients With Chronic
Conditions: A Systematic Review. Archives of Internal
Medicine 2004; 164: 493-501.
25. Jin P. Changes in Heart Rate, Noradrenaline,
Cortisol and Mood During Tai Chi. Journal of
Psychosomatic Research 1989; 33(2): 197–206.
Disclosures
None reported.
106:2 Missouri Medicine w March/April 2009 w 131
MM