Neurocognitive consequences of a paediatric brain tumour and its treatment: a meta-analysis

Neurocognitive consequences of a paediatric brain tumour and itstreatment: a meta-analysis

MARIEKE A DE RUITER1 | ROSA VAN MOURIK2 | ANTOINETTE Y N SCHOUTEN-VAN MEETEREN3 |MARTHA A GROOTENHUIS1 | JAAP OOSTERLAAN2

1 Pediatric Psychosocial Department, Emma Children's Hospital Academic Medical Center, Amsterdam; 2 Department of Clinical Neuropsychology, Vrije Universiteit Amsterdam;3 Department of Pediatric Oncology, Emma Children's Hospital Academic Medical Center, Amsterdam, the Netherlands.

Correspondence to Ms Marieke A de Ruiter, Emma Children's Hospital Academic Medical Center, Meibergdreef 9, room A3-241, 1105 AZ Amsterdam, the Netherlands. E-mail: [email protected].

PUBLICATION DATA

Accepted for publication 22nd August 2012.Published online 15th November 2012.

ABBREVIATIONSCPT Conners' Continuous Performance TestFSIQ Full-scale IQMHRT Mean hit reaction timePBTS Paediatric brain tumour survivorsPIQ Performance IQVIQ Verbal IQ

AIM This meta-analysis provides a systematic review of studies into intellectual and attentional

functioning of paediatric brain tumour survivors (PBTS) as assessed by two widely used

measures: the Wechsler Intelligence Scale for Children (3rd edition; WISC-III) and the Conners’

Continuous Performance Test (CPT).

METHOD Studies were located that reported on performance of PBTS (age range 6–16y).

Meta-analytic effect sizes were calculated for Full-scale IQ, Performance IQ, and Verbal IQ as

measured by the WISC-III, and mean hit reaction time, errors of omission, and errors of

commission as measured by the CPT. Exploratory analyses investigated the possible impacts of

treatment mode, tumour location, age at diagnosis, and time since diagnosis on intelligence.

RESULTS Twenty-nine studies were included: 22 reported on the WISC-III in 710 PBTS and seven

on CPT results in 372 PBTS. PBTS performed below average (ps<0.001) on Full-scale IQ (Cohen’s

d=)0.79), Performance IQ (d=)0.90), and Verbal IQ (d=)0.54). PBTS committed more errors of

omission than the norm (d=0.82, p<0.001); no differences were found for mean hit reaction time

and errors of commission. Cranial radiotherapy, chemotherapy, and longer time since diagnosis

were associated with lower WISC-III scores (ps<0.05).

INTERPRETATION PBTS have seriously impaired intellectual functioning and attentiveness. Being

treated with cranial radiotherapy and ⁄ or chemotherapy as well as longer time since diagnosis

leads to worse intellectual functioning.

In the USA the incidence of cancer in children aged 0 to14 years is almost three per 100 000.1 Approximately 17 to22.5% of children with cancer have a brain tumour.1,2

Advances in medicine have led to an increasing number ofchildren surviving cancer. The 5-year survival rate of childrendiagnosed with a brain tumour under the age of 15 increasedfrom 57% for patients diagnosed from 1975 to 1977 to 74%for patients diagnosed from 1996 to 2004.3

With more children becoming long-term survivors, theneed has grown to understand fully the nature and magnitudeof the late effects of the tumour and treatment. Comparedwith survivors of other malignancies, survivors of braintumours in childhood bear the greatest risk of neurocognitiveimpairment.4 Numerous studies have shown that 40 to 100%of paediatric brain tumour survivors (PBTS) show some formof neurocognitive deficit.5 Frequently reported impairments inPBTS are declining levels of general intelligence and attentiondeficits. Deficits in these areas can have a deleterious effect onacademic achievement and psychosocial functioning.6–8

Besides the burden of the tumour itself, the treatment cancontribute to neurocognitive impairments. Radiotherapy isespecially considered to have an impact on neurocognitive

functioning.9,10 Chemotherapy, however, has also been foundto be associated with poor outcomes in PBTS.11 In additionto the treatment, tumour location can affect the neurocogni-tive outcome of PBTS, with infratentorial tumours being asso-ciated with worse outcomes than supratentorial tumours.12

Furthermore, age at diagnosis is known to have an impact onneurocognitive outcome.13 The young brain is especiallyvulnerable to the adverse effects of treatment because of therapid cell proliferation, dendritic and axonal outgrowth, aswell as myelination, which take place during infancy, child-hood, and adolescence. Therefore, radiotherapy is postponedor omitted in most protocols if the child is under the age of3 years.11 In addition, time since treatment is an importantdeterminant of neurocognitive deficits, as the deficits oftenincrease over time, owing to a slower rate of acquiring newskills and knowledge compared with healthy peers.13,14

The current paper reports the results of a quantitativemeta-analysis, investigating the magnitude and consistency ofneurocognitive deficits in PBTS. Analysis of the literaturedetermined general intelligence and attention as twofrequently studied areas of neurocognitive functioning.General intelligence provides insight into the generic cogni-

408 DOI: 10.1111/dmcn.12020 ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW

tive functioning of the patient and is measured most oftenusing the Wechsler Intelligence Scale for Children (3rd edi-tion; WISC-III).15 Attention is required to some extent fornearly all components of neurocognitive functioning and istherefore a crucial area to study thoroughly. The Conners’Continuous Performance Test (CPT, CPT II) is the mostwidely used measure for attention.16,17 Besides intelligenceand attention, processing speed and working memory areoften studied in PBTS. These areas are important in under-standing the neurocognitive functioning of a patient; they are,however, beyond the scope of this meta-analysis, whichfocuses on the two key areas: intelligence and attention. TheCPT comprises a measure for processing speed; therefore, thisarea is reported as well. Additionally, exploratory analysesinvestigated the possible impact of cranial radiotherapy, che-motherapy, tumour location, age at diagnosis, and time sincediagnosis on general intelligence.

METHODSelection of studiesStudies were searched using the PubMed, Web of Science,and Embase computerized databases. Relevant studies werelocated by combining the search terms: neurocogniti*, neuro-psych*, cogniti*, child*, pediatric*, tumor, tumour, cancer,neoplasm*, central nervous system, and brain.

All retrieved studies were reviewed to include studies meet-ing the following criteria: (1) the participants includedchildren treated for a brain tumour by neurosurgery, radio-therapy, and ⁄ or chemotherapy; (2) intelligence was assessedusing the full WISC-III (as abbreviated versions might yieldunreliable data) and ⁄ or attention was assessed using the CPT;(3) mean age of PBTS at assessment was between 6 years and16 years, corresponding to the age range covered by theWISC-III; (4) the study was published in a peer-reviewedEnglish language journal; and (5) the study was publishedbefore November 2011. The last search was performed on25 November 2011. The reference lists of included studieswere explored to locate additional potentially relevant studiesfor inclusion in the meta-analysis. No research protocol of thepresent meta-analysis exists.

Dependent variablesThe WISC-III is the most widely used intelligence test forchildren aged 6 to 16 years. Dependent measures includeFull-scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ(PIQ), on which normative samples obtain a mean score of100 with a standard deviation (SD) of 15. VIQ is a measure ofthe ability to use and understand language. PIQ assesses per-ceptual reasoning. FSIQ is calculated by averaging VIQ andPIQ. Higher scores indicate better intellectual functioning.WISC-IV studies were not included because the WISC-IVdoes not allow calculation of VIQ and PIQ scores, and onlyfew PBTS studies reported WISC-IV scores.18,19

The CPT is a widely used test to assess attention. In theCPT, a sequence of different letters is shown, one at a time,and the participant is instructed to press the space bar asquickly as possible without committing errors when any letter

other than ‘X’ appears on the screen. Each letter is displayedfor 250 ms, with different time intervals between each letter.Main dependent variables are (1) mean hit reaction time(MHRT), measuring processing speed, (2) errors of omission,measuring inattentiveness, and (3) errors of commission,measuring impulsivity.20 Scores are reported in T scores, witha mean of 50 and an SD of 10. For all CPT variables, higherscores indicate worse performance.

Quality assessmentTwo authors (MAdR and RvM) independently assessed thequality of the included studies using the Newcastle-OttawaScale.21 The Newcastle-Ottawa Scale assesses quality in termsof the selection of children (four criteria), comparability ofstudy groups if applicable (one criterion), and outcome assess-ment (three criteria). Differences in assessment between bothauthors were resolved by consensus. Some criteria were notapplicable to all studies; therefore we used the percentage ofthe applicable criteria each study met as a score.

Statistical analysesThe computer programs Comprehensive Meta-Analysis 2.222

and SPSS version 18.0 (SPSS Inc., Chicago, IL, USA) wereused for statistical analyses. Techniques by Hozo et al. wereused to convert medians into means and SDs if necessary.23–27

Where studies compared two or more subgroups of PBTS,the data were aggregated into one mean and SD per study.

For each of the dependent measures, effect sizes were calcu-lated for each study separately. Effect sizes were calculated interms of Cohen’s d, with sizes of 0.20, 0.50, and 0.80 translat-ing into small, medium, and large effects respectively.28 Onlyone study used a comparison group of healthy participants;29

all other studies used normative data to interpret data derivedfrom PBTS. For comparability, normative data were used tocalculate effect sizes for all studies. For each dependent vari-able, an overall effect size was calculated by weighting all theeffect sizes according to the sample sizes. To test whether thevariability in effect sizes exceeded what could be expected fromsampling error alone, Q and I2 tests of heterogeneity wereconducted.30,31 That is, when homogeneously distributed, anidentical underlying effect size is representative for all studiesand so-called fixed effects analysis can be used for estimatingthe assumed common effect. If the effect sizes are hetero-geneously distributed, a random effects analysis estimates themean of distribution of effects across all studies, which yieldswider confidence intervals for the combined effect size.

A major concern in conducting a meta-analysis is thepresence of publication bias, meaning that studies reportingnon-significant results are less likely to be published, leadingto erroneous inflation of meta-analytic effect sizes. Thepossibility of publication bias was reduced by including

What this paper adds• PBTS show medium- to large-sized depressions in IQ.• PBTS show large-sized increases in commission errors, indicating inattentive-

ness.• Radiotherapy, chemotherapy, and longer time since diagnosis are related to

worse intellectual outcome.

Review 409

unpublished data.32–34 Furthermore, the possibility of publica-tion bias was studied using two methods. First, we calculatedRosenthal’s fail-safe N, which calculates the necessary numberof studies to nullify the overall effect, for each significant com-bined effect size.35 Second, the correlation between samplesizes (the number of PBTS) and effect sizes was calculated foreach dependent variable. A significant negative correlationbetween sample sizes and effect sizes would indicate a ten-dency that significant results in small samples are easier topublish than non-significant results in small samples.

We studied the possible moderating effects of the followingvariables on the study specific effect sizes for the dependentvariables of the WISC-III: (1) cranial radiotherapy as mea-sured by the percentage of patients treated with cranial radio-therapy (% cRT); (2) chemotherapy as measured by thepercentage of patients treated with chemotherapy (% chemo);(3) tumour location as measured by the percentage of patientstreated for infratentorial brain tumour (% infra); (4) age atdiagnosis (age at dx); and (5) time since diagnosis (time sincedx). The effects were analysed using Comprehensive Meta-

Analysis by meta-regression analyses, assessing the relation-ship between the moderating variables and the effect sizes onthe dependent variables. For each moderating variable we cal-culated the proportion of variance accounted for, with 1%,9%, and 25% being interpreted as small, moderate, and largeeffects respectively.28 These analyses were not conducted onthe CPT, because of the limited number of studies available.Alpha was set at 0.05 in all analyses.

RESULTSFigure 1 shows the selection of studies in a flowchart.Twenty-nine studies met inclusion criteria. Twenty-two stud-ies reported scores on the WISC-III for a total of 710PBTS.9,12,23–26,29,34,36–49 Seven studies reported CPT resultsfor a total of 372 PBTS.32,33,50–54 When two or more studiesreported on the same participants, we included the mostrecently published study to prevent erroneously inflatedhomogeneity of meta-analytic results. Grill et al.44 and Kief-fer-Renaux et al.47 report partly on the same participants. Themost recent publication by Grill et al. reports on PIQ and

Studies identified through computerized database searching

(n=3074)

Additional studies identified through reference list searches

(n=0)

Studies after duplicates removed (n=1615)

English language studies(n=1395)

Studies excluded, reported as conference abstract or not

published in English (n=220)

Studies on PBTS (n=708)

Studies excluded, reporting on other patient group

(n=687)

Studies on WISC/CPT (n=34)

Studies included in meta-analysis (n=29)

Studies excluded, not reporting on WISC/CPT

(n=674)

Studies excluded due to overlap in participants

(n=5)

Figure 1: Flow chart of study selection n, number of studies; PBTS, paediatric brain tumour survivors; WISC Wechsler Intelligence Scale for Children; CPT,Conners' Continuous Performance Test.

410 Developmental Medicine & Child Neurology 2013, 55: 408–417

VIQ, but does not report on FSIQ. The earlier publication ofKieffer-Renaux et al., however, does report on FSIQ. There-fore, the study by Grill et al. was included in the meta-analysisof PIQ and VIQ, whereas the study by Kieffer-Renaux et al.was included in the meta-analysis of FSIQ.

For five of the 22 WISC-III studies we aggregated data ontwo or more PBTS subgroups into one mean and SD perstudy: (1) Patel et al.12 compared PBTS according to theirtumour location; (2) Callu et al.39 compared patients withlow-grade gliomas and malignant cerebellar tumours; (3) Lac-aze et al.24 studied three samples of patients with optic path-way tumours who received three different treatments; (4)Kieffer-Renaux et al.47 compared patients with medulloblas-toma who received two different doses of radiotherapy; and (5)Mulhern et al.48 compared patients with medulloblastomawith those having low-grade glioma.

Table I displays details of the studies incorporated in thismeta-analysis. Some studies reported insufficient details toallow calculation of effect sizes. In these cases, authors werecontacted to provide the missing data.50,32–34,51 For somestudies, data were unavailable on one or more of the depen-dent variables, leading to unequal numbers of studies for thesedependent variables.

Figures 2 and 3 display the studies’ effect sizes as well asthe overall effect sizes for each of the dependent variablesand the accompanying 95% confidence intervals. Effect sizesof all dependent variables were heterogeneously distributedand a random effect analysis was used in all analyses. Therewas no significant association between the study quality rat-ings and effect sizes (all ps>0.08) for any of the dependentvariables.

Wechsler Intelligence Scale for Children-IIIPBTS had lower FSIQ scores than their peers, as indicated bya combined random effect size of d=)0.79 (p<0.001), translat-ing into a large effect. Of the 21 studies that reported onFSIQ, 14 reported scores significantly (p<0.05) below theaverage FSIQ of 100,9,12,26,34,36–41,45–48 whereas none of thestudies reported scores significantly higher than average.

PIQ scores were significantly lower in PBTS than in thenormative sample, as indicated by a combined random effectsize of d=)0.90 (p<0.001), again translating into a large effect.Fifteen of the 19 studies found PIQ scores of PBTS signifi-cantly (p<0.05) below average,9,12,24,26,34,36–40,43,44,47–49whereasin none of the studies were scores significantly higher thanaverage found. [Correction added on 27 December 2012, after

Table I: Characteristics of studies included in the meta-analysis

StudyNumber of participantsand diagnosis

Treatment Location Time ⁄ age Quality

% cRT % Chemo % Infra Mean age at dx Time since dxa NOS score

WISC-III Hazin et al.49 13 LGG, 7 MB 35 35 100 8.3 1.9 100Patel et al.12 70 BT 76 71 49 7.8 3.4 100Saury and Emanuelson36 8 MB 100 100 63 7.8 5.1 50Sands et al.37 24 BT 29.2 100 65.4 3.0 3.3 100Aukema et al.29 6 MB 100 100 100 4.7 8.9 50Bonner et al.38 101 BT 74 NA 56 7.0 3.9 100Callu et al.39 20 HGG, 19 LGG 44 36 100 5.4 3.4 100Briere et al.40 12 MB, 6 GNS 94 78 NA 6.3 NA 0Ris et al.26 83 LGG 0 0 16 NA NA 100Sanders et al.41 5 HGG 80 100 40 0.9 11.4 100Jalali et al.23 7 LGG 100b NA <42 NA NA 100Khong et al.42 12 MB 100 100 100 8.5 3.4 50Beebe et al.43 92 LGG 0 0 100 8.1 0.4 100Grill et al.44 76 PF 100 72 100 5.7 6.1 50Spiegler et al.34 34 MB, EP 100 70 100 5.5 2.5 100Lacaze et al.24 21 LGG 38 100 0 NA NA 100Packer45 40 MB 100 100 100 6.0 4.0 50Carey et al.46 15 BT 60 53 NA NA NA 100Kieffer-Renaux et al.47 36 MB 100 100 100 8.0 5.0 50Merchant et al.25 8 GCT 100 0 0 NA NA 100Grill et al.9 19 MB, EP 100 NA 100 6.1 5.3 100Mulhern et al.48 18 MB, 18 LGG 50 50 100 NA NA 100

CPT Butler et al.50 131 BTNS NA NA NA 6.5 5.3 50Mabbott et al.51 64 MB, EP 50 NA 50 5.8 5.6 100Conklin et al.32 61 BTNS NA NA NA 6.5 5.0 50Stargatt et al.52 16 BT 62 69 100 9.9 4.1 100Reeves et al.53 38 MB 100 100 100 8.3 2.0 100Mulhern et al.54 37 BT 100 49 62 NA NA 100Mulhern et al.33 25 MB 100 NA 100 8.2 5.2 100

Ages are in years. aCalculated by subtracting age at assessment and age at diagnosis. bStereotactic radiotherapy. BTNS, brain tumour notspecified; % cRT, percentage of patients treated with cranial radiation therapy; % Chemo, percentage of patients treated with chemotherapy; %infra, percentage of patients with an infratentorial tumour; dx, diagnosis; NOS, Newcastle-Ottawa Scale, in percentages of applicable criteria thatwere met; WISC-III, Wechsler Intelligence Scale for Children (3rd edition). LGG, low-grade glioma; MB, medulloblastoma; BT, mixed diagnosisgroup; NA, not available; HGG, high-grade glioma; GNS, glioma not specified; PF, posterior fossa tumour; EP, ependymoma; GCT, germ celltumour; CPT, Conners’ Continuous Performance Test.

Review 411

dVariable Study p-value

Standard difference and 95% CI

Hazin et al. 2011Patel et al. 2011Saury and Emanuelson 2011Sands et al. 2010Aukema et al. 2009Bonner et al. 2009

Briere et al. 2008Ris et al. 2008Sanders et al. 2007Jalali et al. 2006Khong et al. 2006Beebe et al. 2005Spiegler et al. 2004Lacaze et al. 2003Packer 2002Carey et al. 2001Kieffer-Renaux et al. 2000Merchant et al. 2000Grill et al. 1999Mulhern et al. 1999Combined d


Briere et al. 2008Ris et al. 2008Jalali et al. 2006Khong et al. 2006Beebe et al. 2005

Spiegler et al. 2004Lacaze et al. 2003Kieffer-Renaux et al. 2000Merchant et al. 2000

Grill et al. 2004

Grill et al. 1999Mulhern et al. 1999Combined d

Callu et al. 2009


Briere et al. 2008Ris et al. 2008Jalali et al. 2006Khong et al. 2006Beebe et al. 2005

Spiegler et al. 2004Lacaze et al. 2003Kieffer-Renaux et al. 2000Merchant et al. 2000

Grill et al. 2004

Grill et al. 1999Mulhern et al. 1999Combined d

Callu et al. 2009

Callu et al. 2009

–0.48

–4.00 –2.00 2.00 4.000.00

–0.61–2.79–0.75–1.15–0.90–0.61–1.46–0.39–2.45–1.08

–0.28–1.03–0.53–1.08–0.99–0.96–0.24–1.50–0.60–0.79

–0.79–2.79–0.65–1.10–1.02–0.74–1.42–0.48–0.83–0.24–0.33–1.48–1.14

–1.24

–1.74

–1.01

–1.14

–1.03

–1.18

–0.87

–0.81–0.90

–0.10–0.40

–0.69

–0.64–0.21

–0.27

–0.21–0.77–0.71–0.29–0.59–0.27

–0.85–0.54

–2.26

0.19

–0.80

0.15

0.53

0.130.000.000.01

0.00

0.00

0.00

0.000.01

0.01

0.00

0.00

0.00

0.000.00

0.000.000.000.00

0.000.00

0.00

0.000.000.00

0.00

0.00

0.00

0.000.000.00

0.00

0.010.59

0.090.050.200.15

0.35

0.000.35

0.70

0.76

0.140.560.02

0.020.10

0.02

0.01

0.64

0.09

0.00

0.01

0.01

0.06

0.060.72

0.06

0.02

0.030.07

FSIQ

PIQ

VIQ

Figure 2: Wechsler Intelligence Scale for Children, 3rd edition (WISC-III) study results. CI, confidence interval; FSIQ, Full-scale IQ; PIQ, Performance IQ; VIQ,Verbal IQ.


first online publication: effect size of PIQ corrected tod=0.90].

VIQ scores of PBTS were significantly below average. Thecombined random effect size was d=)0.54 (p<0.001), whichrepresents a medium effect size. Eleven of the 19 studiesreported scores that were significantly (p<0.05) below themean.9,12,23,34,36–38,40,44,47,48 Eight studies reported VIQscores that did not differ significantly from the mean of thenormative sample.24–26,29,39,42,43 The combined effect size forPIQ was significantly higher than the combined effect size forVIQ (d=)0.29, p<0.001), indicating greater impairments inPIQ than in VIQ.

There was no evidence for publication bias for any of theWISC-III measures, as we found high fail-safe N values andnon-significant (ns) positive correlations between sample sizeand effect size (FSIQ: fail-safe N=871, r=0.36, ns; PIQ: fail-safe N=1030, r=0.16, ns; and VIQ: fail-safe N=406, r=0.25, ns).

Conners' Continuous Performance TestThe studies were ambiguous about the scores of PBTS onMHRT of the CPT. Three of seven studies found signifi-cantly slower MHRT,51,53,54 whereas two studies foundresponses of the PBTS to be significantly faster than aver-age.32,33 Two other studies found PBTS scores in the average

range.50,52 Across studies a non-significant combined randomeffect size of d=0.15 was found for MHRT.

The number of errors of omission on the CPT committedby PBTS was higher than the normative sample, as indicatedby a combined random effect size of d=0.82 (p<0.001), whichis considered to be a large effect. All but one study found sig-nificantly higher errors of omission rates in PBTS than thenormative sample.32,33,51–53 Fail-safe N was 64 and there was apositive non-significant correlation between sample sizes andeffect sizes (r=0.85), together indicating that there was no evi-dence for publication bias.

PBTS did not differ from the normative sample on thenumber of errors of commission, as indicated by a non-signifi-cant combined random effect size of d=0.03. Five of sevenstudies found no performance differences between PBTS andthe normative sample;32,33,50,51,54 one study reported PBTS tomake fewer errors of commission than the normative sam-ple,52 and another study found that more errors were made bythe PBTS than the normative sample.53

Exploratory analysesTable II reports the results for the meta-regression analysisfor the five moderating variables. Cranial radiotherapy was astrong predictor of lower intellectual functioning, accounting

Butler et al. 2008Mabbott et al. 2008Conklin et al. 2007Stargatt et al. 2007Reeves et al. 2006Mulhern et al. 2004Mulhern et al. 2001Combined d

d

Butler et al. 2008Mabbott et al. 2008Conklin et al. 2007Stargatt et al. 2007Reeves et al. 2006Mulhern et al. 2004Mulhern et al. 2001Combined d

Butler et al. 2008Mabbott et al. 2008Conklin et al. 2007Stargatt et al. 2007Reeves et al. 2006Mulhern et al. 2001Combined d

MHRT

EO

EC

Variable Study p-value

Standard difference and 95% CI

–2.00 –1.00 0.00 1.00 2.00

0.240.46

–0.53

–0.96

–0.281.06

0.050.010.00

0.000.000.000.540.15

0.44

0.93

0.090.410.491.291.661.320.82

0.00–0.19–0.03

–0.500.91

0.310.260.03

0.460.020.010.000.000.000.00

0.970.280.850.010.030.190.360.78

Figure 3: Conners' Continuous Performance Test (CPT) study results. Higher scores indicate worse performance for all three dependent variables. CI, confi-dence interval; EC, errors of commission; EO, errors of omission; MHRT, mean hit reaction time.

Review 413

for 26%, 32%, and 19% of the variance in FSIQ, PIQ, andVIQ respectively, with cranial radiotherapy leading to lowerscores as opposed to no cranial radiotherapy. Chemotherapyaccounted for 22% of the variance in FSIQ and 29% of thevariance in PIQ scores, with chemotherapy leading to lowerscores as opposed to no chemotherapy. There was no associa-tion between chemotherapy and VIQ. Furthermore, we foundno predictive value of tumour location or age at diagnosis forintelligence scores. Longer time since diagnosis, however, washighly predictive of lower scores on all WISC-III scales,accounting for large proportions of the variance (FSIQ 41%;PIQ 44%; VIQ 25%). As expected, there was a strong associa-tion between cranial radiotherapy and chemotherapy (r=0.54,p<0.05), and between age at diagnosis and time since diagnosis(r=)0.66, p<0.05), not allowing us to distinguish between theeffects of these moderating variables.

DISCUSSIONThis meta-analysis summarized neurocognitive functioning of710 (WISC-III) and 372 (CPT, CPT II) PBTS. We foundsubstantial impairments in intellectual functioning and atten-tional abilities. PBTS scored on average )0.54SD to )0.90SDlower on the WISC-III scales than the normative sample, withPIQ scores being even more depressed than VIQ scores. Thenumber of PBTS in this meta-analysis that were at grade leveland succeeding academically is unknown. However, a largebody of research has demonstrated that intellectual function-ing, as assessed with intelligence tests, is a powerful predictorof academic achievement and vocational success.55,56 In PBTSthis association was substantiated by Reddick et al.,57 whofound a positive relation between intelligence scores of PBTS,as measured with the Wechsler intelligence scales, and aca-demic achievement, as measured with the abbreviated Wechs-ler Individual Achievement Test. Moreover de Boer et al.58

report academic failure and lower intelligence to be risk fac-tors for decreased employment rates in PBTS, with PBTSbeing nearly five times more likely to be unemployed thanhealthy peers.

This meta-analysis found performance intelligence to bemore vulnerable to the detrimental effects of a brain tumourand its associated treatment than verbal intelligence, with theobserved PIQ scores in this meta-analysis being on average

)0.29SD lower than the VIQ scores. Similar findings havebeen reported in other populations at risk for brain damage,including children born very preterm and those with traumaticbrain injury.59,60 The discrepancy between PIQ and VIQ find-ings in PBTS might be related to the high rate of cerebellartumours in this group, as half of the paediatric brain tumoursare located within the posterior fossa.34 PIQ subtests are of amulti-component nature and draw more heavily on motorfunctions, visuomotor integration, visual attention, abstractreasoning, and working memory than the VIQ subtests. Infor-mation about how many PBTS were excluded from the analy-ses because of a persistent motor or sensory disability waslacking. However, it is well known that many of these neuro-cognitive functions depend heavily on cerebellar function-ing.61–63 Therefore damage to the cerebellum is expected tobe related to depressed PIQ scores. Secondly, lower PIQ thanVIQ scores may be related to a general slowing in informationprocessing resulting from white matter damage. Comparedwith VIQ subtests, many PIQ subtests draw heavily on pro-cessing speed owing to their timed character. Although greymatter development peaks during childhood, white mattercontinues to develop gradually until early adulthood.59 Thematuration of white matter is therefore challenged in PBTSbecause cancer therapy damages the healthy cells of the centralnervous system. Glial progenitor cells are especially vulnerableto the effects of chemotherapy and radiotherapy.64 These cellsare responsible for the formation of oligodendrocytes andastrocytes, both myelinating cells that are crucial for whitematter integrity. White matter integrity plays a major role ininformation processing speed with decreased white matterintegrity, resulting in slower processing speed.65

In the present meta-analysis, severe attentional problems inPBTS were revealed, as indicated by the high mean number oferrors of omission committed by PBTS on the CPT com-pared with the normative sample. In addition to the errors ofomission of the CPT, attention problems in PBTS have beenreported using other measures of attention. PBTS performbelow the norm on the Freedom of Distractibility Index, theattentional factor of the WISC-III.40 Also, measuring atten-tion using the Gordon Diagnostic System, PBTS scores onfocused attention have been reported to be almost 1SD belowthe mean of the normative sample and more than 1SD below

Table II: Meta-regression analyses, Wechsler Intelligence Scale for Children (3rd edition) studies

FSIQ PIQ VIQ

n b R2 p n b R2 p n b R2 p

Treatment modulecRT 21 )0.51 0.26 0.001 19 )0.56 0.32 <0.001 19 )0.44 0.19 0.013Chemo 18 )0.47 0.22 0.006 16 )0.54 0.29 0.004 16 )0.36 0.13 0.090

Tumour locationInfra 19 )0.12 0.01 0.591 18 )0.30 0.09 0.188 18 )0.11 0.01 0.633

Age at diagnosis 15 0.40 0.16 0.061 14 0.15 0.02 0.568 14 0.35 0.12 0.114Time since diagnosis 14 )0.64 0.41 <0.001 13 )0.67 0.44 <0.001 13 )0.50 0.25 0.014

FSIQ, Full-scale IQ; PIQ, Performance IQ; VIQ, Verbal IQ; n, number of studies; b, standardized Beta coefficient; R2, R squared; cRT, cranialradiation therapy; Chemo, chemotherapy; Infra, infratentorial tumour.


the mean on selective attention.66 Other researchers have usedthe Conners’ Rating Scale for Parents and Teachers to identifyattention deficits in PBTS; they found more than half of thepatients obtained scores above the 75th centile, indicatingattentional difficulties.67 Attentional abilities develop early inlife and form the basis for other emerging and proliferatingneurocognitive functions.59 As a result, attentional abilities arean important prerequisite for scholastic development and arestrongly associated with academic achievement.59 Reddicket al.57 found worse attentional functioning in PBTS, mea-sured with the CPT, to be associated with lower academicachievement scores, as measured with the abbreviated Wechs-ler Individual Achievement Test.

Interestingly, this meta-analysis found no evidence for slowprocessing speed in PBTS as measured with MHRT on theCPT. Individual studies revealed conflicting findings, withsome researchers reporting worse performance of PBTS thanthe normative sample and others reporting no difference oreven better performance by PBTS. Our failure to find evi-dence for slowed information processing as measured by theMHRT on the CPT does not fit with the frequently observedimpairments in white matter integrity in PBTS. Such impair-ments are expected to result in slower processing speed.65 Per-haps MHRT is a limited measure for processing speed. It ispossible that slowed information processing becomes evidentonly in tasks that place demands on the integration of multiplestimulus modalities and involve more complex mental opera-tions, which would engage widespread neural networks in thebrain. Speed on such complex tasks, for example the perfor-mance subtests of the WISC-III, draw more heavily on whitematter integrity than simple stimulus response tasks such asthe CPT. Indeed, several researchers have reported decreasedscores of PBTS on the processing measures obtained withmore complex tasks such as the speed index of the WechslerScale and the Trail Making Task.12,29,38

Inhibitory control seems to be spared in PBTS, as the num-ber of errors of commission on the CPT was in the averagerange. This result converges with results of earlier studies intoinhibitory control, which failed to find evidence for inhibitoryproblems.68,69 The absence of an effect on inhibitory controlmay be explained in terms of tumour location. Inhibition ofresponses is primarily mediated by the prefrontal cortex, andpaediatric brain tumours in the frontal lobe are rare.59,70 Onthe other hand, there are a multitude of connections betweenthe cerebellum and the frontal lobes, which can be damagedby local radiotherapy, so causing inhibitory problems.61 Also,frontal lobes are irradiated in craniospinal radiotherapy, forexample for medulloblastomas. Indeed Aukema et al.29 foundvulnerability of the white matter in the frontal lobes in survi-vors of medulloblastoma, which was associated with slowerprocessing speed. The fact that we did not find inhibitory con-trol problems might also be caused by the relatively slowdevelopment of the prefrontal cortex at the ages the patientswere tested.59

As described above, cancer treatment inevitably causes celldamage, challenging the normal maturation and myelinationof the neural pathways in the young brain, and consequently

challenging the development of cognitive, motor, behavioural,and emotional functioning.42,57,71,72 In our exploratory analy-ses we found that cranial radiotherapy and chemotherapy areindeed strong predictors of worse intellectual functioning. Inour analyses it was impossible to make the distinction betweendifferent doses and volumes of radiotherapy, but it is knownfrom the literature that higher doses and larger volumes areassociated with worse neurocognitive outcomes.5 The combi-nation of radiotherapy and chemotherapy in adults is believedto play an important role in neurocognitive deficits, owing tothe induced damage to neural progenitor cells for hippocam-pal neurogenesis and the maintenance of subcortical whitematter integrity.64 Moreover, we found that longer time sincediagnosis is highly associated with worse intellectual out-comes. This finding is probably explained in terms of the neu-rocognitive problems such as reduced attentiveness, slowerprocessing speed, and memory problems exhibited by PBTSthat challenge the learning process, causing an increasing gapbetween PBTS and their peers in intellectual functioning. Noeffect was found for tumour location on intellectual function-ing. Although the adverse effects of the tumour and its treat-ment are considered detrimental for the developing brain,interestingly no relationship was found between mean age atdiagnosis and WISC-III scores of PBTS. Longer follow-upsmight reveal effects of age at diagnosis.

This meta-analysis has some limitations that need to betaken into account. A limited number of studies were availablefor this meta-analysis. Also, the available studies did not allowa distinction to be made between the different brain tumourdiagnoses, tumour locations, and treatment intensities. Thismay have contributed to heterogeneity in the study findings.For the quality analysis, we used the most relevant quality rat-ing that we found. Nevertheless, not all criteria were applica-ble to the included studies, which potentially decreased thereliability of the quality ratings. Furthermore, it has beenreported in the literature that there is an effect of sex in out-come, to the disadvantage of female children.72 However,owing to lack of variability in proportions of male and femalechildren in the included studies, it was not possible to includesex in the analyses. It would have been interesting to comparescores of patients on the WISC-III and the CPT; unfortu-nately none of the included studies reported on both a fullWISC-III and the CPT. In addition, with one single excep-tion, the included studies used an uncontrolled study design orcompared PBTS with other patient groups.29 Also, workingmemory and other important cognitive areas have not beenaddressed in this meta-analysis, despite their interdependencewith intelligence, attention, and processing speed. Eventhough the WISC-III and the CPT are well-validated testsand normative data are available, the use of a healthy compari-son group, matched on demographic background characteris-tics, would have been preferable.

CONCLUSIONSThis meta-analysis highlights the negative neurocognitivesequelae of paediatric brain tumours and their treatment interms of intellectual functioning and attentiveness. Moreover,

Review 415

longer time since diagnosis was found to be associated withworse intellectual functioning. Poor intellectual functioningand inattentiveness might underlie the negative outcomes ofPBTS in terms of academic achievement, vocational success,and general adaptive functioning. The field is in urgent needof developing effective screening and treatments for these neg-ative neurocognitive sequelae of PBTS.

ACKNOWLEDGEMENTSThis meta-analysis was performed as part of the PRISMA study, a

study funded by the Dutch Cancer Society (KWF Kankerbestrijding,

grant number UVA 2008-4013). We thank Jason Ashford, Deane W

Beebe, Melanie J Bonner, Robert N Butler, Diane L Fairclough,

Donald L Mabbott, Shawna L Palmer, and Sean Phipps for providing

us with the requested data.

REFERENCES

1. Kaatsch P. Epidemiology of childhood cancer. Cancer Treat

Rev 2010; 36: 277–85.

2. Mariotto AB, Rowland JH, Yabroff KR, et al. Long-term

survivors of childhood cancers in the United States. Cancer

Epidemiol Biomarkers Prev 2009; 18: 1033–40.

3. Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer

Statistics Review, 1975–2005. Bethesda, MD: National

Cancer Institute, 2008.

4. Butler RW, Mulhern RK. Neurocognitive interventions for

children and adolescents surviving cancer. J Pediatr Psychol

2005; 30: 65–78.

5. Duffner PK. Risk factors for cognitive decline in children

treated for brain tumors. Eur J Paediatr Neurol 2010; 14:

106–15.

6. Bhat SR, Goodwin TL, Burwinkle TM, et al. Profile of daily

life in children with brain tumors: an assessment of health-

related quality of life. J Clin Oncol 2005; 23: 5493–500.

7. Koch SV, Kejs AM, Engholm G, Johansen C, Schmiegelow

K. Educational attainment among survivors of childhood

cancer: a population-based cohort study in Denmark. Br J

Cancer 2004; 91: 923–8.

8. Zebrack BJ, Gurney JG, Oeffinger K, et al. Psychological

outcomes in long-term survivors of childhood brain cancer: a

report from the childhood cancer survivor study. J Clin Oncol

2004; 22: 999–1006.

9. Grill J, Renaux VK, Bulteau C, et al. Long-term intellectual

outcome in children with posterior fossa tumors according

to radiation doses and volumes. Int J Radiat Oncol Biol Phys

1999; 45: 137–45.

10. Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE. Pre-

dicting change in academic abilities after conformal radiation

therapy for localized ependymoma. J Clin Oncol 2008; 26:

3965–70.

11. Rutkowski S, Bode U, Deinlein F, et al. Treatment of early

childhood medulloblastoma by postoperative chemotherapy

alone. N Engl J Med 2005; 352: 978–86.

12. Patel SK, Mullins WA, O’Neil SH, Wilson K. Neuropsy-

chological differences between survivors of supratentorial

and infratentorial brain tumours. J Intellect Disabil Res 2011;

55: 30–40.

13. Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett

JM. Intellectual outcome after reduced-dose radiation ther-

apy plus adjuvant chemotherapy for medulloblastoma: a

Children’s Cancer Group study. J Clin Oncol 2001; 19:

3470–6.

14. Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of

intellectual development among survivors of pediatric

medulloblastoma: a longitudinal analysis. J Clin Oncol 2001;

19: 2302–8.

15. Conners CK. Conners’ Continuous Performance Test

(CPT). Toronto, Canada: Multi-Health Systems, 1995.

16. Conners CK. Conners’ Continuous Performance Test (CPT

II). New York: Multi-Health System, 2002.

17. Wechsler D. Wechsler’s Intelligence Scale for Children, 3rd

edn. London: Harcourt Brace, 1992.

18. Hardy KK, Willard VW, Bonner MJ. Computerized cogni-

tive training in survivors of childhood cancer: a pilot study. J

Pediatr Oncol Nurs 2011; 28: 27–33.

19. O’Neil S, Ji LY, Buranahirun C, et al. Neurocognitive out-

comes in pediatric and adolescent patients with central ner-

vous system germinoma treated with a strategy of

chemotherapy followed by reduced-dose and volume irradia-

tion. Pediatr Blood Cancer 2011; 57: 669–73.

20. Strauss E, Sherman EMS, Spreen O. A Compendium of

Neuropsychological Tests: Administration, Norms and

Commentary, 3rd edn. New York, NY: Oxford University

Press, 2006.

21. Wells GA, Shea B, O’Connell D, et al. The Newcastle-

Ottawa Scale (NOS) for Assessing the Quality of Nonran-

domized Studies in Meta-Analysis. http://www.ohri.ca/

programs/clinical_epidemiology/oxford.asp (accessed 1

November 2011).

22. Borenstein M, Rothstein H. Comprehensive Meta-Analysis,

A Computer Program for Research Synthesis, 2nd edn.

Englewood, NJ: Biostat, 1999.

23. Jalali R, Goswami S, Sarin R, More N, Siddha M, Kamble R.

Neuropsychological status in children and young adults with

benign and low-grade brain tumors treated prospectively

with focal stereotactic conformal radiotherapy. Int J Radiat

Oncol Biol Phys 2006; 66: S14–9.

24. Lacaze E, Kieffer V, Streri A, et al. Neuropsychological

outcome in children with optic pathway tumours when

first-line treatment is chemotherapy. Br J Cancer 2003;

89: 2038–44.

25. Merchant TE, Sherwood SH, Mulhern RK, et al. CNS ger-

minoma: disease control and long-term functional outcome

for 12 children treated with craniospinal irradiation. Int

J Radiat Oncol Biol Phys 2000; 46: 1171–6.

26. Ris MD, Beebe DW, Armstrong FD, et al. Cognitive and

adaptive outcome in extracerebellar low-grade brain tumors

in children: a report from the Children’s Oncology Group. J

Clin Oncol 2008; 26: 4765–70.

27. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and

variance from the median, range, and the size of a sample.

BMC Med Res Methodol 2005; 5: 13.

28. Cohen J. The statistical power of abnormal-social psycholog-

ical research: a review. J Abnorm Soc Psychol 1962; 65: 145–

53.

29. Aukema EJ, Caan MW, Oudhuis N, et al. White matter frac-

tional anisotropy correlates with speed of processing and

motor speed in young childhood cancer survivors. Int J

Radiat Oncol Biol Phys 2009; 74: 837–43.

30. Gliner JA, Morgan GA, Harmon RJ. Meta-analysis: formula-

tion and interpretation. J Am Acad Child Adolesc Psychiatry

2003; 42: 1376–9.

31. Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Bo-

tella J. Assessing heterogeneity in meta-analysis: Q statistic or

I2 index? Psychol Methods 2006; 11: 193–206.

32. Conklin HM, Khan RB, Reddick WE, et al. Acute neurocog-

nitive response to methylphenidate among survivors of child-

hood cancer: a randomized, double-blind, cross-over trial. J

Pediatr Psychol 2007; 32: 1127–39.

33. Mulhern RK, Palmer SL, Reddick WE, et al. Risks of young

age for selected neurocognitive deficits in medulloblastoma

are associated with white matter loss. J Clin Oncol 2001; 19:

472–9.

34. Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott

DJ. Change in neurocognitive functioning after treatment

with cranial radiation in childhood. J Clin Oncol 2004; 22:

706–13.

35. Rosenthal R. Writing meta-analytic reviews. Psychol Bull

1995; 118: 183–92.

36. Saury JMG, Emanuelson I. Cognitive consequences of the

treatment of medulloblastoma among children. Pediatr Neu-

rol 2011; 44: 21–30.

37. Sands SA, Oberg JA, Gardner SL, Whiteley JA, Glade-

Bender JL, Finlay JL. Neuropsychological functioning of

children treated with intensive chemotherapy followed by

myeloablative consolidation chemotherapy and autologous

hematopoietic cell rescue for newly diagnosed CNS tumors:

an analysis of the head start II survivors. Pediatr Blood Cancer

2010; 54: 429–36.

38. Bonner MJ, Hardy KK, Willard VW, Gururangan S. Addi-

tional evidence of a nonverbal learning disability in survivors

of pediatric brain tumors. Childrens Health Care 2009; 38:

49–63.

39. Callu D, Viguier D, Laroussinie F, et al. Cognitive and aca-

demic outcome after benign or malignant cerebellar tumor in

children. Cogn Behav Neurol 2009; 22: 270–8.

40. Briere ME, Scott JG, McNall-Knapp RY, Adams RL. Cogni-

tive outcome in pediatric brain tumor survivors: delayed

attention deficit at long-term follow-up. Pediatr Blood Cancer

2008; 50: 337–40.

41. Sanders RP, Kocak M, Burger PC, Merchant TE, Gajjar A,

Broniscer A. High-grade astrocytoma in very young children.

Pediatr Blood Cancer 2007; 49: 888–93.

42. Khong PL, Leung LH, Fung AS, et al. White matter anisot-

ropy in post-treatment childhood cancer survivors: prelimin-

ary evidence of association with neurocognitive function.

J Clin Oncol 2006; 24: 884–90.

43. Beebe DW, Ris MD, Armstrong FD, et al. Cognitive and

adaptive outcome in low-grade pediatric cerebellar astrocyto-

mas: evidence of diminished cognitive and adaptive function-


ing in national collaborative research studies (CCG

9891 ⁄ POG 9130). J Clin Oncol 2005; 23: 5198–204.

44. Grill J, Viguier D, Kieffer V, et al. Critical risk factors for

intellectual impairment in children with posterior fossa

tumors: the role of cerebellar damage. J Neurosurg 2004;

101: 152–8.

45. Packer RJ. Radiation-induced neurocognitive decline: the

risks and benefits of reducing the amount of whole-brain

irradiation. Curr Neurol Neurosci Rep 2002; 2: 131–3.

46. Carey ME, Barakat LP, Foley B, Gyato K, Phillips PC. Neu-

ropsychological functioning and social functioning of survi-

vors of pediatric brain tumors: evidence of nonverbal

learning disability. Child Neuropsychol 2001; 7: 265–72.

47. Kieffer-Renaux V, Bulteau C, Grill J, Kalifa C, Viguier D,

Jambaque I. Patterns of neuropsychological deficits in chil-

dren with medulloblastoma according to craniospatial irradi-

ation doses. Dev Med Child Neurol 2000; 42: 741–5.

48. Mulhern RK, Reddick WE, Palmer SL, et al. Neurocogni-

tive deficits in medulloblastoma survivors and white matter

loss. Ann Neurol 1999; 46: 834–41.

49. Hazin I, Dellatolas G, Garcia D, Pedrosa F, Pedrosa A.

Intellectual Impairment after treatment for medulloblastoma

and astrocytoma in childhood: the Brazilian experience. J Pe-

diatr Hematol Oncol 2011; 33: 506–15.

50. Butler RW, Copeland DR, Fairclough DL, et al. A multicen-

ter, randomized clinical trial of a cognitive remediation pro-

gram for childhood survivors of a pediatric malignancy. J

Consult Clin Psychol 2008; 76: 367–78.

51. Mabbott DJ, Penkman L, Witol A, Strother D, Bouffet E.

Core neurocognitive functions in children treated for poster-

ior fossa tumors. Neuropsychology 2008; 22: 159–68.

52. Stargatt R, Rosenfeld JV, Maixner W, Ashley D. Multiple

factors contribute to neuropsychological outcome in children

with posterior fossa tumors. Dev Neuropsychol 2007; 32:

729–48.

53. Reeves CB, Palmer SL, Reddick WE, et al. Attention and

memory functioning among pediatric patients with medullo-

blastoma. J Pediatr Psychol 2006; 31: 272–80.

54. Mulhern RK, White HA, Glass JO, et al. Attentional func-

tioning and white matter integrity among survivors of malig-

nant brain tumors of childhood. J Int Neuropsychol Soc 2004;

10: 180–9.

55. Deary I, Strand S, Smith P, Fernandes C. Intelligence and

educational achievement. Intelligence 2007; 35: 13–21.

56. Watkins MW, Lei P, Canivez GL. Psychometric intelligence

and achievement: a cross-lagged panel analysis. Intelligence

2007; 35: 59–68.

57. Reddick WE, White HA, Glass JO, et al. Developmental

model relating white matter volume to neurocognitive defi-

cits in pediatric brain tumor survivors. Cancer 2003; 97:

2512–9.

58. de Boer AG, Verbeek JH, van Dijk FJ. Adult survivors of

childhood cancer and unemployment: a metaanalysis. Cancer

2006; 107: 1–11.

59. Anderson V, Northam E, Hendy J, Wrennall J. Develop-

mental Neuropsychology; A Clinical Approach. Hove, East

Sussex: Psychology Press, 2001.

60. Johnson S. Cognitive and behavioural outcomes following

very preterm birth. Semin Fetal Neonatal Med 2007; 12: 363–

73.

61. Cantelmi D, Schweizer TA, Cusimano MD. Role of the cer-

ebellum in the neurocognitive sequelae of treatment of

tumours of the posterior fossa: an update. Lancet Oncol 2008;

9: 569–76.

62. Salman MS. The cerebellum: it’s about time! But timing is

not everything–new insights into the role of the cerebellum

in timing motor and cognitive tasks. J Child Neurol 2002; 17:

1–9.

63. Copeland DR, deMoor C, Moore BD III, Ater JL. Neuro-

cognitive development of children after a cerebellar tumor in

infancy: a longitudinal study. J Clin Oncol 1999; 17: 3476–

86.

64. Monje M, Dietrich J. Cognitive side effects of cancer therapy

demonstrate a functional role for adult neurogenesis. Behav

Brain Res 2012; 227: 376–9.

65. Dockstader C, Gaetz W, Rockel C, Mabbott DJ. White mat-

ter maturation in visual and motor areas predicts the latency

of visual activation in children. Hum Brain Mapp 2012; 33:

179–91.

66. Dennis M, Hetherington CR, Spiegler BJ. Memory and

attention after childhood brain tumors. Med Pediatr Oncol

1998; 30 (Suppl. 1): 25–33.

67. Netson KL, Conklin HM, Ashford JM, Kahalley LS, Wu S,

Xiong X. Parent and teacher ratings of attention during a

year-long methylphenidate trial in children treated for can-

cer. J Pediatr Psychol 2011; 36: 438–50.

68. Kahalley LS, Conklin HM, Tyc VL, et al. ADHD and sec-

ondary ADHD criteria fail to identify many at-risk survivors

of pediatric ALL and brain tumor. Pediatr Blood Cancer 2011;

57: 110–8.

69. Kiehna EN, Mulhern RK, Li C, Xiong X, Merchant TE.

Changes in attentional performance of children and young

adults with localized primary brain tumors after conformal

radiation therapy. J Clin Oncol 2006; 24: 5283–90.

70. Rubia K, Smith AB, Brammer MJ, Taylor E. Right inferior

prefrontal cortex mediates response inhibition while mesial

prefrontal cortex is responsible for error detection. Neuroim-

age 2003; 20: 351–8.

71. Han R, Yang YM, Dietrich J, Luebke A, Mayer-Proschel M,

Noble M. Systemic 5-fluorouracil treatment causes a syn-

drome of delayed myelin destruction in the central nervous

system. J Biol 2008; 7: 12.

72. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun

LE. Late neurocognitive sequelae in survivors of brain

tumours in childhood. Lancet Oncol 2004; 5: 399–408.

Review 417

Documents

Neurocognitive consequences of a paediatric brain tumour and its treatment: a meta-analysis