466
‘Chemobrain’ in Breast Carcinoma?
A Prologue
Jeffrey S. Wefel, Ph.D.1
Renato Lenzi, M.D.2
Richard Theriault, D.O.3
Aman U. Buzdar, M.D.3
Scott Cruickshank, M.A.4
Christina A. Meyers, Ph.D.1
1
Department of Neuro-Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston,
Texas.
2
Department of Gastrointestinal Oncology, The
University of Texas M. D. Anderson Cancer Center,
Houston, Texas.
3
Department of Breast Medical Oncology, The
University of Texas M. D. Anderson Cancer Center,
Houston, Texas.
4
Scott Cruickshank and Associates, Santa Bar-
bara, California.
Supported in part by a Dissertation Research Grant
(to J.S.W.) from the Susan G. Komen Foundation.
The authors thank Gabriel N. Hortobagyi, M.D.
(Nellie B. Connally Chair in Breast Cancer, Depart-
ment of Breast Medical Oncology, The University of
Texas M. D. Anderson Cancer Center), for the
participation of his department in ongoing collab-
orations; and Lori Smythe (Research Coordinator,
Department of Neuro-Oncology, The University of
Texas M. D. Anderson Cancer Center) and Carol
Ann Long, Ph.D. (Director, Medical Affairs Oncol-
ogy, Amgen, Inc.), for their technical assistance.
Address for reprints: Christina A. Meyers, Ph.D., De-
partment of Neuro-Oncology (Box 431), The Univer-
sity of Texas M. D. Anderson Cancer Center, 1515
Holcombe Boulevard, Houston, TX 77030; Fax: (713)
794-4999; E-mail: cameyers@mdanderson.org
Received February 23, 2004; revision received
April 22, 2004; accepted April 30, 2004.
© 2004 American Cancer Society
DOI 10.1002/cncr.20393
Published online 21 June 2004 in Wiley InterScience (www.interscience.wiley.com).
BACKGROUND. Chemotherapy-induced cognitive dysfunction in patients with
breast carcinoma has been described previously. However, those studies only
assessed patients’ postchemotherapy cognitive functioning and were not able to
determine the relation between cognitive function and other treatments, such as
surgery and radiotherapy, that often precede systemic chemotherapy.
METHODS. Eighty-four women with breast carcinoma underwent a comprehensive
neuropsychologic evaluation before receiving adjuvant therapy for nonmetastatic
primary breast carcinoma.
RESULTS. Before the start of systemic therapy, 35% of women in the current cohort
exhibited cognitive impairment. Verbal learning (18%) and memory function (25%)
were impaired significantly more frequently relative to normative expectations.
Although the impairments were not significant in the women who were examined,
nonverbal memory (17%), psychomotor processing speed and attention (13%),
confrontational naming (13%), visuoconstruction (13%), and upper-extremity fine
motor dexterity (12%) were impaired more frequently than was expected. Affective
distress was related significantly to cognitive impairment (Pearson chi-square
⫽ 9.90; P ⫽ 0.002). Given the conservative statistical approach employed, extent of
surgery, hormone replacement therapy history, and current menopausal status
failed to achieve statistical significance, but these variables did exhibit provocative
trends with respect to cognitive impairment.
CONCLUSIONS. Cognitive impairment frequently is observed before the adminis-
tration of systemic chemotherapy. Thus, investigations purporting to measure
chemotherapy-induced cognitive dysfunction must employ study designs that
incorporate prechemotherapy baseline assessments to accurately detect changes
in cognitive function that are attributable to chemotherapy. Cancer 2004;101:
466 –75. © 2004 American Cancer Society.
KEYWORDS: cognition disorders, affect, breast neoplasms, drug therapy.
C ancer and the therapeutic modalities used to treat cancer have
been associated with alterations in patients’ cognitive, emotional,
and neurologic functioning.1 It is widely accepted that disease involv-
ing the central nervous system (CNS) and treatments targeting the
CNS (e.g., radiotherapy) may have adverse effects on cognitive func-
tioning. There is growing awareness that malignant disease outside of
the CNS and the treatment of such malignancies with biologic, im-
munologic, and/or hormonal techniques also may result in alter-
ations in patients’ mental status.2
Breast carcinoma is the second most frequent cause of malignancy-
related death among women in the United States. It is estimated that
nearly one in nine women will develop some form of breast carci-
noma in their lifetime.3 Despite optimal surgical treatment for breast
carcinoma, residual tumor cells may remain and either fail to be

removed at the surgical site or disseminate to other
areas of the body. For this reason, adjuvant therapy
(e.g., radiotherapy, chemotherapy, hormonal thera-
pies) has become a standard component of care for
many women with breast carcinoma. The use of ad-
juvant chemotherapy is widely recognized as an im-
portant component of multimodal treatment. It was
found that adjuvant chemotherapy increased disease-
free and overall survival for many patients with breast
carcinoma.4,5 However, chemotherapy has been asso-
ciated with adverse effects, such as nausea, peripheral
neuropathy, and encephalopathy.6,7 The relation be-
tween chemotherapy and cognitive functioning is an
area of active interest in both clinical and research
settings.
A clear understanding of the relation between
chemotherapeutic treatments and cognitive function-
ing is critical, because there is a growing group of
malignancy survivors who often want to return to their
former occupational, scholastic, or familial activities.
In many patients, the integrity of cognitive function-
ing is critical to the fulfillment of this goal. Recently, a
number of studies of women with breast carcinoma
have described changes in cognitive functioning that
are purportedly associated with chemotherapy. Sev-
eral retrospective studies have examined cognitive
functioning months to years after chemotherapy and
concluded that chemotherapy in patients with breast
carcinoma is associated with persistent cognitive def-
icits after the completion of treatment.8 –13 The term
chemobrain has been coined in the lay press to de-
scribe the cognitive decline associated with chemo-
therapy. However, to examine the cognitive effects of
a therapeutic intervention rigorously, it is of para-
mount importance that investigators obtain a pre-
treatment measure of neuropsychologic functioning.
Only in this manner can investigators determine
whether the observed performance in subsequent
evaluations (i.e., postchemotherapy) represents a
change in functioning secondary to treatment or
whether the observed deficits were present before the
administration of the therapeutic agent(s). Remark-
ably, this critical assessment time point has been ab-
sent in all published neuropsychologic studies to date.
Each of those studies concluded that there was clini-
cally significant cognitive impairment associated with
chemotherapy. However, conclusive support for this
association requires longitudinal data that include ob-
jective measurement of patients’ prechemotherapy
cognitive functioning. Anecdotally, several patients at
our institution (The University of Texas M. D. Ander-
son Cancer Center, Houston, TX) have expressed res-
ervations regarding the receipt of agents with known
beneficial effects secondary to concerns about acquir-
Chemobrain in Breast Carcinoma?/Wefel et al. 467
ing ‘chemobrain’. This finding exemplifies emerging
public awareness and concern surrounding the issue
of chemobrain and underscores the importance of
performing methodologically rigorous studies to help
assess the frequency and nature, as well as the poten-
tial mechanisms, of chemotherapy-induced neurotox-
icity.
The potential neurotoxic effects of adjuvant che-
motherapeutic treatments are a serious concern for
many women with breast carcinoma, and well de-
signed investigations to help elucidate the potential
risks and benefits of such treatments are necessary.
Characterizing the neuropsychologic profiles of
women with breast carcinoma who have not previ-
ously received chemotherapy will enhance our under-
standing of the multiple factors that may contribute to
cognitive dysfunction in this population. In addition,
these data should reinforce the importance of using
prospective trials to assess change in cognitive func-
tion secondary to chemotherapy, as the use of retro-
spective analytic techniques is a methodologic limita-
tion of all published trials to date. To this end, we have
examined data that were generated by three separate
prospective clinical research trials conducted at the
University of Texas M. D. Anderson Cancer Center
examining the effects of hormonal treatments (2001–
2003) and chemotherapeutic treatments (1992–1995
and 1994 –998) on cognitive functioning in a popula-
tion of patients with nonmetastatic breast carcinoma.
In each investigation, patients received a comprehen-
sive neuropsychologic evaluation before the start of
systemic chemotherapy or hormonal therapy.
MATERIALS AND METHODS
Patients were recruited as part of three institutional
review board–approved research protocols that were
initiated collaboratively by the Neuropsychology Sec-
tion and the Department of Breast Medical Oncology
at the University of Texas M. D. Anderson Cancer
Center. However, neuropsychologic outcome was a
nonfunded endpoint in two of those trials. Patient
enrollment and collection of data on this endpoint
were terminated early due to funding issues; thus, the
overall patient pool for the analysis of this endpoint
was smaller than the patient pool that was available in
the primary medical trials. All patients who met initial
screening criteria and consented to participate in the
trials were registered consecutively into a protocol for
evaluation. All patients had a diagnosis of primary
breast carcinoma and no evidence of metastatic dis-
ease, were age ⱖ 18 years, had completed ⱖ 8 years of
formal education, and spoke fluent English. No pa-
tient had a history of other primary malignancy or a
previous or current neurologic or psychiatric disorder,
468 CANCER August 1, 2004 / Volume 101 / Number 3

and no patient used substances that were active in the TABLE 1

CNS and were believed to affect cognition (e.g., nar- Neuropsychologic Tests Grouped by Principle Cognitive Domain
cotics, antiemetics, or steroids) ⱕ 1 week before test-
Domain/test namea Test abbreviation
ing. Ninety-seven patients met the initial screening
criteria for participation. Eighty-four patients with a Attention
diagnosis of Stage I breast carcinoma (T1N0M0; n WAIS-R15/WAIS-III16 Digit Span WAIS-R/III DSpan
⫽ 32), Stage II breast carcinoma (T2N0M0; n ⫽ 41), or WAIS-R Digit Symbol WAIS-R DSymbol
WAIS-R Arithmetic WAIS-R Arith
Stage IIIA breast carcinoma (T2N2M0; n ⫽ 11) quali- WAIS-III Letter-Number Sequencing WAIS-III LN
fied for study entry and underwent neuropsychologic WMS-III17 Mental Control WMS-III MC
evaluation before beginning chemotherapy. Thirteen Trail Making Test18 Part A TMTA
patients did not meet the inclusion criteria and were Memory
HVLT19 Trials 1–3 HVLT T1–T3
not part of the subsequent analyses. Of these, seven
HVLT Recognition Discriminability HVLT DISCRIM
patients stated that they did not have time to partici- VSRT20 Long-Term Storage VSRT LTS
pate, two patients had educational limitations that VSRT Delayed Recall VSRT DR
precluded valid assessment, two patients had histories NVSRT21 Long-Term Storage NVSRT LTS
NVSRT Delayed Recall NVSRT DR
of major depression, one patient had a history of sub-
ROCFT22 Delayed Recall ROCFT DR
stance abuse, and one patient had a history of previ- Language
ous breast carcinoma. MAE23 Controlled Oral Word Association COWA
Of the 84 patients who were included in the anal- Boston Naming Test24 BNT
yses, 50% (n ⫽ 42) had undergone surgical resection MAE Sequential Commands MAE SC
Executive
for primary breast carcinoma, and 50% (n ⫽ 42) had
Trail Making Test Part B TMTB
undergone core-needle biopsy before the neuropsy- Category Test25 CT
chologic evaluation in association with their partici- WAIS-III Similarities WAIS-III Sim
pation in a trial that involved neoadjuvant chemother- Visuospatial
WAIS-R Block Design WAIS-R BD
apy after biopsy for pathologic verification.
ROCFT Copy ROCFT Copy
Approximately 12% of all patients (n ⫽ 10) had re- Judgment of Line Orientation26 JLO
ceived adjuvant radiotherapy to the chest wall with or Motor
without the inclusion of regional lymphatic chains Grip Strength (dominant hand)27 GRIP (dominant)
before neuropsychologic evaluation. The mean (⫾ Grooved Pegboard (dominant hand)28 PEG (dominant)
Depression
standard deviation [SD]) patient age was 50.4 years (⫾ Beck Depression Inventory29 BDI
9.1 years). On average, patients had completed 14 Beck Depression Inventory, Second Edition30 BDI-2
years of education (⫾ 2.6). Ethnically, 69 patients MMPI (Depression scale)31 MMPI (Scale 2)
(82%) were Caucasian, 8 (10%) were Hispanic, 6 (7%) Anxiety
State-Trait Anxiety Inventory—State score32 STAIS
were African American, and 1 (1%) was Asian. Data on
Beck Anxiety Inventory33 BAI
menopausal status (based on review of patients’ med- MMPI (Psychasthenia scale) MMPI (Scale 7)
ical records) were available for all patients: approxi-
mately 42% (n ⫽ 35) were naturally postmenopausal, WAIS-R/III: Wechsler Adult Intelligence Scale—Revised or Third Edition; WMS-III: Wechsler Memory
15% (n ⫽ 13) had a history of surgically induced Scale—Third Edition; HVLT: Hopkins Verbal Learning Test; VSRT: Verbal Selective Reminding Test;
NVSRT: Nonverbal Selective Reminding Test; ROCFT: Rey–Osterreith Complex Figure Test; MAE:
menopause, 2% (n ⫽ 2) were perimenopausal, and Multilingual Aphasia Examination; MMPI: Minnesota Multiphasic Personality Inventory.
40% (n ⫽ 34) were premenopausal at the time of a
Superscript numerals refer to the list of references.
neuropsychologic evaluation. Data on prior use of
hormone replacement therapy (HRT) were available
for 67 of 84 patients: Thirty patients (45%) had previ- measures, which required approximately 40 –120 min-
ously used HRT, whereas 37 (55%) had never used utes to be completed.
HRT. The median time between neuropsychologic Patients’ raw cognitive test score performances
evaluation and last use of HRT was 52 days (range, 4 were converted to standardized scores (z scores: mean
days to 23.9 years). ⫾ SD, 0 ⫾ 1) based on published normative data to
Due to the nature of the research studies and facilitate comparisons between measures. An Overall
changes in clinical practice, patients received a variety Cognitive Function Index (OCFI) for each patient’s
of cognitive tests. To facilitate interpretation, these test performance was calculated. Impaired OCFI
tests were grouped into domains based on previous (OCFI-I) was ascertained using a 2-step criterion: 1) if
neuropsychologic research14 (Table 1). All patients un- a patient had multiple test performance z scores
derwent an assessment that included 5–14 different ⱕ ⫺1.5, then she was considered to have impaired

functioning (OCFI-I); 2) if a patient had only 1 test that
met the aforementioned criteria (i.e., z score ⱕ ⫺1.5),
then that single z score had to be ⱕ ⫺2.0 for the
patient to be classified as having impaired function-
ing. This two-step approach was used to minimize the
number of false-positive errors due to multiple tests
and to determine the frequency of impairment rather
than the frequency of low performance levels. In a
normal, healthy population, approximately 7% and 2%
of the population would have scores ⬍ ⫺1.5 and
⬍ ⫺2.0, respectively, by chance alone. If a patient did
not exhibit impaired performance, then the OCFI clas-
sification was not impaired (OCFI-NI).
For each cognitive measure, a binomial test was
conducted to determine whether the frequency of im-
pairment observed in the study group differed from
normative expectations. To correct for multiple com-
parisons, ␣, the cutoff value for determining statistical
significance, was set at 0.01. The overall frequency of
cognitive impairment based on the OCFI and the fre-
quency of impairment within each domain were then
calculated.
Self-reports of anxious and depressive symptoms
warranted a classification of clinically significant dis-
tress–impaired (CSD-I) if the reports exceeded the lim-
its recommended by the measures’ manuals. Specifi-
cally, patients with raw scores ⱖ 18 on the Beck
Depression Inventory (BDI), the BDI Second Edition
(BDI-2), and the Beck Anxiety Inventory (BAI) received
a classification of CSD-I. Similarly, patients who had
scores ⱖ the 95th percentile on the ‘State’ subscale of
the State-Trait Anxiety Inventory (STAIS) received a
classification of CSD-I. Patients with scores lower than
these specified values received a classification of not
clinically significantly distressed (CSD-NI). All patients’
Minnesota Multiphasic Personality Inventory (MMPI)
profiles yielded adequate validity scale indices to be
considered for further clinical scale interpretation.34
Scale 2 of the MMPI measures depression through
true/false statements regarding affective symptoms
(e.g., poor morale), cognitive symptoms (e.g., hope-
lessness), and physical symptoms (e.g., sleep distur-
bances). Scale 7 of the MMPI measures anxiety across
the domains of neuroticism, anxiety, withdrawal, poor
concentration, agitation, psychotic tendencies, and
poor physical health. Patients with T scores ⱖ 70 on
Scale 2 or Scale 7 of the MMPI received a classification
of CSD-I; patients with scores below this cutoff re-
ceived a classification of CSD-NI.
Pearson correlations between mood measures
(i.e., BDI, BDI-2, and BAI raw scores; STAIS percen-
tiles; and MMPI Scale 2 and Scale 7 T scores) and
standard scores for marker variables from each do-
main were analyzed to decrease the number of statis-
Chemobrain in Breast Carcinoma?/Wefel et al. 469
tical tests performed. Cognitive tests that appeared to
be most sensitive were selected as marker variables
(i.e., the Trailmaking Test Part A [TMTA]; the Verbal
Selective Reminding Test, Long-Term Storage [VSRT
LTS]; the VSRT Delayed Recall [DR]; the Nonverbal
Selective Reminding Test [NVSRT] DR; the Boston
Naming Test [BNT]; the Trailmaking Test Part B
[TMTB]; the Rey–Osterreith Complex Figure Test
[ROCFT] Copy; and the Grooved Pegboard Test [dom-
inant hand]). Given the large number of statistical
tests performed, ␣, the cutoff value for determining
statistical significance, was set at 0.01.
RESULTS
Using the classification criteria described above, ap-
proximately 35% (29 of 84 patients; binomial test: P
⬍ 0.001) received a classification of OCFI-I before the
initiation of adjuvant chemotherapy. Of the patients
who had impaired functioning, approximately 31% (9
of 29) exhibited impairment on 1 test, whereas ap-
proximately 69% (20 of 29) exhibited impairment on 2
or more tests. The frequency of cognitive impairment
within each domain varied as a function of the test
that was used to make the measurement (Table 2).
Women with breast carcinoma exhibited impaired
verbal learning (VSRT LTS; Binomial test: P ⬍ 0.01)
and verbal memory (VSRT DR; Binomial test: P ⬍ 0.01)
significantly more frequently relative to normative ex-
pectations. In addition, 1 measure of psychomotor
processing speed and attention approached signifi-
cance (TMTA; P ⫽ 0.017). Several other measures of
cognitive functioning (NVSRT DR, BNT, ROCFT Copy,
and PEG [dominant hand]) that revealed levels of im-
pairment similar to those revealed by the TMTA failed
to approach significance, probably due to small sam-
ple sizes.
In the current cohort, 26% of patients (20 of 78)
reported symptoms of anxiety and/or depression that
met the criteria for a classification of CSD-I. Chi-
square analysis demonstrated that patients who were
classified as having reported significant affective dis-
tress (i.e., CSD-I) were significantly more likely to be
cognitively impaired (i.e., OCFI-I; chi-square ⫽ 9.90; P
ⱕ 0.005; Fig. 1). Among patients with a classification of
OCFI-I who completed mood assessment (n ⫽ 28),
⬍ 50% (13 of 28) received a classification of CSD-I.
Scores on the self-report measures of affective distress
for patients with a classification of CSD-I were as
follows: BDI raw score range, 24 –28; BDI-II raw score,
20; BAI raw score range, 19 –29; STAIS percentile
range, ⬍ 1 to 6; MMPI Scale 2 T score range, 71– 80;
and MMPI Scale 7 T score, 74. Overall, these scores are
consistent with mild-to-moderate ranges of affective
distress, and no patient received a psychiatric diagno-
470 CANCER August 1, 2004 / Volume 101 / Number 3

TABLE 2 TABLE 3
Mean Scores and Impairment Frequencies Before Chemotherapy on Coefficients for Correlations between Mood Measures
Tests Grouped by Principle Cognitive Domain and Cognitive Marker Variables

No. of Mood measurea

Cognitive domain patients tested Mean (SD) Impaired (%)
MMPI MMPI
Attention Cognitive test BDI BDI-2 BAI STAIS (Scale 2) (Scale 7)
WAIS-R/III DSpana 84 10.0 (3.0) 5
WAIS-R DSymbola 60 11.7 (2.5) 2 Attention
WAIS-R Aritha 18 10.2 (2.6) 6 TMTA 0.20 NA NA ⫺0.30 0.31 ⫺0.11
WAIS-III LNa 24 11.7 (3.3) 4 Learning
WAIS-III MCa 24 11.2 (2.6) 0 VSRT LTS NA NA NA NA ⫺0.07 0.01
TMTAb 84 ⫺0.11 (1.37) 13 Memory
Learning VSRT DR NA NA NA NA ⫺0.16 ⫺0.14
HVLT T1–T3b 42 ⫺0.09 (0.90) 10 NVSRT DR NA NA NA NA ⫺0.38 ⫺0.15
VSRT LTSb 40 ⫺0.27 (1.20) 18c Language
NVSRT LTSb 18 0.11 (0.83) 6 BNT NA ⫺0.44 ⫺0.44 NA NA NA
Memory Executive
HVLT DISCRIMb 42 0.29 (0.71) 2 TMTB 0.04 NA NA ⫺0.42b ⫺0.25 ⫺0.24
VSRT DRb 40 ⫺0.54 (1.80) 25d Visuospatial
NVSRT DRb 18 0.00 (1.04) 17 ROCFT Copy NA ⫺0.32 ⫺0.30 NA NA NA
ROCFT DRb 24 0.13 (0.82) 4 Motor
Language PEG NA NA NA NA ⫺0.20 ⫺0.36
Expressive
COWAb 84 6 BDI: Beck Depression Inventory; BDI-2: Beck Depression Inventory—Second Edition; BAI: Beck Anxiety
BNTb 24 13 Inventory; STAIS: State-Trait Anxiety Inventory—State scale; MMPI: Minnesota Multiphasic Personality
Receptive Inventory; TMTA: Trail Making Test, Part A; VSRT: Verbal Selective Reminding Test; LTS: Long-Term
MAE SCb 24 0 Storage; DR: Delayed Recall; NVSRT: Nonverbal Selective Reminding Test; BNT: Boston Naming Test;
Executive function TMTB: Trail Making Test, Part B; ROCFT: Rey–Osterreith Complex Figure Test; PEG: Grooved Pegboard
TMTBb 84 0.13 (1.90) 6 Test; NA: not administered (due to variation between protocols, neither measure was administered).
CTb 41 0.22 (0.91) 0 a
Metric: raw score for BDI, BDI-2, and BAI; percentile for STAIS; T score for MMPI Scale 2 and Scale
WAIS-III Sima 42 12.1 (3.4) 5 7; and z score for cognitive tests.
Visuospatial b
Pearson correlation: P ⬍ 0.01.
Perceptual
JLOb 24 0.91 (0.38) 0
Perceptual-motor TABLE 4
WAIS-R BDa 18 11.4 (2.9) 0 Frequency of Clinically Significant Before Chemotherapy Distress
ROCFT Copyb 24 0.31 (1.34) 13 on Self-Report Measures by Domain
Motor
GRIP (dominant)b 18 0.11 (0.98) 0 Psychologic domain No. of patients assessed CSD-I (%)
PEG (dominant)b 42 0.02 (1.14) 12
Depression
SD: standard deviation; WAIS-R/III: Wechsler Adult Intelligence Scale—Revised or Third Edition;
MMPI (Scale 2) 17 35
DSpan: Digit Span; DSymbol: Digit Symbol; Arith: Arithmetic; LN: Letter-Number Sequencing; WMS-III
BDI-2 24 8
MC: Wechsler Memory Scale—Third Edition, Mental Control; TMTA: Trail Making Test, Part A; HVLT
BDI 42 4
T1–T3: Hopkins Verbal Learning Test (LVLT) Trials 1–3; VSRT: Verbal Selective Reminding Test; LTS:
Anxiety
Long-Term Storage; NVSRT: Nonverbal Selective Reminding Test; DISCRIM: Recognition Discrim-
MMPI (Scale 7) 17 35
inability; DR: Delayed Recall; ROCFT: Rey–Osterreith Complex Figure Test; COWA: Multilingual Aphasia
STAIS 42 32
Examination (MAE) Controlled Oral Word Association; BNT: Boston Naming Test; SC Sequential
BAI 24 8
Commands; TMTB: Trail Making Test, Part B; CT: Category Test; Sim: Similarities; JLO: Judgment of
Lone Orientation; BD: block design; GRIP (dominant): Grip Strength (dominant hand); PEG (dominant):
CSD-I: clinically significant distress; MMPI: Minnesota Multiphasic Personality Inventory; BDI-2: Beck
Grooved Pegboard (dominant hand).
a
Depression Inventory—Second Edition; BDI: Beck Depression Inventory; STAIS: State-Trait Anxiety
Scaled scores: mean, 10; standard deviation, 3.
b
Inventory—State scale; BAI: Beck Anxiety Inventory.
z scores: mean, 0; standard deviation, 1.
c
Binomial test (P ⬍ 0.01).
d
Binomial test (P ⬍ 0.001).
sociations between mood and cognitive function were
detected. Differences in the frequency of distress
sis of major depression or an anxiety disorder. Analy- within the domains of mood function also varied,
sis of Pearson correlations between domain-specific depending on the measure used (Table 4), with the
cognitive marker variables and mood measures re- MMPI appearing most sensitive to depression and
vealed that STAIS scores were significantly correlated roughly equal to the STAIS in terms of sensitivity to
with TMTB scores (Table 3). No other significant as- symptoms of anxiety.
 Chemobrain in Breast Carcinoma?/Wefel et al. 471

Exploratory analyses were conducted to identify

demographic, disease-related, and treatment-related
factors that may be associated with the presence of
cognitive impairment (i.e., OCFI-I) before chemother-
apy. An adjusted ␣ level of 0.01 was chosen for the
assessment of statistical significance, given our desire
to correct for multiple comparisons and minimize the
possibility of Type I error. Association between OCFI
and age and education were explored using indepen-
dent-sample t tests. Association of disease-related and
treatment-related variables with OCFI were examined
using chi-square analyses. All disease- and treatment-
related variables were dichotomized. For disease
stage, women were divided into 2 groups: women with
Stage I or II disease (n ⫽ 74) and women with Stage
IIIA disease (n ⫽ 10). Women also were divided into 2
groups on the basis of extent of surgery: women who FIGURE 1. Overall Cognitive Function Index (OCFI) in relation to affective
underwent surgical resection (n ⫽ 41) and women status. CSD-I: clinically significant distress–impaired; CSD-NI: clinically signif-
who underwent biopsy only (n ⫽ 43). Women who icant distress–not impaired; OCFI-I: OCFI-impaired; OCFI-NI: OCFI–not im-
previously had received chest wall irradiation (n ⫽ 10) paired. Pearson ␹2(1, N ⫽ 78) ⫽ 9.90; P ⫽ 0.002.
were distinguished from women who had never re-
ceived irradiation (n ⫽ 74). Women who were post-
menopausal either naturally or due to surgery were
grouped together (n ⫽ 48) and were compared with
women who were either premenopausal or perimeno-
pausal (n ⫽ 36). Postmenopausal women with avail-
able data on HRT use were classified as HRT users (n
⫽ 30) if they had any history of HRT use or as HRT
nonusers (n ⫽ 18) if they had never used HRT.
Patients in the OCFI-I and OCFI-NI groups did not
differ significantly with regard to age (t[82] ⫽ 2.02; P
⫽ 0.05; mean ⫾ SD: OCFI-I, 53.1 ⫾ 9.8 years; OCFI-NI,
48.9 ⫾ 8.4 years) or education (t[82] ⫽ 1.92; P ⫽ 0.06;
mean ⫾ SD: OCFI-I, 13.2 ⫾ 2.7 years; OCFI-NI, 14.4
⫾ 2.4 years). Women who were postmenopausal (Fig.
1), had no history of HRT use (Fig. 2), or had under-
gone lumpectomy/mastectomy (Fig. 3) were nearly FIGURE 2. Overall Cognitive Function Index (OCFI) in relation to menopausal
status. Postmeno: postmenopausal; Premeno: premenopausal; OCFI-I: OCFI-
twice as likely to be cognitively impaired compared
impaired; OCFI-NI: OCFI–not impaired. Pearson ␹2(1, N ⫽ 84) ⫽ 4.22; P
with women who did not have such characteristics;
⫽ 0.04.
however, for none of these differences was P ⱕ 0.01.
Women with a classification of OCFI-I did not differ
significantly from women with a classification of evaluation of cognitive functioning against which
OCFI-NI in terms of any other demographic, disease- postchemotherapy changes in performance could be
related, or treatment-related variable. compared. A longitudinal design of this nature is nec-
essary to clearly demonstrate the relation between
DISCUSSION adjuvant chemotherapy and cognitive functioning.
Adjuvant chemotherapy has been reported to be as- In the current study, we found that 36% of women
sociated with the development of both early and de- with breast carcinoma demonstrated impaired overall
layed cognitive dysfunction in a population of women cognitive function before the initiation of adjuvant
with breast carcinoma. However, methodologic limi- chemotherapy. Cognitive impairment in the domains
tations in all studies on this topic that have been of verbal learning and memory was observed signifi-
published to date make these conclusions controver- cantly more frequently in the study cohort than in the
sial.35,36 Perhaps most significantly, previous studies comparison group of normal control patients. In ad-
failed to include a pretreatment neuropsychologic dition, differences in psychomotor processing speed
472 CANCER August 1, 2004 / Volume 101 / Number 3
FIGURE 3. Overall Cognitive Function Index (OCFI) in relation to hormone
replacement therapy (HRT) status. HRT nonusers had no history of HRT use,
whereas HRT users did have a history of HRT use. OCFI-I: OCFI-impaired;
OCFI-NI: OCFI–not impaired. Pearson ␹2(1, N ⫽ 48) ⫽ 2.29; P ⫽ 0.13.
FIGURE 4. Overall Cognitive Function Index (OCFI) in relation to extent of
surgery. Lump/mast: lumpectomy or mastectomy; OCFI-I: OCFI-impaired; OCFI-
NI: OCFI–not impaired. Pearson ␹2(1, N ⫽ 84) ⫽ 4.95; P ⫽ 0.03.
and attention, nonverbal memory, confrontational
naming, complex visuoconstruction, and fine motor
dexterity approached significance. In five previously
published cross-sectional studies that assessed pa-
tients’ cognitive status after chemotherapy, cognitive
dysfunction was defined inconsistently and often far
less rigorously than in the current investigation, with
these definitions sometimes including performance
scores that were within the ranges for normal control
patients. The finding that many patients who were
treated with chemotherapy had performance scores
that fell within normal ranges makes attributions of
neurotoxicity in these patients particularly dubious.
Across these studies, the frequency of cognitive dys-
function ranged from 17% to 75%. Given the current
documentation of objective cognitive impairment be-
fore adjuvant systemic therapy, a large proportion of
patients in previously published reports who per-
formed at levels below what was expected when they
were assessed after chemotherapy may well have per-
formed at that same level before chemotherapy. Those
previous studies, therefore, may have overestimated
the true incidence of decreases in cognitive function-
ing secondary to chemotherapy.
The assessment of cognitive impairment in the
current study involved comparison of patients’ scores
on measures of cognitive skills with published norma-
tive data. We propose that test performance scores for
a group of individuals without breast carcinoma con-
stituted a valid control for the purposes of the study.
Women diagnosed with nonmetastatic breast carci-
noma are not commonly believed to experience neu-
rologic dysfunction. Thus, their performance is ex-
pected to be similar to that of individuals with similar
demographic backgrounds (e.g., in terms of age and
education). The use of normative data means that
study patients are being compared with just such a
control group. Normative data often have the advan-
tage of representing much larger populations than the
control populations recruited by individual investiga-
tors on a study-by-study basis. This leads to two im-
portant design features: 1) stratification according to
relevant demographic variables (e.g., age and educa-
tion) can be performed, so that the study group is
compared with appropriately matched control pa-
tients; and 2) the larger cohort associated with the
normative data provides a more stable estimate of the
mean and SD in the population from which the rep-
resentative sample was drawn, and thus a more accu-
rate and valid estimate of the true score for the control
group with which the study cohort is compared.
This approach has been criticized, because it fails
to control for potential differences in emotional dis-
tress that may accompany being diagnosed with a
medical illness. Thus, a similarly affected control
group often is desirable to control for this potentially
confounding influence on cognitive function. How-
ever, because the current cohort was untreated, it was
not possible to recruit another breast carcinoma co-
hort that would control for issues of emotional distress
while not also controlling for our variable of interest,
cognitive function in women with breast carcinoma
before treatment. The use of another medically af-
fected population also is problematic, because there is

evidence that the presence of disease without direct
CNS involvement may nonetheless have effects on the
CNS in some instances. For example, newly diagnosed
(i.e., untreated) patients with small cell lung carci-
noma who had no evidence of CNS involvement ex-
hibited cognitive dysfunction before the initiation of
any therapy,37 further underscoring the importance of
obtaining pretreatment measures of cognitive func-
tion. Thus, the use of another population that is af-
fected by disease may also obscure the very phenom-
enon that is of interest to the investigator. Due to
these considerations, we chose to use relevant norma-
tive data as our control and supplemented our assess-
ment with measures of emotional well-being to inves-
tigate the correlation between emotional distress and
cognitive function.
Methodologic limitations notwithstanding, a con-
sistent pattern of cognitive dysfunction attributable to
chemotherapy has not emerged from previously pub-
lished studies. The involved domains of cognitive
function have included learning and memory, pro-
cessing speed, attention, and visuoperception. The
variability in findings of cognitive dysfunction may be
attributable in part to the choice of measures used in
each study and the differential sensitivity of each mea-
sure, as suggested in the current investigation. In gen-
eral, researchers interested in studying perturbations
of the underlying neural networks that are responsible
for various cognitive functions may wish to employ
the most sensitive measure for each specific cognitive
domain. The effects of a treatment (or any neurologic
condition), as demonstrated previously,38 may be ob-
servable only when a cognitive system is stressed suf-
ficiently so that it unmasks the dysfunction and
overwhelms potential compensatory mechanisms.
Relatively insensitive tests, such as cognitive screening
tools (e.g., the Mini-Mental State Examination39), tend
to underestimate the nature and extent of cognitive
dysfunction, often lack specificity for any particular
cognitive domain, and may fail to capture subtle but
meaningful changes in a patient’s cognitive status.40
We also attempted to discern factors related to the
occurrence of cognitive impairment in patients with
breast carcinoma. Although correlations between cog-
nitive function before chemotherapy and demo-
graphic, disease-related, and clinical characteristics
did not exceed our adjusted ␣ value for determining
statistical significance, several provocative trends
emerged. Patients who underwent more invasive sur-
gery (lumpectomy or mastectomy), patients who were
postmenopausal, and patients who had not previously
used any HRT appeared to have a greater risk of pre-
senting with cognitive impairment.
Debate continues about the adverse effects of car-
Chemobrain in Breast Carcinoma?/Wefel et al. 473
diac and noncardiac surgery on patients’ postacute
cognitive function, with some investigations demon-
strating declines in postoperative cognitive func-
tion41,42 and others reporting no significant decline
approximately 1 month after surgery.43 All women in
the current study who underwent lumpectomy or
mastectomy subsequently underwent neuropsycho-
logic evaluation an average of 53 days (SD, 39.8 days)
after surgery. Follow-up analyses in the current sam-
ple did not detect significant differences between pa-
tients who exhibited cognitive impairment (OCFI-I;
mean ⫾ SD, 63.8 ⫾ 50.3 days) and patients with a
classification of cognitively not impaired (OCFI-NI;
mean ⫾ SD, 44.4 ⫾ 25.8 days) in terms of the length of
time between surgery and neuropsychologic evalua-
tion. Thus, there is no evidence that women who were
assessed more acutely postoperatively were more
likely to exhibit cognitive impairment.
Alterations in women’s hormonal milieu report-
edly have been associated with changes in cognitive
function. Although controversy remains regarding the
cognitive effects of HRT,44 there is evidence that sur-
gical or chemical induction of menopause is associ-
ated with impairments in cognitive function and
mood.45,46 The presence of affective distress was asso-
ciated with cognitive impairment in the current inves-
tigation; however, it was not causally related to cog-
nitive impairment. Thus, depression, anxiety, and
cognitive dysfunction appear to be separable, albeit
comorbid, conditions in this population.
We recognize that a short screening measure that
can be administered and interpreted by a variety of
health care professionals with minimal training in
neuropsychology would be highly desirable. Unfortu-
nately, the sensitivity of these measures (e.g., the
Mini-Mental State Examination) in detecting cognitive
disturbances that are not severe enough to be consid-
ered dementia is poor.40 Currently, clinicians should
continue discussing cognitive functioning with their
patients and should refer patients for neuropsycho-
logic evaluation if they or their family members report
changes in their ability to think. In this way, a com-
prehensive evaluation may be undertaken that can
yield differential diagnostic information and provide
treatment recommendations.
To our knowledge, the current report is the first to
document the presence of cognitive impairment in a
cohort of patients with breast carcinoma without CNS
involvement before the initiation of systemic adjuvant
therapy. Although the current study does not afford a
comprehensive examination of the many potential eti-
ologic agents responsible for this dysfunction, it is
speculated that both host-related factors and disease-
related factors may be involved. Research is actively
474 CANCER August 1, 2004 / Volume 101 / Number 3
pursuing host-related, or soil, characteristics, such as
genetic polymorphisms, immune reactivity, nutri-
tional factors, hormonal histories, or lack of cognitive
reserve, that are associated with an increased likeli-
hood of developing cognitive dysfunction either be-
fore or in concurrence with the administration of ad-
juvant therapy. In addition, disease-related, or seed,
factors, including tumor gene mutations, induction of
proinflammatory cytokines, and paraneoplastic disor-
ders, as well as interactions between disease-related
factors and host-related factors, may contribute to the
development of cognitive dysfunction. Interdiscipli-
nary investigations of both the behavioral expression
of perturbations within the neural networks responsi-
ble for cognition and the potential mechanistic con-
tributors to the observed neurotoxicity will assist in
the development of rational, targeted therapeutic op-
tions (e.g., cytokine antagonists or neuroprotectants)
in the future.
There appears to be justification for concern re-
garding the potential neurotoxicities associated with
systemic antitumor agents used therapeutically to
treat and cure breast carcinoma. However, our current
understanding of the cognitive and neurobehavioral
effects of these treatments is extremely limited. This
issue is of significant clinical importance given the
prevalence of breast carcinoma; the increased use of
chemotherapy as adjuvant therapy; the increasing use
of more aggressive dosing schedules; the increasing
survival rates being achieved; and patients’ natural
desire to return to their normal occupational, aca-
demic, and social pursuits. Thus, it is imperative that
future investigations use well designed longitudinal
methodologies that will assist in defining the relative
risks and benefits inherent in the available treatments
so that truly informed treatment decisions can be
made. The results of our own prospective longitudinal
trials will be available soon.
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