A Meta-analysis of Chemotherapy related Cognitive Impairment in Patients with Breast Cancer

Jin-Hee Park; Sun Hyoung Bae

doi:10.4040/jkan.2012.42.5.644

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Park and Bae: A Meta-analysis of Chemotherapy related Cognitive Impairment in Patients with Breast Cancer

Original Article

J Korean Acad Nurs 2012;42(5):644-658.

Published online: 12 October 2012

DOI: https://doi.org/10.4040/jkan.2012.42.5.644

A Meta-analysis of Chemotherapy related Cognitive Impairment in Patients with Breast Cancer

Jin-Hee Park¹, Sun Hyoung Bae²

¹College of Nursing, Ajou University, Suwon, Korea

²College of Nursing, Yonsei University, Seoul, Korea

Address reprint requests to : Bae, Sun Hyoung San 5, Wonchon-dong, Yeongtong-gu, Suwon 443-721, Korea. Tel: +82-31-219-7019 Fax: +82-31-219-7020 E-mail: baega7695@hanmail.net

Received 13 April 2012 Revised 25 April 2012 Accepted 21 September 2012

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

The purpose of this study was to evaluate the cognitive effects of chemotherapy in patients with breast cancer.

Methods

Using several databases, prospective studies were collected up to August 2011. Of 2,106 publications identified, 12 met the inclusion criteria, and 8 studies were used to estimate the effect size of chemotherapy on cognitive impairment.

Results

Twelve studies were done since 2005 and most of the research was performed in Europe or North America. Eight studies were used to generate effect size across the cognitive domains of attention/concentration, verbal and visual memory, executive function, visuospatial skill, language, and subjective cognitive function. Each of the cognitive domains showed small effect sizes (-0.02 ~ -0.26), indicating diminished cognitive function for the chemotherapy group compared with non-chemotherapy groups.

Conclusion

Finding suggests that breast cancer patients who undergo chemotherapy may experience mild cognitive decline. Further study is needed to generate knowledge and guideline for interventions to address chemotherapy related cognitive impairment in these patients.

Keywords: Chemotherapy, Mild cognitive impairment, Attention, Memory, Breast neoplasms

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Figure 1.

Flow diagram of study screening.

Table 1

Characteristics of Studies Included in the Systematic Review

Study ID C	Country	Sample	Age (year), M±SD	Education level	Staging and treatment*	Measurement	Type of neuropsychological test^†	Other variables and tools^‡	Quality assessment^§	Included in meta-analysis
Ahles et al. (2010)	U.S.A.	BC, CTx (n=60)	51.7±7.1	No differences among groups	Staging: Stage 0, I, II, III (Exact percentages were not reported) Standard-dose chemotherapy: 30% AC, 36.7% AC plus paciltaxel, 3.3% AC plus taxotere, 1.8% CAF, 11.7% CMF, 16.7% FEC Local treatment: 81% RTx HRTx: 80% tamoxifen or anastrozole	T1: Baseline (before CTx) T2: 1 month T3: 6 months T4: 18 months after CTx	CVLT; Color-word interference test (DKEFS); Digit symbol-coding; Distractibility, reaction time (CPT); Faces I & II; Grooved pegboard; Logical memory I & II; PASAT; Sorting test; Trail making test; Verbal fluency test; Vocabulary (WAIS)	Anxiety (STAI) Depression (CES-D) Fatigue (FSI) Subjective cognitive ability (MASRQ)	+	Subjective cognitive function
		BC, nonCTx (n=72)	56.6±8.3		Staging: Stage 0, I, II, III (Exact percentages were not reported) Local treatment: 72% RTx HRTx: 66% tamoxifen or anastrozole
		Comparison (n=45)	52.9±10.0		Healthy women
Bender et al. (2006) Collins et al.	U.S.A Canada	BC, CTx (n=19)	40.1±6.5	No differences among groups No differences	Staging: 32% Stage I, 68% Stage II Standard-dose chemotherapy: 40% AC, 40% AC plus a taxane, 20% CMF	T1: Baseline T2: 1 week T3: 12 months after CTx	Digit vigilance test; Four word short memory test; RAVLT; RCFT; Trail making test-B	Anxiet (POMS) Depression (BDI-II) Fatigue (POMS) Subjective cognitive ability (PAOF)	−	Objective & subjective cognitive function Objective
		BC, nonCTx (n=15)	44.1±3.5		Staging: 40% Stage I, 60% Stage II Standard-dose chemotherapy:
					Standard-dose chemotherapy: 33% AC, 42% AC plus a taxane, 25% doxorubicin and a taxane HRTx: 100% tamoxifen
		BC (n=12)	44.5±4.2		Staging: 100% DCIS
Collins et al. (2009)	Canada	BC, CTx (n=53)	57.9±3.7	No differences between groups	Staging: 28.3% Stage I, 67.9% Stage II, 3.8% Stage III Standard-dose chemotherapy: 24.5% AC, 5.7% AC plus taxol, 9.4% CEF, 3.7% EC plus taxol, 5.7% FAC, 49.1% FEC, 1.9% Adriamycin and cisplatin HRTx: 11% tamoxifen, 4% arimidex, 2% letrozole	T1: Baseline(before CTx) T2: 1 month T3: 12 months after CTx	Arithmetic; Block design; Boston naming test; CVLT; Consonant trigrams; Phonemic word fluency(COWAT); Digit span-forward + backward; Digit symbol, Coding; Family pictures II; Grooved pegboard; Letter-number sequencing; PASAT; RVLT; Spatial span; Trail making test A or B; Wisconsin card sorting test	Anxiety (POMS) Depression (POMS) Fatigue (POMS)	+ +	Objective cognitive function
		BC, nonCTx (n=40)	57.6±4.0		Staging: 87.5% Stage I, 12.5% Stage II
					HRTx: 63% tamoxifen, 27% arimidex, 10% switched (tamoxifen to arimidex)
Debess et al. (2010)	Denmark	BC, CTx (n=75) BC, nonCTx (n=26) BC(n=19)	47.2 (Range: 29~59) 56.2 (Range: 44~59) 49.7 (Range: 39~59)	No differences among groups	Staging was not reported Standard-dose chemotherapy: 100% CEF Local treatment: 69% RTx Staging was not reported Local treatment: 65% RTx HRTx: tamoxifen 100% Staging was not reported Local treatment: 53% RTx	T1: Baseline (before CTx) T2: 1 month after CTx	Visual verbal learning test; Concept shifting test; Stroop color word interference test; Letter–digit coding test	Anger (POMS) Confusion (POMS) Coping capacity (GPS) Depression (POMS) Fatigue (POMS) Quality of life (EORTC QLQ-C30) Subjective cognitive ability (SCF) Tension (POMS)	+ +	No
		Comparison (n=208)	48.1 (Range: 28~59)		Healthy women
Fan et al. (2005)	Canada	BC, CTx (n=104)	Median=48	No differences between groups	Staging was not reported Standard-dose chemotherapy: 19% AC, 63% CEF, 18% other Local treatment: RTx, 6.7% at T1, 68.1% at T2, 65.4% at T3 HRTx: Tamoxifen or anastrozole, 4.8% at T1, 62.6% at T2, 66.7% at T3	T1: Baseline (before CTx) T2: 1 year T3: 2 years after CTx	Conner’s continuous performance test; Trail making test	Fatigue (FACT-F) Menopausal symptoms (FACT-ES) Quality of life (FACT-G) Subjective cognitive ability (HSCS)	+	No
		Comparison (n=102)	Median=47		Healthy women
Mehlsen et al. (2009)	Denmark	BC, CTx (n=36) Comparison (n=14)	48.6±8.0 39.3±11.7	Significant differences between groups (p=.001)	Staging was not reported Standard-dose chemotherapy: 100% CEF Healthy people (6 males, 11 females)	T1: Baseline (before CTx) T2: 4-6 weeks after CTx (Comparison: 3-4 months)	Arithmetic; Coding & symbol search; Digit span, Forward or Backward; Letter-number sequencing; Logical memory; RAVLT; RCFT; Stroop test; Trail making test A & B; Word fluency test	Confusion (POMS) Depression (BDI-II) Life satisfaction (SLS) Sleep quality (PSI) Social support (SSQT) Stress (PSS)	+ +	Objective cognitive function
Noal et al. (2011)	France France	BC, CTx (n=161)	Median=53 (Range: 31-71)	No differences between groups	Staging was not reported Standard-dose chemotherapy: 54% FEC, 30% FEC plus docetaxel, 16% other Local treatment: 100% RTx HRTx: 81% tamoxifen, anastrozole, or tamo+LH-RH analogue	T1: Baseline T2: 3 weeks after baseline T3: End of RTx T4: 4 months T5: 12 months after RTx	Digit span-forward or backward; RAVLT; Trail making test	Quality of life(FACT-G) Fatigue(FACT-F) Anxiety(HADS) Depression(HADS)	+ +	No
		BC, nonCTx (n=141)	Median=58 (Range: 36~84)		Staging was not reported Local treatment: 100% RTx HRTx: 89% tamoxifen, anastrozole, or tamo+LH-RH analogue 89%
Ouimet et al. (2009)	Canada	BC, CTx (n=49) BC, nonCTx (n=46) Comparison (n=28)	57.5±3.9 57.5±4.2 59.4±4.1	Significant differences among groups (p=.014)	Staging: Stage I, II (Exact percentages were not reported) Standard-dose chemotherapy: CEF, FAC, FEC (Exact percentages were not reported) Staging: Stage I, II (Exact percentages were not reported) HRTx: not reported Healthy women	T1: Baseline (before CTx) T2: End of CTx (approximately within 6 months)	Arithmetic; Block design; Boston naming test; CVLT; Consonant trigrams; COWAT; Digit span, forward + backward; Digit symbol-coding & symbol coding; Family pictures; Grooved pegboard; Letter–number sequencing; Logical memory; PASAT; RVLT; Spatial span; Trail making test A & B	Psychological distress (POMS)	−	Objective cognitive function
Quesnel et al. (2009)	Canada	BC, CTx (n=41)	50.3±7.2	No differences among groups	Staging: 34.1% Stage I, 48.8% Stage II, 17.1% Stage III Standard-dose chemotherapy: 56.1% AC, 14.6% FEC, 29.3% TAC Local treatment: 100% RTx HRTx: 75.6%	T1: Baseline (before CTx or RTx) T2: Post CTx or RTx T3: 3 months after CTx or RTx	Digit span; RAVLT; RCFT; Ruff 2 & 7 test; Symbol digit modalities test; Trail making test A & B; Verbal fluency test; Visual memory span (WMS-R)	Quality of life (EORTC QLQ-C30) Subjective cognitive ability (CFQ)	+ +	Objective & subjective cognitive function
		BC, nonCTx (n=40)	57.7±4.9		Staging: 90.0% Stage I, 10.0% Stage II HRTx: 77.5%
		Comparison (n=45); CCTx (n=23); CnonCTx (n=22)	CCTx, 47.9±7.4; CnonCTx, 55.0±7.1		Healthy women
Shilling et al. (2005)	U.K.	BC, CTx (n=50) Comparison (n=43)	51.1±8.6 52.3±5.8	No differences between groups	Staging was not reported Standard-dose chemotherapy: 2% AC, 2% CMF, 84% FEC, 12% FEC plus docetaxel HRTx: 28.0% Healthy women HRTx: 51.2%	T1: Baseline (before CTx) T2: 1 month after CTx	Digit span; Letter cancellation; Letter-number sequencing; Logical memory; RAVLT; RCFT; Spatial span; Stroop test	Fatigue (FACT-F) General health (GHQ12) Menopausal symptoms (FACT-ES) Quality of life (FACT-B) Subjective cognitive ability (CFQ)	) +	Objective & subjective cognitive function
Tager et al. (2010)	U.S.A.	BC, CTx (n=30) BC, nonCTx (n=31)	60.3±5.6 61.1±6.2	No differences between groups	Staging: 30% Stage I, 70% Stage II Standard-dose chemotherapy: 23.3% AC, 46.7% ACT, 30.0% CMF Local treatment: 56.7% RTx HRTx: 40% Staging: 35.5% DCIS, 51.6% Stage I, 12.9% Stage II Local treatment: 64.5% RTx HRTx: 64.5%	T1: Baseline (before CTx) T2: 1 month T3: 6 months after CTx	Arithmetic; Benton visual retention test; Boston naming test; Busckle selective reminding test; COWAT; Digit span; Digit symbol; Finger tapping test; Grooved pegboard; Letter–number sequencing; RCFT; Trail making test	Depression (BDI-II) Anxiety (ZAS) Subjective cognitive ability (interview)	y +	No
Vearncombe et al.(2009)	Australia	BC, CTx (n=136) BC, nonCTx (n=21)	49.4±7.9 54.0±8.2	No differences between groups	Staging: 27.2% Stage I, 72.8% Stage II Standard-dose chemotherapy: 5.1% AC, 19.7% AC plus taxol/ taxotere, 8.9% CAF, 3.2% CEA, 0.6% CMF, 44.6% FEC, 3.2% FEC plus taxotere, 0.6% FEA, 0.6% Cyclophosphamide plus taxotere Staging: 81% Stage I, 19% Stage II Local treatment: not reported HRTx: not reported	T1: Baseline (before CTx) T2: 1 month after CTx	AVLT; COWAT; Digit Span-backward; Card sorting task (DKEFS); Matrix reasoning (WAIS-III); Purdue pegboard; Stroop test; Symbol digit modalities test; Test of everyday attention-visual elevator & telephone search; Visual reproduction (WMS-III)	Anxiety and depression (HADS) Fatigue (FACT-F) Quality of life (FACT-B)	+	Objective cognitive function

* AC=Doxorubicin and cyclophosphamide; ACt=Doxorubicin, cyclophosphamide, and taxane; CAF=Cyclophosphamide, doxorubicin, and 5-fluorouracil; CEA=Cyclophosphamide, epirubicin, and adriamycin; CEF=Cyclophosphamide, epirubicin, and 5-fluorouracil; CMF=Cyclophosphamide, methotrexate, and 5-fluorouracil; EC=Epirubicin and cyclophosphamide; FAC=5-fluorouracil, doxorubicin, and cyclophosphamide; FEA=5-fluorouracil, epirubicin, and adriamycin; FEC=5-fluorouracil, epirubicin, and cyclophosphamide; LH-RH=Luteinizing hormone-releasing hormone; TAC=Taxotere, adriamycin, and cyclophosphamide.

†AVRT=Auditory verbal learning test; COWAT=Controlled oral word association test; CPT=Continuous performance test; CVLT=California verbal learning test; DKEFS=Delis-Kaplan executive function system; PASAT=Paced auditory serial addition test; RAVLT=Rey auditory verbal learning test; RCFT=Rey complex figure test; RVLT=Rey visual learning test; WAIS=Wechsler adult intelligence scale; WMS-III=Wechsler memory scale-version 3; WMS-R=Wechsler memory scale-revised.

‡BDI-II=Beck depression inventory-version 2; CES-D=Center for epidemiological study–depression; CFQ=Cognitive failures questionnaire; EORTC QLQ-C30=European organization for the research and treatment of cancer quality of life questionnaire; FACT-B=Functional assessment of cancer therapy scale - for breast cancer; FACT-ES=Functional assessment of cancer therapy scale – endocrine symptom; FACT-F=Functional assessment of cancer therapy scale – fatigue; FACT-G=Functional assessment of cancer therapy scale - general; FSI=Fatigue symptom inventory; GHQ12=General health questionnaire 12; GPS=General perceived self-efficacy; HADS=Hospital anxiety and depression scale; HSCS=High sensitivity cognitive screen; MASRQ=Multiple ability self-report questionnaire; PAOF=Patient’s assessment of own functioning; POMS=Profile of mood states; PSI=Pittsburgh sleep inventory; PSS=Perceived stress scale; SCF=Subjective cognitive functioning; SLS=Satisfaction with life scale; SSQt=Social support questionnaire of transactions; STAI=State trait anxiety inventory; ZAS=Zung anxiety scale.

§Quality assessment of literature by Scottish Intercollegiate Guidelines Network checklist. ‘+ +’ indicates that all or most of the criteria have been fulfilled. ‘+’ indicates that some of the criteria have been fulfilled. ‘-’ indicates fe or no criteria fulfilled.

Abbreviation: BC=Breast cancer; CCTx=Comparison group who matched with breast cancer treated with chemotherapy; CnonCTx=Comparison group who matched with breast cancer not treated with chemotherapy; CTx=Treated with chemotherapy; DCIS=Ductal carcinoma in situ; HRTx=Treated with hormone therapy; M=mean; nonCTx=Not treated with chemotherapy; RTx=Treated with radiotherapy; SD=Standard deviation; U.K.=United Kingdom; U.S.A.=United States of America.

Table 2.

Characteristics of 12 Research Studies (N=12)

Characteristics	Categories	n (%)	Range
Publication year	2005	2 (16.7)
	2006	1 (8.3)
	2009	5 (41.7)
	2010	3 (25.0)
	2011	1 (8.3)
Region	North America	7 (58.4)
	Europe	4 (33.3)
	Other	1 (8.3)
Sample size	<50	1 (8.3)	46-328
	50-100	4 (33.3)
	≥101	7 (58.4)
Mean age of study participants (year)	<50	3 (30.0)
	50_-60	6 (60.0)
	≥61	1 (10.0)
	Not reported	2
Instrument of subjective cognitive ability	Cognitive failures questionnaire	2 (33.3)
	Multiple ability self-report questionnaire	1 (16.7)
	Patient's assessment of own functioning	1 (16.7)

	Subjective cognitive functioning	1 (16.7)
	Interview	1 (16.7)
	Not measured	6
Post-test period after treatment (months)	<1	3 (25.0)	0.25-12
	1-3 4	7 2 (58.4) (16.7)
	≥4	2 (16.7)
Follow up period after treatment (months)	<6 6 12	5 4 (41.7) (33.3)	1-24
	6-12 13	4 3 (33.3) (25.0)
	≥13	3 (25.0)

Table 3.

Effect Sizes for Chemotherapy on Cognitive Function

Test	No. of studies*	n^†	Effect size^‡	Lower 95% CI	Upper 95% CI	Z	p	Nfs
Attention/concentration	19	1,515	−0.14	−0.24	−0.03	2.57	.010	15
Digit span-forward and backward	3	265	−0.08	−0.32	0.16	0.64	.524
Digit span-forward	2	127	−0.24	−0.73	0.25	0.96	.337
Trails making test-part A	5	392	−0.06	−0.27	0.14	0.61	.538
Arithmetic	4	311	−0.06	−0.29	0.17	0.49	.626
Letter-number sequencing	5	420	−0.28	−0.48	−0.08	2.78	.005
Memory	30	2,204	−0.17	−0.25	−0.08	3.66	<.001	73
Verbal memory	20	1,602	−0.17	−0.28	−0.07	3.19	.001	32
CVLT short delay free recall	3	265	−0.39	−0.64	−0.14	3.11	.002
CVLT long delay free recall	3	265	−0.08	−0.33	0.16	0.68	.500
CVLT long delay recognition	3	265	_-0.06	_-0.30	0.19	0.47	.636
RAVLT immediate recall	6	458	−0.21	−0.41	0.00	1.94	.052
RAVLT long delay recall	5	349	−0.11	−0.36	0.14	0.86	.392
Visual memory	10	602	−0.15	−0.32	0.01	1.85	.063	0
RCFT immediate recall	5	301	−0.19	−0.42	0.04	1.59	.113
RCFT long delay recall	5	301	−0.12	−0.35	0.11	1.04	.297
Executive function	17	1,407	_-0.08	_-0.18	0.03	1.35	.176	0
Digit symbol–coding subset	4	311	−0.09	−0.32	0.14	0.76	.444
Digit symbol-symbol search subset	4	311	−0.09	−0.32	0.14	0.80	.421
Trails making test-part B	5	392	−0.09	−0.30	0.11	0.90	.366
Digit span-backward	4	393	−0.03	−0.24	0.19	0.24	.812
Visuospatial skill	2	127	−0.11	−0.47	0.26	0.58	.562	−
RCFT copy	2	127	_-0.11	_-0.47	0.26	0.58	.562
Language	3	265	−0.02	−0.26	0.23	0.13	.902	0
Boston naming test	3	265	−0.02	−0.26	0.23	0.13	.902
Subjective cognitive function	6	474	−0.26	−0.44	−0.07	2.76	.006	6

CI=Confidence interval; CVLT=California verbal learning test; Nfs=Fail-safe N; RAVLT=Rey auditory verbal learning test; RCFT=Rey complex figure test. *The number of studies included per cognitive domain;

^† Total number of participants per effect size;

^‡ Weighted standardized mean difference.

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