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1742 BRIEF COMMUNICATIONS Journal of the National Cancer Institute, Vol. 98, No. 23, December 6, 2006
 Change in Cognitive FunctionAfter Chemotherapy: aProspective Longitudinal Studyin Breast Cancer Patients
Sanne B. Schagen , Martin J.Muller  , Willem Boogerd  , Gideon J.Mellenbergh , Frits S. A. M. van Dam
Some breast cancer survivors ex-perience cognitive decline followingchemotherapy. We prospectively ex-amined changes in cognitive perfor-mance among high-risk breast cancerpatients who had received high-dosechemotherapy with cyclophospha-mide, thiotepa, and carboplatin (CTCgroup; n = 28) or standard-dose che-motherapy with 5-
fl
uorouracil, epiru-bicin, and cyclophosphamide (FECgroup; n = 39); stage-I breast cancerpatients who had received no systemicchemotherapy (no-CT group; n = 57);and healthy control subjects (n = 60).All patients underwent neuropsycho-logic testing before and 6 months aftertreatment (12-month interval); controlsubjects underwent repeated testingover a 6-month interval. No differenc-es in cognitive functioning between thefour groups were observed at the
fi
rstassessment. More of the CTC groupthan the control subjects experienceda deterioration in cognitive perfor-mance over time (25% versus 6.7%;odds ratio [OR] = 5.3, 95% con
fi
denceinterval [CI] = 1.3 to 21.2,
 P 
 
= .02). Nosuch difference was observed for theFEC or the no-CT groups (FEC versuscontrol: OR = 2.2, 95% CI = 0.5 to 9.1,
 P 
 
= .27; no-CT versus Control: OR =2.2, 95% CI = 0.6 to 8.0;
 P 
 
= .21). Somecytotoxic treatment for breast canceraffects cognition in a subset of women.[J Natl Cancer Inst 2006;98:1742 – 5]
There is growing evidence that some breast cancer patients show impairedcognitive performance on neuropsycho-logic tests after they receive cytotoxictreatment. For example, a cross-sectionalstudy conducted at The NetherlandsCancer Institute in 1998
( 1 )
found thatamong women who participated in a ran-domized trial of adjuvant treatment for high-risk breast cancer, those whoreceived adjuvant high-dose chemother-apy had a statistically signi
fi
cantly higher risk of cognitive impairment comparedwith breast cancer patients who receivedno chemotherapy (i.e., the control group;odds ratio [OR] = 8.2, 95% con
fi
denceinterval [CI] = 1.8 to 37.7,
 P 
= .006),whereas patients who received standard-dose chemotherapy did not show astatistically signi
fi
cantly elevated risk compared with the control group (OR =2.4, 95% CI = 0.5 to 11.5,
 P 
= .287).Since then, several cross-sectional stud-ies
( 2 – 7  )
have reported that some breastcancer patients have cognitive de
fi
citsfollowing chemotherapy treatment andthat some of these effects persist for up to 10 years after the completion of therapy.These
fi
ndings need to be veri
fi
ed inlongitudinal studies in which the cogni-
 
 Af 
  fi
liations of authors:
Departments of Psycho-social Research and Epidemiology (SBS, MJM,FSAMvD), and Neuro-Oncology (WB), Nether-lands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Depart-ment of Psychology, University of Amsterdam,The Netherlands (FSAMvD, GJM).
Correspondence to:
Sanne B. Schagen, PhD,Department of Psychosocial Research and Epide-miology, Netherlands Cancer Institute – Antoni vanLeeuwenhoek Hospital, Plesmanlaan121, 1066 CXAmsterdam, The Netherlands (e-mail: s.schagen@nki.nl).
See
“ Notes” following “References.” DOI: 10.1093/jnci/djj470© The Author 2006. Published by Oxford UniversityPress. All rights reserved. For Permissions, pleasee-mail: journals.permissions@oxfordjournals.org.
tive performance of patients is assessedover time and compared with pretreat-ment performance. An assessment of cognitive performance before treatmentis essential because of the possibility of  preexisting cognitive de
fi
cits in some patients undergoing cytotoxic treatment
( 8 )
 . Few prospective studies of cognitivefunction among women receiving adju-vant chemotherapy have been publishedto date
( 9 – 12 )
 ; these studies were lim-ited because of a small sample size
( 9 ,12 )
 or because they lacked pretreatment cog-nitive assessment
( 10 )
or a control group
( 12 )
or did not correct for the effects of repeated testing
( 9 ,10 )
 . In addition, noneof these studies compared the effects of different cytotoxic regimens. A recently published
fi
fth study
( 13 )
 , which was anextended version of an earlier prospec-tive study
( 11 )
 , addressed some of theselimitations. However, because the major-ity of patients (70%) were treated withlow-dose FEC chemotherapy, no com- parison between the effects of differentregimens could be made
( 13 )
 .To further investigate the cognitivesequelae of chemotherapy, we conduct- ed a longitudinal study using subjectsrecruited from the same population of  breast cancer patients that was used inour previous cross-sectional study
( 1 ).
 The current study used three groups of  breast cancer patients and a control groupof healthy women without cancer. Twoof the three groups of breast cancer  patients were recruited from amonghigh-risk breast cancer patients who had participated in a trial
( 14 )
in whichthey were randomly assigned to receiveeither adjuvant high-dose chemother-apy with cyclophosphamide, thiotepa,and carboplatin (CTC group; n = 28) or 
 
Journal of the National Cancer Institute, Vol. 98, No. 23, December 6, 2006 BRIEF COMMUNICATIONS 1743
standard-dose chemotherapy with 5- 
fl
uorouracil, epirubicin, and cyclophos- phamide (FEC group; n = 39), followed by radiotherapy and tamoxifen (40 mgdaily for 2 – 5 years); the third group of  breast cancer patients included womenwith stage I breast cancer who had beentreated with radiotherapy but who hadnot received systemic chemotherapy(no-CT group; n = 57). Women in thecontrol group (n = 60) were recruitedfrom among female friends of the patients in the three groups. The high-risk patients were recruited from sevendifferent hospitals, and the stage I patients were recruited from a singleinstitution. This study was approved bythe ethics committees of the participat-ing hospitals, and all subjects providedwritten informed consent.All subjects underwent neuropsycho-logic testing on two separate occasions.Subjects in the CTC and FEC groupswere tested before the start of chemo-therapy and again 6 months after com- pletion of therapy, i.e., 12 months after the
fi
rst assessment. Patients in the no-CT group were also tested over a 12-month interval. Subjects in the controlgroup were tested over a 6-month inter-val. The neuropsychologic examinationconsisted of 10 tests
( 15 – 21 )
 , comprising24 test indices, covering the followingdomains: focused – sustained attention,working – verbal – visual memory, pro- cessing speed, executive function, andverbal/motor function. On the
fi
rst as-sessment, the Dutch Adult Reading test
( 22 )
was used to obtain a measure of verbal premorbid intelligence. Exclusioncriteria for neuropsychologic testingwere 1) presence of metastatic disease or relapse, 2) a previous or current neuro-logic or psychiatric disorder [de
fi
nedaccording to Diagnostic and StatisticalManual-VI criteria
( 23 )
 ] believed toaffect performance on cognitive tests,3) use of medication believed to affect cur -rent cognitive functioning (i.e., opioidanalgesics, anxiolytics, or antidepres-sants), and 4) alcohol and/or drug addic-tion. To assess these exclusion criteria,the medical records of all patients werechecked. For the subjects in the healthycontrol group, a questionnaire was devel-oped to inspect these criteria.Patients in the FEC, the CTC, and theno-CT groups were treated during the pe-riod from September 7, 1998, to January19, 2002. A total of 52 FEC patients, 36CTC patients, and 82 no-CT patientswere eligible for the
fi
rst neuropsycho-logic assessment. Seven FEC patients(13.5%),
fi
ve CTC patients (13.9%), and17 no-CT patients (20.7%) refused to participate. At the second neuropsycho-logic assessment, a total of 17 patientscould not be retested; of these, 12 patients(four FEC patients, two CTC patients,and six no-CT patients) no longer metthe inclusion criteria and
fi
ve patients(two FEC patients, one CTC patient andtwo no-CT patients) refused to partici- pate. Of the 66 healthy women whounderwent the baseline neuropsycho-logic examination, one developed breastcancer, two were diagnosed with aneurologic disorder, and three refusedfurther participation. Nonparticipants atfollow-up did not differ from participantswith regard to age, premorbid intelli-gence quotient (IQ), or neuropsychologic performance at the
fi
rst examination.We considered a subject to be cogni-tively impaired on a test index if shescored two standard deviations belowthe mean of the healthy control groupon that test index
( 24 )
 . A patient wasclassi
fi
ed as cognitively impaired whenshe scored, on at least three of the 24
Table 1
 
.
Sociodemographic and clinical characteristics of the four study groups*CharacteristicFEC (n = 39)CTC (n = 28)No CT (n = 57)Control (n = 60)
 P 
 †Mean age at
fi
rst assesssment, y (SD)45.5 (6.6)45.2 (5.8)50.5 (7.7)48.8 (6.0).00Mean premorbid IQ score‡ (SD)100.8 (15.7)100.2 (17.1)100.8 (17.2)105.1 (14.1).38Postmenopausal§
 
, %At
fi
rst assessment28255638.01At second assessment80936340.00On tamoxifen at second assessment, %971000 – .00 *FEC =
fi
ve cycles of 
fl
uorouracil, 500 mg/m
2
intraveneously (iv); epirubicin, 90 mg/m
2
iv; cyclophosphamide, 500 mg/m
2
iv; CTC = four cycles of FECfollowed by cyclophosphamide, 6 g/m
2
iv; thiotepa, 480 mg/m
2
iv; and carboplatin, 1.6 g/m
2
iv; No CT = no adjuvant chemotherapy; control = healthy subjects;SD = standard deviation; IQ = intelligence quotient; – = not applicable.†Two-sided
 P 
value: analysis of variance in case of mean age and IQ score, chi-square in case of menopausal status and tamoxifen use.‡Assessed by using the Dutch Adult Reading test as a surrogate measure of pretreatment intelligence.§ Postmenopausal status de
fi
ned by the absence of (ir)regular menstrual cycles from the time of completion of chemotherapy (for the FEC and CTC groups)until the second neuropsychologic assessment point or by the absence of menstrual cycles for 6 consecutive months (for the no-CT and healthy control groups).
test indices, two standard deviations below the mean of the healthy group[the 95th percentile of the healthy groupwas used as a cutoff score to distinguish between impaired and unimpaired cog-nitive functioning
( 1 ,5 )
 ]. For all analy-ses, a two-sided
 P 
value less than or equal to .05 was considered statisticallysigni
fi
cant.Table 1 presents the characteristicsof the four groups of subjects. All CTCand FEC patients received the plannedcourses of chemotherapy (see Table 1notes for description of regimens).At the
fi
rst neuropsychologic assess-ment, univariate analysis of variancewith correction for age and IQ scorerevealed no statistically signi
fi
cant dif-ferences in the raw neuropsychologictest scores among the four groups of sub- jects (data not shown). A logistic regres-sion model with correction for age andIQ (Table 2) revealed no statistically sig-ni
fi
cant differences between any of the patient groups and the control group inthe percentage of subjects who wereclassi
fi
ed as cognitively impaired at the
fi
rst neuropsychologic assessment (CTCgroup versus control group: OR = 2.3,95% CI = 0.6 to 9.2,
 P 
= .22; FEC groupversus control group: OR = 1.1, 95%CI = 0.3 to 4.4,
 P 
= .89; no-CT groupversus control group: OR = 2.4, 95%CI = 0.7 to 7.7,
 P 
= .12). A similar analy-sis revealed no statistically signi
fi
cantdifferences between any of the patientgroups and the control group in the per-centage of impaired subjects at the sec-ond assessment (Table 2; CTC groupversus control group: OR = 3.3, 95%CI = 0.7 to 14.4,
 P 
= .11; FEC group ver-sus control group: OR = 1.2, 95% CI =0.3 to 5.8,
 P 
= .78; no-CT group versuscontrol group: OR = 2.1, 95% CI = 0.5 to8.4,
 P 
= .26). In this latter analysis,
 
1744 BRIEF COMMUNICATIONS Journal of the National Cancer Institute, Vol. 98, No. 23, December 6, 2006
95% CI = 0.5 to 9.1,
 P 
= .27; no-CTgroup versus control group: OR = 2.2,95% CI = 0.6 to 8.0,
 P 
= .21). Repeated-measures multiple analysis of covarianceshowed that deterioration in cognitive performance over time occurred across avariety of tests that measured severalcognitive functions. However, the neuro- psychologic measures that were sensi-tive to so-called executive functionexhibited the strongest effects. Executivefunctions include skills such as planning,inhibiting or delaying responding, initi-ating behavior, and the ability to shifting between activities in a
fl
exible way, allof which are aspects of behavior that patients who are treated with chemother-apy frequently complain about
( 27  )
 .For all groups, cognitive performanceat baseline and follow-up, and change in performance over time, was not statisti-cally signi
fi
cantly associated with sub- jects’ reports of anxiety, depression [asassessed with the Hopkins SymptomChecklist
( 28 )
 ], or fatigue [as assessedwith the Multidimensional Fatigue Index
( 29 )
 ] (data not shown). Menopausal sta-tus was also not associated with changesin cognitive performance. We tested thisassociation by comparing the change incognitive performance between patientswhose menopausal status did not changefollowing chemotherapy and patients who became postmenopausal after treatment(de
fi
ned as the absence of regular men-strual cycles, from the time of comple-tion of chemotherapy until the secondneuropsychologic assessment point).The strengths of our study include the pre- and posttreatment assessment, thetesting of patients who were randomlyassigned to different chemotherapyregimens, and the comparisons with breast cancer patients who were nottreated with systemic therapy as well ashowever, no correction was made for  practice effects. In neuropsychology, practice effects refer to the impact of repeated assessments on a subject’s per-formance. With repetition of the sameneuropsychologic test, systematic changesin test scores can be observed withoutthe occurrence of a true change in cogni-tive performance. Therefore, we alsoevaluated, for all subjects, the magnitudeof cognitive changes from the
fi
rst neu-ropsychologic assessment to the second,while taking into account repeated test-ing effects by using the reliable changeindex with correction for practice effects
( 11 ,12 ,25 ,26  )
 , which was based on thedifferences between the neuropsycho-logic scores of the
fi
rst and the secondassessment of the healthy control group.Using this index, participants wereclassi
fi
ed per test as having either cogni-tive performance that statistically sig-ni
fi
cantly improved or deteriorated or remained stable over time. The 95th per-centile of the healthy reference groupwas used as a cutoff to de
fi
ne deteriora-tion; we considered a subject to havedeteriorated in cognitive functioningonly when she showed a statistically sig-ni
fi
cant decline in performance on atleast four of the 24 tests (Table 2). Alogistic regression model with adjust-ment for age and IQ score revealed thatthe percentage of patients in the CTCgroup whose cognitive performance haddeteriorated was statistically signi
fi
-cantly higher than the percentage of healthy subjects in the control groupwhose cognitive performance had dete-riorated (25% versus 6.7%; OR = 5.3,95% CI = 1.3 to 21.2,
 P 
= .02). For theFEC and the no-CT groups, no suchdecline in performance compared withthe control group was observed (FECgroup versus control group: OR = 2.2,
Table 2.
Number of cognitively impaired subjects at
fi
rst and second assessment and number of subjectsclassi
fi
ed as having cognitive deterioration over time*Study groupn No. impaired at
fi
rstassessment (%) No. impaired at secondassessment (%) No. having cognitive deteriorationfrom
fi
rst to second assessment (%)FEC395 (12.8)4 (10.3)5 (12.8)CTC286 (21.4)6 (21.4)7 (25.0) No CT5717 (29.8)13 (22.8)10 (17.5)Control606 (10.0)4 (6.7)4 (6.7) *Cognitive impairment is de
fi
ned as a score that was two standard deviations below the mean scoreof the healthy control group on at least three of the 24 test indices. Cognitive deterioration is de
fi
ned asa statistically signi
fi
cant decline (based on the reliable change index with correction for practice effects)on at least four of the 24 test indices. FEC =
fi
ve cycles of 
fl
uorouracil, 500 mg/m
2
intraveneously (iv);epirubicin, 90 mg/m
2
iv; cyclophosphamide 500 mg/m
2
iv; CTC = four cycles of FEC followed by cy-clophosphamide, 6 g/m
2
iv; thiotepa, 480 mg/m
2
iv; and carboplatin, 1.6 g/m
2
iv; No CT = no adjuvantchemotherapy; control = healthy subjects.
with healthy control subjects. Our studyhas several limitations. First, becauseall chemotherapy patients and none of the no-chemotherapy patients receivedtamoxifen, we cannot determine the potential contributory role of tamoxifenon the cognitive test performance. How-ever, even though both the CTC and theFEC treatments were followed by tamox-ifen, a difference in cognitive functionwas found between the CTC and FECgroups. Second, we retested our three patient groups after a 12-month interval,whereas the control group was retestedafter 6 months. Because our correctionfor practice effects was based on theretest data of the healthy control group,this difference in retesting interval mighthave led to an underestimation of the prevalence of cognitive impairment or decline in our patient groups.Our results con
fi
rm the
fi
ndings of our earlier cross-sectional study
( 1 )
 ; thatis, more patients treated with high-doseCTC chemotherapy than patients treatedwith standard-dose FEC chemotherapyshowed a decline in cognitive perfor-mance compared with healthy controlsubjects. Our results also show that anal-yses of cognitive change that correct for the effects of repeated testing are essen-tial for an accurate interpretation of cog-nitive performance in studies with alongitudinal design.
R 
EFERENCES
 
(1)
van Dam FS, Schagen SB, Muller MJ,Boogerd W, vd Wall E, Droogleever FortuynME, et al. Impairment of cognitive functionin women receiving adjuvant treatment for high-risk breast cancer: high-dose versusstandard-dose chemotherapy. J Natl Cancer Inst 1998;90:210 – 8.
(2)
Ahles TA, Saykin AJ, Furstenberg CT, ColeB, Mott LA, Skalla K, et al. Neuropsycho-logic impact of standard-dose systemic che-motherapy in long-term survivors of breastcancer and lymphoma. J Clin Oncol 2002;20: 485 – 93.
(3)
Brezden CB, Phillips KA, Abdolell M,Bunston T, Tannock IF. Cognitive functionin breast cancer patients receiving adju-vant chemotherapy. J Clin Oncol 2000;18: 2695 – 701.
(4)
Castellon SA, Ganz PA, Bower JE, PetersenL, Abraham L, Greendale GA. Neurocog-nitive performance in breast cancer sur-vivors exposed to adjuvant chemotherapyand tamoxifen. J Clin Exp Neuropsychol2004;26:955 – 69.
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Schagen SB, van Dam FS, Muller MJ,Boogerd W, Lindeboom J, Bruning PF. Cog-nitive de
fi
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of 00

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