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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. Schagen Purpose
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 Downloaded from jco.ascopubs.org by Noa Ben-Baruch on November 3, 2012 from 109.64.161.243 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 Downloaded from jco.ascopubs.org by Noa Ben-Baruch on November 3, 2012 from 109.64.161.243 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 Downloaded from jco.ascopubs.org by Noa Ben-Baruch on November 3, 2012 from 109.64.161.243 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 Downloaded from jco.ascopubs.org by Noa Ben-Baruch on November 3, 2012 from 109.64.161.243 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 Downloaded from jco.ascopubs.org by Noa Ben-Baruch on November 3, 2012 from 109.64.161.243 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
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