Sex-specific attention problems in long-term survivors of pediatric acute lymphoblastic leukemia†
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.
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 characteristics that have been associated with differential outcomes. The relation between these patient characteristics 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).
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).
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).
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. © 2009 American Cancer Society.
Survival rates for childhood acute lymphoblastic leukemia (ALL) have improved significantly during the past few decades, with 5-year rates now exceeding 80%.1 However, the intensive therapy required to reach these rates has been associated with increased neurocognitive late effects in several children, often only becoming evident between 2 and 5 years after treatment completion.2, 3 Deficits in attention and processing speed have consistently been noted as common late sequelae.4-6 However, significant individual variability in neurocognitive outcomes exist, with roughly 20% to 40% of survivors demonstrating significant impairment.7 To date, few studies have examined attention problems and individual variability in a comprehensive manner in children treated with chemotherapy only.
Recent studies have associated methotrexate intensity (MTX) with poor neurocognitive outcome, particularly attention problems.8-10 MTX treatment has also been associated with acute leukoencephalopathy, and related impact on white matter volume has been correlated 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 hematologic 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 differential 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 limited aspects of attention problems. The present study focused on examining attention using a multidimensional neurocognitive approach that would account for differences in the anterior and posterior cortical attention systems, as well as subcortical attention systems. These components are different, although overlapping and interdependent, aspects of attention that differentially invoke related neural substrates. The frontomedial and dorsolateral cortical brain regions of the anterior attention system account for the capacity to hold and manipulate information in working memory, initiate and inhibit or control goal-directed activities, and shift attention.23 Furthermore, the frontomedial brain regions are connected to subcortical brain regions via abundant connections.24 The posterior attention system, particularly the superior temporal and inferior parietal regions, accounts for basic information processing including filtering and focusing on incoming information.25 The subcortical attention system, 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 function 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 diagnosis and intensity of treatment.
MATERIALS AND METHODS
Participants were long-term survivors of pediatric ALL, routinely referred by their attending oncologist for a neurocognitive evaluation as part of institutional standard of care. These evaluations were conducted as part of routine monitoring; thus, patients were a clinical sample of convenience. Detailed recruitment information was not collected for this particular study. However, a similar neurocognitive study conducted in the same clinic at about the same time and using similar recruitment procedures, for which detailed information was available, indicated an 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 therapy 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 preexisting developmental disorder (eg, Down syndrome), treatment with cranial radiation, and non-English speaker status. A total of 103 long-term ALL survivors were identified as meeting established inclusion and exclusion criteria.
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 participation was obtained from the children.
Children participated in a neurocognitive evaluation using standardized testing procedures. The neurocognitive measures included clinical tests that individually assessed a broad spectrum of attention constructs, including the Digit Span subtest,27 the Gordon Diagnostic System (GDS),28 and the Trail Making Test Parts A and B.29 Shifting attention, inhibitory control, and working memory (ie, anterior attention system) were assessed through performance on the Trail Making Test Part B, commission errors on the GDS, and the backward Digit Span tests, respectively.30 Focused attention and attention span (ie, posterior attention system) were assessed through performance 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
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 correlations were used to assess the association between the treatment variables and attention outcome measures. Multivariate analysis of variance (MANOVA) was used to examine the impact of sex and risk stratification on the outcome measures. The alpha level was set at .05 for all statistical 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 η2) values for analysis of variance, with a small effect conceptualized 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 for Windows Version 15.0 (SPSS Inc., Chicago, Ill).
The sample included a similar number of girls and boys (51% boys, n = 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, n = 103) = 6.23, P < .044. Demographic information for the sample is reported in Table 1.
Table 1. Demographic Data for Total Study Sample
|Sex|| || |
| Girls, n=50||3 y, 11 mo (2 y, 4 mo)||11 y, 8 mo (2 y, 7 mo)*|
| Boys, n=53||3 y, 10 mo (1 y, 10 mo)||11 y, 2 mo (2 y, 7 mo)*|
|Risk|| || |
| High, n=37||3 y, 4 mo (2 y, 4 mo)||11 y, 1 mo (2 y, 5 mo)*|
| Standard, n=66||4 y, 2 mo (1 y, 11 mo)||11 y, 7 mo (2 y, 8 mo)*|
A 1-way between-groups MANOVA was performed to investigate the relation between sex and performance on outcome measures, F6,96 = 9.73, P < .001, partial η2 = 0.38. When the results for the dependent variables were considered separately, performance on Trails B for girls (mean = 96.82) indicated poorer shifting attention compared with boys (mean = 102.26), F1,101 = 4.25, P < .042, partial η2 = 0.04. Similarly, girls performed more poorly on the GDS number correct (mean = 90.15) compared with boys (mean = 98.24), reflecting increased difficulty with sustained attention, F1,101 = 15.00, P < .001, partial η2 = 0.13. Boys performed more poorly on GDS commissions (mean = 94.87) compared with girls (mean = 99.02), reflecting problems with inhibition, F1,101 = 4.37, P < .039, η2 = 0.04. Boys also demonstrated increased difficulty on Digit Span Backward (mean = 79.91) compared with girls (mean = 87.10), indicating difficulty with working memory, F1,101 = 9.50, P < .003, η2 = 0.09.
When comparing the sex-based performance differences to the normative distribution of the tests, performance on working memory was significantly lower for girls, t(49) = −7.06, P < .001, d = 0.92, and boys t(52) = −13.65, P < .001, d = 1.54. The girls' sustained attention performance was also significantly below the normative mean = t(49) = −6.17, P < .001, d = 0.74. The boys' performance on inhibitory control was significantly below the normative mean = t(52) = −3.39, P < .001, d = 0.39. The mean scores and standard deviations for the variables are reported in Table 2.
Table 2. Attention Performance Data for Sex*
|Anterior attention system|| || || || |
| Shifting||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 system|| || || || |
| Focused||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 system|| || || || |
| Sustained||GDS correct||90.15 (11.05)||98.24 (9.23)||<.001|
As expected, a 1-way between-groups MANOVA demonstrated a statistically significant effect of risk on the combined outcome measures, F6,96 = 5.48, P < .001, partial η2 = 0.26. The high-risk group performed more poorly (mean = 90.89) than the standard risk group (mean = 97.86) on the GDS number correct, a measure of sustained attention, F1,101 = 10.47, P < .002, partial η2 = 0.09. However, the standard-risk group (mean = 94.94) performed more poorly compared with the high-risk group (mean = 99.05) on GDS commissions, indicative of problems with inhibitory control, F1,101 = 3.95, P < .05, η2 = 0.04.
When considering the risk-based performance differences compared with the normative distribution, both the high- and standard-risk groups performed significantly lower on working memory, t(36) = −6.10, P < .001, d = 0.96 and t(65) = −13.43, P <.001, d = 1.38, respectively. Furthermore, the high-risk group demonstrated reduced performance on sustained attention, t(36) = −4.51, P <.001, d = 0.66, whereas the standard-risk group demonstrated reduced performance on inhibitory control, t(65) = −3.91, P <.001, d = 0.39.
There was no significant difference between the standard- and high-risk groups in cumulative amounts of intrathecal (IT) MTX, t(44.89) = 0.10, P>.90, d = 0.02, or cumulative amounts of intravenous (IV) MTX, t(98) = −1.04, P>.30, d = 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 diagnosis, 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 significant correlations between cumulative IV MTX and outcome measures (range, −.11 to .11). Correlations between age at diagnosis and outcome were not significant and ranged from −.16 to .11. The mean scores and standard deviations for the variables are reported in Table 3.
Table 3. Attention Performance Data for Risk*
|Anterior attention system|| || || || |
| Shifting||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 system|| || || || |
| Focused||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 system|| || || || |
| Sustained||GDS correct||90.89 (12.29)||97.86 (9.35)||.002|
The interaction between sex and risk stratification on the outcome measures did not reach significance, F6,94 = 0.53, P > .78, η2 = 0.03.
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 functioning.35-37 Both the shifting attention and sustained attention 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. Specifically, 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 maturation. As indicated earlier, the rates of myelination of various 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 difficulties 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 subsequently 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. However, children treated on high-risk protocols performed 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 disinhibited responding. In other words, to demonstrate poor inhibitory 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 performance 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 period 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 chemotherapy are more susceptible to interruption of myelination development in the brain, which has been evidenced by leukoencephalopathy in frontal white matter regions during active treatment and acute recovery and in posterotemporal/parietal and occipital white matter regions during 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 vulnerable to the associated deficits in the ability to sustain attention.5
Overall, this study characterized the nature of attention 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 interaction 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 survivors of pediatric leukemia may be limited. Another limitation 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 consequently failure to identify additional factors that may have influenced the sex and outcome effect. It will be important 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 disruption in addition to performing neurocognitive testing. Future research with this population should be prospective in design and should include neuroimaging so as to capture concurrent measurements of white matter development 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 experienced by long-term survivors of ALL.
Conflict of Interest Disclosures
The authors made no disclosures.