Sex-specific attention problems in long-term survivors of pediatric acute lymphoblastic leukemia

Sex-Specific Attention Problems inLong-Term Survivors of PediatricAcute Lymphoblastic LeukemiaNeelam Jain, PhD1,2,3; Pim Brouwers, PhD4,5,6; M. Fatih Okcu, MD, MPH4,5; Paul T. Cirino, PhD1;

and Kevin R. Krull, PhD1,2,3,4

BACKGROUND: Neurocognitive problems are a frequent outcome of chemotherapy for pediatric leukemia,

although individual differences exist in patient outcome. Sex of the patient and age at diagnosis are 2 char-

acteristics that have been associated with differential outcomes. The relation between these patient char-

acteristics and specific attention deficits (ie, initiating, inhibiting, shifting, focusing, sustaining attention,

and working memory) has not been well researched. The purpose of this study was to evaluate the pattern

of attention problems in male and female long-term survivors of pediatric acute lymphoblastic leukemia

(ALL). METHODS: One hundred three long-term survivors (ie, �5 years from diagnosis; 51% boys, mean

age at diagnosis of 3.9 years, and mean time since diagnosis 7.5 years) completed standardized measures

of basic and complex attention skills related to anterior (ie, inhibition, shifting attention, working memory),

posterior (ie, focusing), and subcortical brain systems (ie, sustaining). RESULTS: Treatment intensity was

related to sustained attention, with those patients treated on high-risk protocols displaying significantly

lower performance. Girls performed worse than boys on measures related to the anterior attention system

(ie, shifting attention, P < .042) and the subcortical attention system (ie, sustained attention, P < .001),

whereas boys performed worse than girls on different measures of anterior control (ie, inhibition, P < .039;

working memory, P < .003). CONCLUSIONS: The results of this study suggest that children diagnosed with

and treated for pediatric ALL perform poorly on select measures of attention and executive control, and

that this performance is influenced by sex and treatment intensity. Cancer 2009;115:4238–45. VC 2009

American Cancer Society.

KEY WORDS: acute lymphoblastic leukemia, long-term survivors, attention problems, sex.

Survival rates for childhood acute lymphoblastic leukemia (ALL) have improved significantly duringthe past few decades, with 5-year rates now exceeding 80%.1 However, the intensive therapy required toreach these rates has been associated with increased neurocognitive late effects in several children, oftenonly becoming evident between 2 and 5 years after treatment completion.2,3 Deficits in attention and

Received: November 17, 2008; Revised: January 28, 2009; Accepted: January 30, 2009

Published online June 17, 2009 in Wiley InterScience (www.interscience.wiley.com)

DOI: 10.1002/cncr.24464, www.interscience.wiley.com

Corresponding author: Neelam Jain, PhD, Department of Epidemiology & Cancer Control, St. Jude Children’s Research Hospital, 262 Danny

Thomas Place, MS 735, Memphis, TN 38105-3678; Fax: (901) 595-5845; [email protected]

1Department of Psychology, University of Houston, Houston, Texas; 2Child Psychology, Texas Children’s Hospital, Houston, Texas; 3Department of

Epidemiology and Cancer Control, St Jude Children’s Research Hospital, Memphis, Tennessee; 4Department of Pediatrics, Baylor College of Medicine,

Houston, Texas; 5Texas Children’s Cancer Center, Houston, Texas; 6Division of AIDS & Health and Behavior Research, National Institute of Mental

Health, Rockville, Maryland

The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health, National Institutes of Health,

Health and Human Services, or the US Government.

4238 Cancer September 15, 2009

Original Article

processing speed have consistently been noted as commonlate sequelae.4-6 However, significant individual variabili-ty in neurocognitive outcomes exist, with roughly 20% to40% of survivors demonstrating significant impairment.7

To date, few studies have examined attention problemsand individual variability in a comprehensive manner inchildren treated with chemotherapy only.

Recent studies have associated methotrexate inten-

sity (MTX) with poor neurocognitive outcome, particu-

larly attention problems.8-10 MTX treatment has also

been associated with acute leukoencephalopathy, and

related impact on white matter volume has been corre-

lated to sustained attention problems.11,12 In addition,

individual biologic differences in the pharmacokinetics or

pharmacodynamics of antifolate therapy (ie, MTX) have

been associated with variability in these outcomes. For

example, the presence of specific folate pathway genetic

polymorphisms has been associated with increased rates of

development of problems with inattention in childhood

leukemia survivors.13

Sex of the patient has been identified as a potential

moderator of late effects and neurocognitive outcomes.

Boys are reported to display worse event-free survival at 2

and 5 years after diagnosis, and higher rates of hemato-

logic relapse.14,15 Conversely, girls appear more sensitive

to the purine antimetabolite mercaptopurine, requiring

more frequent dosage decreases in comparison with

boys.16 Girls also appear to be at increased risk for adverse

neurocognitive outcomes after chemotherapy.5,17-19

Differences in neurocognitive outcome may be

related to varied sexual dimorphism in male and female

brains. Throughout maturation boys display more age-

related decreases in gray matter and increases in white

matter volume compared with girls.20 The result is that

girls have a higher percentage of gray matter, whereas boys

have a higher percentage of white matter.21 This differen-

tial neuroanatomical development may predispose girls to

neurocognitive deficits dependent on subcortical white

matter integrity, whereas boys may be more impacted by

disruption of cortical gray matter integrity.22

Previous neurocognitive outcome studies in long-

term survivors of pediatric ALL have examined only lim-

ited aspects of attention problems. The present study

focused on examining attention using a multidimensional

neurocognitive approach that would account for differen-

ces in the anterior and posterior cortical attention systems,

as well as subcortical attention systems. These compo-

nents are different, although overlapping and interde-

pendent, aspects of attention that differentially invoke

related neural substrates. The frontomedial and dorsolat-

eral cortical brain regions of the anterior attention system

account for the capacity to hold and manipulate informa-

tion in working memory, initiate and inhibit or control

goal-directed activities, and shift attention.23 Further-

more, the frontomedial brain regions are connected to

subcortical brain regions via abundant connections.24 The

posterior attention system, particularly the superior tem-

poral and inferior parietal regions, accounts for basic in-

formation processing including filtering and focusing on

incoming information.25 The subcortical attention sys-

tem, comprised of rostral midbrain structures, including

the mesopontine reticular formation and midline and

reticular thalamic nuclei, is involved in the maintenance

of attention or vigilance over time.26

The purpose of this study was to examine patterns of

attention problems in survivors of pediatric ALL as a func-

tion of sex. We hypothesized that girls would be more

likely to demonstrate impairment on measures reflective

of subcortical brain systems because of their relatively

lower ratio of white to gray matter volume in comparison

to boys. Conversely, boys were expected to demonstrate

impairment on measures reflective of anterior cortical

brain systems because of their relatively lower gray to

white matter volume in comparison to girls. Finally, we

expected the attention problems to be mediated by risk

stratification, as determined by factors such as age at diag-

nosis and intensity of treatment.

MATERIALS AND METHODS

Participants

Participants were long-term survivors of pediatric ALL,

routinely referred by their attending oncologist for a neu-

rocognitive evaluation as part of institutional standard of

care. These evaluations were conducted as part of routine

monitoring; thus, patients were a clinical sample of con-

venience. Detailed recruitment information was not

collected for this particular study. However, a similar neu-

rocognitive study conducted in the same clinic at about

the same time and using similar recruitment procedures,

for which detailed information was available, indicated an

Attention Problems in ALL/Jain et al

Cancer September 15, 2009 4239

82% recruitment rate.7 Approximately 15% of the eligible

patients had to be excluded because of lack of sufficient

mastery of the English language. Recruitment patterns are

expected to be comparable for the current investigation.

All participants in the current study had completed ther-

apy at least 2 years previously and were between the ages

of 6 and 16 at the time of the evaluation. For the purposes

of analyses, exclusionary criteria included the presence of

central nervous system disease at diagnosis, history of

relapse, history of bone marrow transplantation, a preex-

isting developmental disorder (eg, Down syndrome),

treatment with cranial radiation, and non-English speaker

status. A total of 103 long-term ALL survivors were iden-

tified as meeting established inclusion and exclusion

criteria.

Procedure

The procedures used in this study were reviewed and

approved by the institutional review board at the Baylor

College of Medicine, Texas Children’s Hospital, and the

University of Houston. Informed consent was obtained

from all parents/legal guardians, and assent for participa-

tion was obtained from the children.

Children participated in a neurocognitive evaluation

using standardized testing procedures. The neurocogni-

tive measures included clinical tests that individually

assessed a broad spectrum of attention constructs, includ-

ing the Digit Span subtest,27 the Gordon Diagnostic Sys-

tem (GDS),28 and the Trail Making Test Parts A and B.29

Shifting attention, inhibitory control, and working mem-

ory (ie, anterior attention system) were assessed through

performance on the Trail Making Test Part B, commis-

sion errors on the GDS, and the backward Digit Span

tests, respectively.30 Focused attention and attention span

(ie, posterior attention system) were assessed through per-

formance on the Trail Making Test Part A and forward

Digit Span tests, respectively.31 Sustained attention (ie,

subcortical attention system) was assessed through the

number of correctly identified targets on the GDS.32,33

Data Analysis

Chi-square tests of independence were used to analyze the

association between sex, risk, and race. Independent-

samples t tests were used to evaluate the association

between the amounts of MTX administered to standard

and high-risk groups. Pearson product-moment correla-

tions were used to assess the association between the

treatment variables and attention outcome measures. Mul-

tivariate analysis of variance (MANOVA) was used to

examine the impact of sex and risk stratification on the out-

come measures. The alpha level was set at .05 for all statisti-

cal tests, and Bonferroni correction was used when

appropriate to account for multiple comparisons. Effect

sizes, the measure of the strength of the relation between 2

variables, were reported as partial eta-square (partial g2)

values for analysis of variance, with a small effect concep-

tualized as 0.01, a moderate effect as 0.06, and a large effect

as 0.14, or Cohen d values for t tests, with a small effect

conceptualized as 0.2, a moderate effect as 0.5, and a large

effect as 0.8.34 Statistical assessments were carried out using

SPSS forWindows Version 15.0 (SPSS Inc., Chicago, Ill).

RESULTS

The sample included a similar number of girls and boys

(51% boys, n¼ 53). Caucasian (51.5%) and Hispanic

(35%) children were the predominant ethnic groups. Sex

was not significantly confounded with ethnicity or risk

stratification, although there were proportionately more

high-risk Hispanic children compared with the remainder

of the sample, chi-square (2, n¼ 103)¼ 6.23, P < .044.

Demographic information for the sample is reported in

Table 1.

A 1-way between-groups MANOVA was performed

to investigate the relation between sex and performance

on outcome measures, F6,96¼ 9.73, P < .001, partial

g2¼ 0.38. When the results for the dependent variables

Table 1. Demographic Data for Total Study Sample

Age atDiagnosisMean (SD)

Age atEvaluationMean (SD)

SexGirls, n550 3 y, 11 mo (2 y, 4 mo) 11 y, 8 mo (2 y, 7 mo)*

Boys, n553 3 y, 10 mo (1 y, 10 mo) 11 y, 2 mo (2 y, 7 mo)*

RiskHigh, n537 3 y, 4 mo (2 y, 4 mo) 11 y, 1 mo (2 y, 5 mo)*

Standard, n566 4 y, 2 mo (1 y, 11 mo) 11 y, 7 mo (2 y, 8 mo)*

SD indicates standard deviation.

* Independent-samples t test results for group differences were not signifi-

cant at P < .05.

Original Article


were considered separately, performance on Trails B for

girls (mean¼ 96.82) indicated poorer shifting attention

compared with boys (mean¼ 102.26), F1,101¼ 4.25, P<

.042, partial g2¼ 0.04. Similarly, girls performed more

poorly on the GDS number correct (mean¼ 90.15) com-

pared with boys (mean ¼ 98.24), reflecting increased dif-

ficulty with sustained attention, F1,101¼ 15.00, P< .001,

partial g2¼ 0.13. Boys performed more poorly on GDS

commissions (mean ¼ 94.87) compared with girls

(mean ¼ 99.02), reflecting problems with inhibition,

F1,101¼ 4.37, P < .039, g2¼ 0.04. Boys also demon-

strated increased difficulty on Digit Span Backward

(mean ¼ 79.91) compared with girls (mean ¼ 87.10),

indicating difficulty with working memory,

F1,101¼ 9.50, P< .003,g2¼ 0.09.

When comparing the sex-based performance differ-

ences to the normative distribution of the tests, perform-

ance on working memory was significantly lower for girls,

t(49)¼�7.06, P < .001, d¼ 0.92, and boys

t(52)¼�13.65, P < .001, d¼ 1.54. The girls’ sustained

attention performance was also significantly below the

normative mean ¼ t(49)¼�6.17, P < .001, d¼ 0.74.

The boys’ performance on inhibitory control was signifi-

cantly below the normative mean ¼ t(52)¼�3.39, P <

.001, d¼ 0.39. The mean scores and standard deviations

for the variables are reported in Table 2.

As expected, a 1-way between-groups MANOVA

demonstrated a statistically significant effect of risk on the

combined outcome measures, F6,96¼ 5.48, P < .001,

partial g2¼ 0.26. The high-risk group performed more

poorly (mean ¼ 90.89) than the standard risk group

(mean ¼ 97.86) on the GDS number correct, a measure

of sustained attention, F1,101¼ 10.47, P < .002, partial

g2¼ 0.09. However, the standard-risk group (mean ¼94.94) performed more poorly compared with the high-

risk group (mean¼ 99.05) on GDS commissions, indica-

tive of problems with inhibitory control, F1,101¼ 3.95,

P< .05,g2¼ 0.04.

When considering the risk-based performance dif-

ferences compared with the normative distribution, both

the high- and standard-risk groups performed signifi-

cantly lower on working memory, t(36)¼�6.10, P <

.001, d¼ 0.96 and t(65)¼�13.43, P < .001, d¼ 1.38,

respectively. Furthermore, the high-risk group demon-

strated reduced performance on sustained attention,

t(36)¼�4.51, P< .001, d¼ 0.66, whereas the standard-

risk group demonstrated reduced performance on inhibi-

tory control, t(65)¼�3.91, P< .001, d¼ 0.39.

There was no significant difference between the

standard- and high-risk groups in cumulative amounts of

intrathecal (IT) MTX, t(44.89)¼ 0.10, P>.90, d¼ 0.02,

or cumulative amounts of intravenous (IV) MTX,

t(98)¼�1.04, P>.30, d¼ 0.22. Because age at diagnosis

is also a factor used in risk stratification, the relation

between cumulative MTX dose, age at the time of diagno-

sis, and outcome measures was investigated using Pearson

product-moment correlation coefficients. Correlations

between the cumulative IT MTX and outcome measures

ranged from �.09 to �.01. Similarly, there were no sig-

nificant correlations between cumulative IV MTX and

outcome measures (range, �.11 to .11). Correlations

between age at diagnosis and outcome were not significant

Table 2. Attention Performance Data for Sex*

Attention System NeurocognitiveMeasures

FemaleMean (SD)

MaleMean (SD)

P

Anterior attention systemShifting Trails B time 96.82 (14.49) 102.26 (12.29) .042

Inhibitory control GDS commissions 99.02 (8.96) 94.87 (11.03) .039

Working memory Digit span backward 87.10 (12.92) 79.91 (10.72) .003

Posterior attention systemFocused Trails A time 97.94 (14.29) 99.19 (12.84) .641

Attention span Digit span forward 96.10 (12.65) 97.77 (13.02) .510

Subcortical attention systemSustained GDS correct 90.15 (11.05) 98.24 (9.23) <.001


* Scores are standard scores based on a mean of 100 and a standard deviation of 15.



and ranged from�.16 to .11. The mean scores and stand-

ard deviations for the variables are reported in Table 3.

The interaction between sex and risk stratification

on the outcome measures did not reach significance,

F6,94¼ 0.53, P> .78,g2¼ 0.03.

DISCUSSION

Sex of the participant was associated with the type of

attention deficit they experienced. Girls performed more

poorly than boys on tasks commonly associated with the

frontomedial anterior attention system and the subcortical

attention system. Specifically, they had difficulty with

shifting attention (ie, rapidly alternating between 2 sets of

information) and with sustaining attention over time (ie,

continuously differentiating rapidly presented target from

nontarget stimuli over a lengthy time course). Although

performances for both girls and boys remained within the

average range, and the associated statistically significant

difference was small, the performance of the girls is a

relative weakness, and previous research suggests that it

may indicate a decline from expected levels of function-

ing.35-37 Both the shifting attention and sustained atten-

tion tasks are speed dependent, and likely rely upon the

integrity of anterior white matter.38,39 Conversely, boys

performed more poorly than girls on tasks commonly

associated with the cortical anterior attention system. Spe-

cifically, boys had difficulty with working memory and

inhibitory control over responding. Both of these skills

involve cortical control over more basic processes and, as

such, are often referred to as executive functions. They are

typically considered to be dependent upon the integrity of

neocortical prefrontal brain areas (ie, those areas in the

dorsolateral prefrontal system that are dependent upon

gray matter integrity), and less dependent upon white

matter integrity.40,41

These differences between the performance of boys

and girls on the neurocognitive measures may be related

to sex-based differences in brain morphology and matura-

tion. As indicated earlier, the rates of myelination of vari-

ous brain regions differ between boys and girls during

early development, with boys displaying a larger increase

in white matter development during childhood.20 This

rapid increase in myelination in boys may buffer them

from processes that impact white matter development and

enhance subsequent performance on tasks dependent on

white matter integrity, as in the case of chemotherapeutic

treatment for ALL. Consistent with the findings of this

study, it would be expected that boys would evidence dif-

ficulties on tasks mediated by gray matter, as their rate of

gray matter development during childhood is slower than

that for girls. The converse is true for girls, who experience

a slower rate of white matter development, which subse-

quently would result in reduced performance on tasks

related to white matter functioning, a finding that is also

consistent with the current results.

There was a significant difference between high- and

standard-risk groups in performance on neurocognitive

measures of attention. Specifically, performance on the

measures of inhibitory control and sustained attention

differed between the groups, with effect sizes within the

small to moderate range.34 Children treated on high-risk

protocols performed worse on the measure of sustained

attention than children treated on standard-risk protocols.

Table 3. Attention Performance Data for Risk*

Attention System NeurocognitiveMeasures

High RiskMean (SD)

Standard RiskMean (SD)

P

Anterior attention systemShifting Trails B time 100.19 (13.44) 99.30 (13.67) .751

Inhibitory control GDS commissions 99.05 (9.23) 94.94 (10.52) .05

Working memory Digit span backward 86.22 (13.75) 81.79 (11.01) .077

Posterior attention systemFocused Trails A time 98.78 (12.45) 98.79 (14.16) .999

Attention span Digit span forward 99.86 (11.02) 95.30 (13.61) .085

Subcortical attention systemSustained GDS correct 90.89 (12.29) 97.86 (9.35) .002


* Scores are standard scores based on a mean of 100 and a standard deviation of 15.

Original Article


However, children treated on high-risk protocols per-

formed better on the measures of inhibitory control.

Although at first glance this pattern seems contradictory,

the relation between these 2 outcome measures warrants

further consideration. By definition, individuals who

demonstrate reduced sustained attention in a task are not

as engaged and are, thus, less likely to engage in disinhib-

ited responding. In other words, to demonstrate poor in-

hibitory control, one must be engaged and sustaining

attention to the task to which one is disinhibited.

These results are consistent with previous literature

demonstrating treatment-related group differences in per-

formance on measures of attention. The performance of

the high-risk group on measures of sustained attention

suggests difficulty maintaining a high state of readiness to

respond to the demands of the task over an extended pe-

riod of time. This ability to sustain attention is directly

related to executive functioning skills, which are largely

mediated by the frontal and prefrontal cortices in the

brain.42 Children who received higher doses of chemo-

therapy are more susceptible to interruption of myelina-

tion development in the brain, which has been evidenced

by leukoencephalopathy in frontal white matter regions

during active treatment and acute recovery and in postero-

temporal/parietal and occipital white matter regions dur-

ing long-term recovery from treatment.12,43,44 These

anatomical interruptions to development are reportedly

related to problems with attention and processing speed.43

Disruption of myelination to the prefrontal, frontal, and

subcortical brain regions would make these children vul-

nerable to the associated deficits in the ability to sustain

attention.5

Overall, this study characterized the nature of atten-

tion problems in a large sample of children treated for

ALL with chemotherapy. The results confirm that long-

term survivors of ALL have a specific pattern of problems

with the anterior and subcortical attention systems after

chemotherapy treatment. Risk level, as traditionally

defined for medical management, does not fully account

for the pattern or degree of attention problems. Sex-based

attentional differences, which may be related to an inter-

action of disruption of myelination and neuroanatomical

sexual dimorphism, contribute to the pattern and degree

of attention problems.

Given that this sample was 1 of clinical convenience,

generalization to the rest of the population who are survi-

vors of pediatric leukemia may be limited. Another limita-

tion was that several treatment protocols were used, and as

a function thereof, the amounts of IV and IT MTX

administered were inconsistent across participants; this

could have resulted in increased type 2 error and conse-

quently failure to identify additional factors that may have

influenced the sex and outcome effect. It will be impor-

tant for future studies to be sensitive to the differences in

patient and treatment characteristics that are most likely

to result in attention difficulties and to comprehensively

assess attention to better define sex- and treatment-based

attentional difficulties. To further assess the attention

problems found in this population, future studies will

need to evaluate the specific nature of the myelination dis-

ruption in addition to performing neurocognitive testing.

Future research with this population should be prospec-

tive in design and should include neuroimaging so as to

capture concurrent measurements of white matter devel-

opment and attentional dysfunction in each participant in

an effort to further develop individualized and targeted

interventions. Such interventions may be differentiated by

sex and age and then further tailored to each individual

participant based on their particular attentional needs.

Despite the stated limitations, this study provides the basis

for refined research on attention through a systematic

approach to evaluating the moderating effect of sex and

risk after brain insult. Furthermore, the results illuminate

the specific types of attention-related problems experi-

enced by long-term survivors of ALL.

Conflict of Interest Disclosures

The authors made no disclosures.

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Original Article


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