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Neuropsychological Performance in Survivors of BreastCancer More Than 20 Years After Adjuvant Chemotherapy
Vincent Koppelmans, Monique M.B. Breteler, Willem Boogerd, Caroline Seynaeve, Chad Gundy,†and Sanne B. SchagenPurpose Adjuvant chemotherapy for breast cancer can have adverse effects on cognition shortly after
administration. Whether chemotherapy has any long-term effects on cognition is largely unknown,
yet it becomes increasingly relevant because of the widespread use of chemotherapy for
early-stage breast cancer and the improved survival. We investigated whether cyclophosphamide,
methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer is associated with worse
cognitive performance more than 20 years after treatment. Patients and Methods
This case-cohort study compared the cognitive performance of patients with breast cancer who
had a history of adjuvant CMF chemotherapy treatment (six cycles; average time since treatment,
21 years; n ϭ 196) to that of a population-based sample of women never diagnosed with cancer
(n ϭ 1,509). Participants were between 50 and 80 years of age. Exclusion criteria were ever use
of adjuvant endocrine therapy, secondary malignancy, recurrence, and/or metastasis. Results The women exposed to chemotherapy performed significantly worse than the reference group on
cognitive tests of immediate (P ϭ.015) and delayed verbal memory (P ϭ.002), processing speed(P Ͻ.001), executive functioning (P ϭ.013), and psychomotor speed (P ϭ.001). They experienced
fewer symptoms of depression (P Ͻ.001), yet had significantly more memory complaints on two
of three measures that could not be explained by cognitive test performance. Conclusion
Survivors of breast cancer treated with adjuvant CMF chemotherapy more than 20 years ago
perform worse, on average, than random population controls on neuropsychological tests. The
pattern of cognitive problems is largely similar to that observed in patients shortly after cessation
of chemotherapy. This study suggests that cognitive deficits following breast cancer diagnosis and
subsequent CMF chemotherapy can be long lasting. J Clin Oncol 30:1080-1086. 2012 by American Society of Clinical Oncology
genetic susceptibility, in patients with breast can-
INTRODUCTION
cer who have been exposed to chemotherapy are
Chemotherapy has well-recognized acute adverse
topics of ongoing research.23 Besides differences in
effects, including nausea and hair loss. Cognitive
cognitive performance, structural brain differences
impairment is a potential short-term adverse effect
have been observed in patients who underwent
that has gained more attention only in the last
chemotherapy compared with controls, including
decade.1-20 Several studies have shown that chemo-
more white-matter hyperintensities, microstruc-
therapy can induce cognitive changes up to 5 years
tural damage to white-matter tracts, and gray matter
after treatment.2,5,14,20 Differences are primarily ob-
alterations,1,7,24-30 whereas functional magnetic res-
served in the domains of memory, processing speed,
onance imaging (fMRI) studies revealed measurable
and executive function and are generally not explained
differences in task-specific responsiveness between
by sociodemographic and clinical variables.21 Never-
patients exposed to chemotherapy and con-
theless, cognitive dysfunction has also been ob-
trols.5,26,31 The observational studies in humans are
served in the domains of visuospatial functioning22
and psychomotor speed.15 Potential predictors for
Whether chemotherapy has long-term effects
cognitive problems, such as cognitive reserve and
on brain function is still largely unknown. However,
2012 by American Society of Clinical Oncology
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Copyright 2012 American Society of Clinical Oncology. All rights reserved. Cognitive Performance in Survivors of Cancer Long After Chemotherapy
this question is becoming increasingly relevant because the number of
physician, who were between 50 and 80 years of age at the time of neuropsy-
long-term survivors is rapidly increasing.
chological assessment. In total, 1,509 participants met these criteria.
We investigated the late effects of chemotherapy on cognitive
Methods
functioning by comparing the neuropsychological test performance of
Examination of the participants took place at the Rotterdam Study
women with breast cancer who received adjuvant cyclophosphamide,
research center.34 Participants underwent neuropsychological examinations
methotrexate, and fluorouracil (CMF) chemotherapy on average
and an interview identical with those used in the Rotterdam Study. Subse-
more than 20 years before that of a population sample of women who
quently, blood was drawn, height and weight were measured, and participants
had never been diagnosed with cancer.
underwent MRI of the brain, carotid ultrasound imaging, and an electrocar-diogram. Results from the latter measures will be described separately. Neuropsychological Examination PATIENTS AND METHODS
Seven neuropsychological tests were administrated and scored by expe-
rienced test assistants from the Rotterdam Study. These tests yielded 17 out-comes in the following cognitive domains: processing speed, verbal learning,
Participants
memory, inhibition and word fluency as elements of executive functioning,
Our case group consisted of survivors of breast cancer who had under-
visuospatial ability, and psychomotor speed. In addition, the Mini-Mental
gone adjuvant chemotherapy in either of two specialized cancer clinics in the
State Examination (MMSE) was included as a dementia screener. For an
Netherlands. The reference group of controls was selected from an ongoing
overview of the tests and domains,35-42 see Table 1.
population study in the Netherlands. The review boards of the participatinginstitutes (the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospi-
Interview
tal and the Erasmus University Medical Center) approved this study.
Participants completed an interview on clinical and sociodemographic
factors, which included questions regarding medical history of neurologic,
Patients Exposed to Chemotherapy
psychiatric, and cardiovascular diseases. Depressive symptoms were assessed
From the registries of the Netherlands Cancer Institute/Antoni van Leeu-
with the Center for Epidemiologic Studies Depression scale (CES-D),43 which
wenhoek Hospital and the Erasmus University Medical Center-Daniel den
was converted to a sum-score according to the standard scoring rules.44 Sub-
Hoed Cancer Center, we identified consecutive female patients with breast
jective memory complaints were measured with three yes/no questions: (1) Do
cancer who, as part of their primary treatment had received six cycles of
you have more problems remembering things than before? (2) Has there been
adjuvant CMF chemotherapy (cyclophosphamide 100 mg/m2 orally on days 1
an increase in the times that you forgot what you were up to? and (3) Do you
through 14, methotrexate 40 mg/m2 intravenously on days 1 and 8, and
have more word-finding problems than before? Subsequently, participants
fluorouracil 600 mg/m2 intravenously on days 1 and 8) between 1976 and
were asked whether these problems had an acute onset (yes/no) and if the
1995. Eligibility criteria included age between 50 and 80 years at recruitment in
severity of the problems had changed over time (no change/problems in-
2008 and sufficient command of the Dutch language. Only those women who
never had a relapse, secondary primary tumor, or distant metastasis wereselected. Exclusion criteria were ever use of adjuvant endocrine therapy and
Statistical Analysis
We compared differences in sociodemographic variables between
Potential participants (n ϭ 359) were sent an invitation letter and infor-
groups by means of binary, ordinal, and multinomial logistic regression anal-
mation on the study. Twenty patients (5.6%) could not be reached either
ysis. Group differences in neuropsychological performance and depressive
because their current address was unavailable, or they did not respond to the
symptoms were investigated with analysis of covariance, adjusted for age and
invitation or subsequent reminders. Fifteen patients (4.2%) had a health-
education. Although studies on the cognitive effects of chemotherapy shortly
related contraindication for MRI, 30 (8.4%) were ineligible for MRI assess-
after treatment do not show a strong relationship between depressive symp-
ment because of claustrophobia, and two patients (0.6%) had insufficient
toms and neuropsychological performance,45 no information is available on
command of the Dutch language. The final number of eligible patients was 292
this potential association long after chemotherapy. Therefore, we subsequently
of whom 196 (67.1%) eventually agreed to participate and provided written
adjusted our analyses for CES-D sum-score. We used Bonferroni correction to
informed consent. Examinations were performed between October 2008 and
The age distribution of the reference group was more skewed toward
Main reasons for decline were not wanting to be reminded of the cancer
younger ages than that of the survivors of cancer exposed to chemotherapy. To
episode (21.9%) and unwillingness to undergo MRI assessment (26.0%).
check whether any residual confounding by age remained after standard ad-
Decliners were older than participants (F
justment for age, we executed all analyses with propensity scores for age and
To assess possible selection bias, eligible women who declined participa-
used an age-matched reference group randomly drawn from the total refer-
tion and women for whom claustrophobia was the only contraindication were
ence group. Since these additional analyses yielded results similar to those of
invited to complete the interview and the neuropsychological assessments at
the primary analyses, their results are not separately reported.
home. Test results of these initial decliners were compared with the results of
Although the different cognitive tests in our battery were intended to
those who participated in this study. Of the 126 invited initial decliners (96
measure different domains, an individual's scores on cognitive tests were often
decliners ϩ 30 claustrophobic women), 48 (38.1%) agreed to participate. They
related. To account for this interdependency between test scores, we calculated
were assessed between November 2009 and June 2010.
for each individual the Mahalanobis Distance (MD)46 as a summary measureof overall performance.47 The MD takes into account the correlations between
Reference Group
test scores and the different variances of the test scores and can be interpreted
A reference group was selected from the Rotterdam Study,33 a
as the distance to the mean of the multidimensional distribution of the neuro-
population-based prospective cohort study ongoing since 1990 in Rotterdam,
psychological test scores of the reference group.
the Netherlands. By the end of 2008, 14,926 participants had been included in
MD was based on all tests, except for the Design Organization test
three separate subcohorts. Rotterdam Study III is the most recent subcohort,
because few women from the reference group completed this test and the
comprising 3,932 persons who have been assessed only once between February
MMSE because it screens for dementia. We calculated age, education, and
2006 and December 2008. To date, it is the only cohort that has been assessed
CES-D score-adjusted residuals of the neuropsychological tests, although the
with an extensive set of neuropsychological tests and is therefore the most
computation of the relevant means and (co)variances was based on the resid-
uals of the reference group.47,48 We assigned a value of zero to all residual
From Rotterdam Study III, we selected all women without a history of
scores that were greater than their respective mean score from the reference
cancer on the basis of self-reports and linkage with data from their general
group, such that positive test scores could not compensate for negative
2012 by American Society of Clinical Oncology
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Copyright 2012 American Society of Clinical Oncology. All rights reserved. Koppelmans et al Table 1. Outcome Measures
Immediate recall No. of words remembered immediately after
No. of words remembered after 20 minutesء
Processing speed and inhibition as an Houx et al39
Seconds needed to complete the first 4 lines†
Seconds needed to complete the first 4 lines†
Seconds needed to complete the first 4 lines†
No. of animals mentioned within 1 minuteء
No. of pins inserted in the board within 1 minuteء
No. of pins inserted in the board within 1 minuteء
No. of pins inserted in the board within 1 minuteء
Abbreviations: 15-WLT, 15-Word Learning Test; DOT, Design Organization Test; LDST, Letter Digit Substitution Test; MMSE, Mini-Mental State Examination; PPB,
Purdue Pegboard test; SD, standard deviation; WFT, Word Fluency Test.
ءHigher score indicates better performance. †Lower score indicates better performance.
scores.49 We transformed the MD with log base 2 because of skewness of its
higher level of education. They had been diagnosed, on average, at age
distribution and subsequently used one-way analysis of variance to compare
42.9 and received chemotherapy, on average, 21.2 years before enroll-
MD between the patients exposed to chemotherapy and the reference group.
ment onto this study. No differences were observed in the prevalence
Spearman rank correlation coefficients with two-sided P values were
of neurologic, psychiatric, or cardiovascular diseases.
calculated to obtain the associations between memory complaints, neuro-psychological test outcomes, and mood. For all analyses, ␣ levels were set atP ϭ.05. Neuropsychological Outcomes
On all neuropsychological tests, survivors of breast cancer who
had been exposed to chemotherapy performed similar to or worsethan those in the reference group. These differences were significant
Table 2 presents the baseline characteristics of the patients with breast
for nearly all trials of immediate and delayed recall of the 15-Word
cancer who were exposed to chemotherapy and the reference group.
Learning Test (15-WLT), for the color card and the color-word card of
On average, survivors of breast cancer were older and had completed a
the Stroop test, and for nondominant-hand performance on the Pur-due pegboard test (Table 3; Fig 1). After Bonferroni corrections, dif-ferences on the 15-WLT delayed recall, the Stroop color card, and thePurdue pegboard test for the nondominant-hand condition remained
Table 2. Sociodemographic and Clinical Characteristics of Former Patients
significant. MMSE scores did not differ between groups. Excluding
With Breast Cancer Exposed to Chemotherapy and the Reference Group
participants with neurologic or psychiatric diseases did not change the
The log base 2 of the MD was significantly larger for survivors
exposed to chemotherapy (mean, 2.8; standard deviation [SD], 2.6)
than for the reference group (mean, 2.2; SD, 2.8; F1,1648, 7.3; P ϭ.007),
indicating that the former had worse overall cognitive performance.
Time since diagnosis was not associated with neuropsychological per-
formance in survivors exposed to chemotherapy. Depressive Symptoms and Memory Complaints
The reference group reported significantly more depressive
symptoms than the survivors of breast cancer exposed to chemo-
therapy (age-adjusted mean sum-score of the reference group on
the CES-D, 6.7; SD, 8.4; age-adjusted mean sum-score of the
chemotherapy-exposed survivors on the CES-D, 4.7; SD, 8.0;
F1,1696, 9.54; P ϭ.002). There was a low correlation between
Abbreviation: SD, standard deviation.
memory complaints and total score on the CES-D ( ϭ.275;P Ͻ.001) in survivors exposed to chemotherapy.
2012 by American Society of Clinical Oncology
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Copyright 2012 American Society of Clinical Oncology. All rights reserved. Cognitive Performance in Survivors of Cancer Long After Chemotherapy
Survivors of breast cancer exposed to chemotherapy who partic-
Table 3. Neuropsychological Test Outcomes
ipated at the Rotterdam Study research center did not differ from
participants who declined participation at the research center but
agreed to cognitive testing in their own home regarding age, education
level, Bonferroni-corrected cognitive scores, or mood status. Without
correction for multiple testing, home participants performed worsethan center participants on one of the 17 cognitive measures: the word
card of the Stroop test (P ϭ.011). DISCUSSION
To the best of our knowledge, this is the first report on the cognitive
effects of adjuvant CMF chemotherapy in survivors of breast can-
cer who completed their treatment, on average, more than 21 years
before. Compared with women from the general population with-
out cancer, survivors of breast cancer who were exposed to chem-
otherapy performed worse on cognitive tests covering the domains
of learning, immediate and delayed verbal memory, information
processing speed, inhibition, and psychomotor speed. No differ-
ences were observed in scores on a dementia screener. The results
persisted after controlling for several confounders including age,
Abbreviations: 15-WLT, 15-Word Learning Test; DOT, Design Organization
education level, and depression score. After subsequent correction
Test; LDST, Letter Digit Substitution Test; MMSE, Mini-Mental State Exami-
for multiple comparisons, survivors exposed to chemotherapy still
nation; PPB, Purdue Pegboard test; SD, standard deviation.
performed worse on tests measuring delayed verbal memory, pro-cessing speed, and psychomotor speed. In addition, on a summarymeasure of the neuropsychological tests that takes correlations
The proportion of patients who reported problems with remem-
between multiple measures into account, survivors exposed to
bering did not differ between groups, yet survivors of breast cancer
chemotherapy performed significantly worse than women from
who were exposed to chemotherapy were more likely to report an
increase in word-finding problems and in the frequency of forgetting
Further, survivors of breast cancer exposed to chemotherapy
pursuits (Table 4). These subjective memory complaints were not
more often reported memory complaints, which were not associated
related to neuropsychological performance.
with test performance but were weakly correlated with mood. Survi-vors exposed to chemotherapy had fewer depressive symptoms thanthe reference group, although both groups scored below the cutoff
score of 16, which is indicative for clinical depression.43
Strengths of our study are the large sample size, the long
interval since chemotherapy, the homogeneous study population
regarding cytotoxic agents (regimen, cycles), and the large
population-based reference group without cancer. Possible selec-
tion bias within the chemotherapy-exposed group has been inves-
tigated and was found to be unlikely.
We compared chemotherapy-exposed survivors of breast
cancer to a population-based sample of healthy controls without a
history of cancer because we wanted to investigate to what extent
chemotherapy-exposed survivors of breast cancer deviate from the
norm regarding cognitive functioning. Subsequently, because ta-
moxifen was not part of standard treatment in the Netherlands
until the mid 1990s, it was not possible to include a comparison
group of long-term tamoxifen-exposed survivors. Because of our
design, we were unable to distinguish the effect of chemotherapyon cognition from the possible effect of breast cancer itself.
It has been suggested that patients with breast cancer may already
Chemotherapy worse | Chemotherapy better
perform worse on tests of cognitive function compared with healthycontrols before the start of chemotherapy.8-10,15,18,50,51 Since we do
Fig 1. Difference between standardized (Z) scores of the chemotherapy-
not have pretreatment assessments to use for adjusting our results, our
exposed survivors of breast cancer and reference subjects. 15-WLT, 15-Word
findings might partially reflect group differences already present be-
Learning Test; DOT, Design Organization Test; LDST, Letter Digit SubstitutionTest; MMSE, Mini-Mental State Examination; PPB, Purdue Pegboard test.
fore chemotherapy. The mechanisms for pretreatment differences are
2012 by American Society of Clinical Oncology
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Copyright 2012 American Society of Clinical Oncology. All rights reserved. Koppelmans et al Table 4. Subjective Cognitive Complaints in Patients With Breast Cancer Exposed to Chemotherapy and in a Reference Group From the General Population
Do you have more problems remembering things
Has there been an increase in the times that you
Do you have more word-finding problems than
Abbreviations: CES-D, Center for Epidemiologic Studies Depression scale; OR, odds ratio.
ءDepression score (CES-D) and age adjusted. †No change over time.
largely unknown, although the prevalence of cognitive problems at
and problems with fine motor functioning that we observed in
baseline has been associated with the stage of breast cancer.51 Sug-
chemotherapy-exposed survivors adds to this profile. This profile
gested explanations for pretreatment problems include diminished
is suggestive for disruption of the frontal-subcortical network and
cognitive reserve, stimulation of proinflammatory cytokines,18 and
matches the profile observed in other studies.65
the effect of anesthetic drugs received for breast surgery.52 Because the
The fact that chemotherapy-exposed survivors of breast cancer
effect of anesthesia is transient,52 we consider its influence on cogni-
performed worse on the nondominant condition of the Purdue peg-
tion more than 20 years post treatment unlikely. Moreover, follow-up
board test, but not on the dominant condition, has been observed
studies demonstrated a larger prevalence of cognitive decline from
before in patients treated with chemotherapy7 and other patient pop-
baseline in chemotherapy-exposed patients than in patients who un-
ulations. It has been related to neurologic damage66 and may possibly
derwent only locoregional therapy, indicating that at least part of the
be related to interhemispheric transfer deficits.67
deficits are indeed associated with cytotoxic treatment.3,15,53-56
Our neuropsychological test battery was identical with the one used
Although information on hormone replacement therapy was
in the Rotterdam Study but less extensive than some used in previous
not available, we do not think this confounded our findings in any
studies.15,22,54,68,69 Some domains (eg, visual memory), which are known
significant way because the use of hormone replacement therapy in
to be affected by cytotoxic treatment, were not explicitly examined.15,22,70
the Netherlands tended to be low in the years under study (Ͻ 2.5%
Although we found several significant differences in cognitive functioning
between chemotherapy-exposed survivors and the reference group, we
An important question is to what extent our observations
may have underestimated the effects of CMF chemotherapy on cognitive
extend to other chemotherapy regimens. The CMF regimen is no
functioning. The effects of chemotherapy might extend to more cognitive
longer the most optimal adjuvant chemotherapy for early-stage
domains than we showed in this study.
breast cancer. However, it was the standard regimen up to the
When we compare our study outcomes with those of other
1990s, and it is the only regimen that enables the investigation of
studies investigating the cognitive effects of CMF chemotherapy,
the late effects of chemotherapy in sufficiently large numbers of
there are several similarities. One study20 showed that patients who
patients. In addition, there is still an extensive group of women who have
underwent CMF at least 10 years ago performed worse than healthy
been treated with CMF in the late 1990s, some of whom may experience
controls on tests measuring executive functioning, psychomotor
itscognitiveadverseeffectsinthefuture.Furthermore,cyclophosphamide
speed, and attention. Another study71 found that a subgroup of
and fluorouracil continue to be incorporated into currently used regi-
patients treated with CMF showed impaired information process-
mens for early-stage breast cancer. Even if the findings of our study were
ing speed 5 years after completion of treatment. Animal studies
specific to CMF, they would remain relevant.
support our findings and have pointed out that methotrexate,
Several studies have found impairments in cognitive domains in
cyclophosphamide, and the combination of fluorouracil and
patients with cancer shortly after treatment with chemotherapy.4, 58-65
methotrexate are associated with impaired learning and memory
Impairments frequently observed in chemotherapy-exposed patients
with breast cancer are learning problems and deficits in memory
In conclusion, the cognitive functioning of survivors of breast
retrieval with more preserved retention, as well as problems with
cancer on average 21 years after adjuvant CMF chemotherapy is
information processing speed and more complex aspects of attention.
worse than that of women from the general population who have
Imaging studies showed that some chemotherapy regimens may in-
never been diagnosed with cancer. These data suggest that cogni-
duce structural brain alterations.1,7,24,25,27,28
tive deficits following breast cancer diagnosis and subsequent CMF
This study resembles this pattern: chemotherapy-exposed
chemotherapy are at least partially long lasting. Our results are
survivors of breast cancer from our study also had more problems
highly relevant in the field of survivorship because, with the current
with learning and memory retrieval although retention was intact.
treatment strategies, the number of long-term survivors of breast
The combination of worse processing speed, inhibition problems,
cancer is increasing because of improved recognition of early-stage
2012 by American Society of Clinical Oncology
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Copyright 2012 American Society of Clinical Oncology. All rights reserved. Cognitive Performance in Survivors of Cancer Long After Chemotherapy
breast cancer, aging of the population, and improved survival after
AUTHOR CONTRIBUTIONS
breast cancer diagnosis.77,78 Further studies into the late effects ofadjuvant chemotherapy for cancer are needed to corroborate theseresults and to gain further insight into the mechanisms underlying
Conception and design: Monique M.B. Breteler, Sanne B. Schagen Financial support: Monique M.B. Breteler, Sanne B. Schagen Provision of study materials or patients: Willem Boogerd, Caroline Seynaeve AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS Collection and assembly of data: Vincent Koppelmans OF INTEREST Data analysis and interpretation: All authors Manuscript writing: All authors
The author(s) indicated no potential conflicts of interest. Final approval of manuscript: All authors 14. Scherwath A, Mehnert A, Schleimer B, et al:
gotic twins: possible effects of breast cancer chem-
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SOUTH ASIA VULTURES: CATASTROPHIC DECLINES AND ENVIRONMENTAL IMPACT The Meeting Rooms, The Zoological Society of London, Regent’s Park, London NW1 4RY Chair: Andrew Routh, Chief Veterinary Officer, ZSL Declines in large raptors Jemima Parry-Jones MBE, Director of the International Centre for Birds of Prey Global y the large raptors are under threat. Habitat decline, inc
Personal Information First Name: Rezvan Last Name: Esmaeil Gender: Female Date of birth: 1980 Marriage Status: Married Address: No. 45, Vahid Nazari St, Abu Reihan St, Enghelab Ave., Tehran, Iran, P.O. Box Tel: (Office) +9821 66952040 , Fax: +9821 66952040 Email: r_esmaili1359@yahoo.com Education 2010- PhD candidate in molecular genetics, Tarbiat Modares Univer