Journal of Pediatric Psychology, Vol. 26, No. 1, 2001, pp. 1-9
© 2001 Society of Pediatric Psychology
Chemotherapeutic CNS Prophylaxis and Neuropsychologic Change in Children With Acute Lymphoblastic Leukemia: A Prospective Study
1 Southern Illinois University, 2 University of Arizona, 3 Clyde L. Choate Mental Health and Developmental Center, 4 University of California-San Francisco
All correspondence should be sent to Kimberly Andrews Espy, Department of Psychiatry, Mail Stop 6503, Southern Illinois University School of Medicine, Carbondale, Illinois 62901-6503. E-mail: kespy{at}siumed.edu .
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Abstract |
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Objective: To determine whether prophylactic CNS chemotherapy for childhood acute lymphoblastic leukemia is associated with declines in neuropsychological abilities.
Methods: Growth curve analysis was used to examine neuropsychological outcome and treatment-related change in children (N = 30) who were treated at two childhood cancer centers. A comprehensive test battery was administered at baseline (8 months), 2, 3, and 4 years postdiagnosis (age at diagnosis M = 5.90 years, SD = 4.2C).
Results: Results indicated modest declines in arithmetic, visual motor integration, and verbal fluency. Intrathecal and systemic treatment was related to poorer visual motor integration at 4 years postdiagnosis and a faster rate of decline in visual motor integration skills across the observation period than intrathecal treatment alone. Arithmetic proficiency at 4 years after diagnosis was related to maternal education, but the rate of decline was not. Verbal fluency was unrelated to demographic or treatment variables.
Conclusions: These findings suggest that neuropsychological outcome and declines are related to both demographic and treatment characteristics depending on the cognitive domain examined.
Key words: childhood cancer; CNS late effects; neuropsychology; growth curve analysis.
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Introduction |
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The routine use of central nervous system (CNS) prophylaxis therapy, including whole brain radiation, intrathecal chemotherapy, and high-dose systemic chemotherapy, has contributed to the progress in long-term disease-free survival from acute lymphoblastic leukemia (ALL) in children. Despite the importance of prophylactic CNS treatment to ALL survival, children subsequently may experience declines in intellectual, academic, and neuropsychological skills, often called "CNS late effects" (Fletcher & Copeland, 1988
). Declining neuropsychological function is thought to result
from treatment-related effects on nonmalignant cells in the CNS, but the
specific mechanisms are not well understood. Risk factors for CNS late effects
include (1) pretreatment functioning
(Rowland, Glidewell, & Sibley,
1984), (2) radiation therapy
(Fletcher & Copeland,
1988), (3) age younger than 6 years at ALL diagnosis
(Cousens, Waters, Said, & Stevens,
1988), (4) female sex (Waber
et al., 1995), and (5) time since CNS treatment
(Mulhern, Fariclough, & Ochs,
1991). Whole brain radiation has been studied most extensively
(Stehbens et al., 1991), while
the putative role of chemotherapy in the development of CNS late effects
remains controversial (Butler, Hill, &
Steinherz, 1994; Dowell,
Copeland, & Francis, 1991).
Although researchers initially identified CNS late effects, many of these
were retrospective or clinical studies
(Fletcher & Copeland,
1988) and largely have compared outcome between radiation and
chemotherapy treatments. Radiation is now used mostly in those children at
highest risk for CNS disease, whereas chemotherapy alone is the treatment of
choice for children at lower risk. The few large-scale prospective studies
(Copeland, Moore, Francis, Jaffe, &
Culbert, 1996; Mulhern et al.,
1991) that studied chemotherapy-only effects have found consistent
declines in academic arithmetic. Copeland et al. also found declines in
perceptual motor skills; however, children with multiple disease etiologies
were studied. Studies conducted at St. Jude
(Mulhern et al., 1991;
Ochs et al., 1991) randomly
assigned ALL patients to radiation versus chemotherapy-only treatment
protocols to assess differential treatment-related change and outcome and
found no differences on specific neuropsychological measures. In the current
study, the effects of two different chemotherapeutic approaches to CNS
prophylaxis were compared by examining outcome in ALL survivors treated at two
different cancer centers.
One design limitation shared among many CNS treatment outcome studies is
the use of difference scores between performance assessed at only two time
points. Difference scores are inadequate measures of change for conceptual
reasons, as individual change is confounded with measurement timing, and for
statistical reasons, as difference scores underestimate true change
(Willett, 1988). Such problems
can lead to equivocal results. For example, Ochs et al.
(1991) found significant
declines when using differences between the initial and final intellectual
scores. However, when a longitudinal, repeated measures design was used
(Mulhern et al., 1991), there
were no treatment-related intellectual declines. With the advent of recent
statistical techniques, such as growth curve analysis
(Bryk & Raudenbush, 1992),
more complex questions can be addressed. Growth curve analysis is particularly
advantageous in examining performance declines in childhood cancer survivors
(Francis, Shaywitz, Stuebing, Shaywitz & Fletcher, 1991). Unlike the
multivariate approach to repeated measures, subjects with missing data can be
included, a common problem with clinical studies in which children cannot be
tested at all time points. The assessment intervals also can be more flexible,
as time is treated as a continuous variable. Therefore, if testing at a
particular time point is delayed, the data can be used without adding error
variance. Finally, subjects with more precise data (more points or optimally
spaced evaluations) are differentially weighted in determining group curves
with the maximum likelihood algorithm. Conceptually, growth curve analysis
examines the nature of individual change and identifies particular correlates
of change that systematically relate to the parameters of the individual
growth curves.
Prior to the Children's Oncology Group, the two major childhood cancer
treatment cooperative groups (Pediatric Oncology Group, POG; Children's Cancer
Group, CCG) used different approaches for CNS prophylaxis to reduce CNS
relapse. In general, POG protocols used both intrathecal and intermediate-dose
systemic methotrexate for CNS prophylaxis. Children treated at CCG centers
received single agent, methotrexate intrathecal therapy and did not receive
any systemic methotrexate therapy. Additionally, children treated at POG
centers received three intrathecal agents, methotrexate, hydrocortisone, and
Ara-C. Other phases of ALL treatment (induction, consolidation, and
maintenance) were comparable across treatment protocols. Intermediate-dose
systemic methotrexate crosses the blood brain barrier
(Balis & Poplack, 1989)
thereby possibly potentiating the CNS effects of the intrathecal methotrexate.
The purpose of this study was to prospectively investigate chemotherapeutic
treatment-related changes in neuropsychologic function in ALL survivors and to
compare outcome among children who received differing methods of CNS
prophylaxis using growth curve analysis.
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Method |
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Participants
Forty-seven children with newly diagnosed ALL were recruited prospectively at diagnosis from two childhood cancer treatment centers between September 1990 and October 1994. Eight children subsequently received radiation therapy and were excluded from analyses. Seven children died prior to study completion, and two families declined participation, leaving a sample of 30 ALL survivors who form the basis of this report. Sixteen (eight boys, eight girls) of these children were treated at a POG center (University of Arizona Health Sciences Center; UA), with age-adjusted doses of intrathecal methotrexate, hydrocortisone, and Ara-C, along with intermediate-dose systemic (1 gm/m2) methotrexate on Protocols 8602, 9006, 9005, and 9602 (IT + IV group). Four of these children also received systemic Ara-C. The other 14 children (seven boys, seven girls) were treated at a CCG center (University of California, San Francisco Medical Center, UCSF) and received only intrathecal methotrexate chemotherapy on protocols 1901, 1881, 1891, and 1922, at a similar age-adjusted dose level (ITO group). Informed consent procedures were followed and approved by the respective institutional internal review committees.
There were 19 Caucasian children and 11 children of ethnic minority status
(n = 9 Hispanic, n = 2 African American), with no
differences between sites in sex (
2 = 0.00, p
>.99) or minority status (2 = 1.43, p >.20).
Sample mean maternal education was 14.10 years (range 11-18 years) and was
comparable across sites, F(1, 26) = 0.19, p >.67. The
sample mean age at diagnosis was 5.90 years (SD = 4.20), but differed
significantly between sites (UA M = 7.39; UCSF M = 4.20;
F[1, 29] = 4.86, p <.04). Children treated at UA ranged
in age from 1.67-17.17 years at diagnosis, with six children over the age of 9
at diagnosis, whereas the range for children treated at UCSF was 2.25-6.58
years with no children over the age of 9 at ALL diagnosis. There also was a
significant mean difference between treatment sites in overall intelligence
(WISC-R Full Scale IQ or MCSA General Cognitive Index) at base-line (UA
M = 98.63; UCSF M = 112.14; F[1, 29] = 9.13,
p <.01). UA is the only childhood cancer treatment center in
Southern Arizona, whereas UCSF serves a higher income population, as there are
several treatment options in the San Francisco area. There were, however, no a
priori reasons to explain site-related differences in age at diagnosis.
Materials
The neuropsychological battery was chosen to measure a wide range of
cognitive functions, including intelligence, academic achievement, language,
visual-spatial-motor, memory, and executive skills. Measures were chosen in
order to cover the wide age range in age at ALL diagnosis, while maintaining
consistency of measurement across age. The neuropsychological battery is
depicted in Table I. Because
children varied in age at testing, some tests were not administered to
children at all ages. Where a particular test was not appropriate for younger
children, subtests from the McCarthy Scales of Children's Abilities (MCSA;
McCarthy, 1972) that were
similar in content to these tests were used. Particular scores or subtests
were chosen for analysis to maximize the amount of available data across age,
for example, Wisconsin Card Sorting Test
(Chelune & Baer, 1986)
Categories, instead of perseverative errors, was chosen for analysis because
of the availability of an MCSA analogue (Sorting subtest). The median
correlation between overall MCSA and WISC-R performance indices is.75
(Sattler, 1992), with subjects
typically scoring higher on the WISC-R by about six points. Correlations among
specific MCSA and neuropsychological test performance have not been reported.
For analysis, standard scores were calculated from available normative
information and were transformed to same metric if necessary (M =
100, SD = 15).
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Procedure
The neuropsychological battery was administered by a neuropsychologist in a
quiet examination room, adjacent to the pediatric oncology clinic.
Neuropsychological evaluations were conducted after completion of the
consolidation phase of treatment. The baseline assessment was conducted at
around 8 months postdiagnosis (M = 7.22 months, SD = 4.23)
in order to minimize the impact of fatigue, emotional distress, and
hospitalization on neuropsychological performance
(Mulhern et al., 1991).
Assessments were conducted again at about 2 (M = 2.02, SD =
0.40), 3 (M = 3.09, SD = 0.31) and 4 (M = 4.40,
SD = 0.70) years after ALL diagnosis. All children were not evaluated
at all occasions due to scheduling difficulties. Nine children received four
evaluations, 10 children completed three evaluations, and 11 children were
administered two evaluations. Correspondingly, there were 25 children with
baseline assessments, 18 children with 2-year evaluations, 18 children who
completed 3-year evaluations, and 26 children with final assessments. The time
since diagnosis at the final evaluation (IT + IV M = 57.00, ITO
M = 51.40; F(1, 19) = 2.89, p >.12) and the
number of children who received final evaluations (2 = 2.07,
p >.15) did not differ significantly between sites. The
neuropsychological battery was two to three hours in length.
Analysis
A multilevel approach (i.e., growth curve analysis) was used to analyze the
longitudinal data (Bryk & Raudenbush,
1992). Conceptually, the multilevel approach simultaneously
considers two aspects of longitudinal change: the individual (within-subject
or unconditional model) phase and the group (between-subject or conditional
model) phase. Statistically, these analyses are carried out simultaneously.
The change hypotheses were examined using mixed models (PROC MIXED from SAS
version 6.12) with restricted maximum likelihood estimation.
First, in the unconditional models, individual linear performance curves were calculated by regressing the pertinent neuropsychological score on time since diagnosis (in years) in order to estimate the within subject model parameters. The purpose of these models was to characterize how neuropsychological performance of individual children changed over time, independent of any predictors. The unconditional models included an intercept of the individual performance trajectory, representing the child's expected neuropsychological performance at the centered value or arbitrary zero point of time since ALL diagnosis, and a slope parameter, defined as the constant rate of neuropsychological performance change per year across the observation period. In the analyses reported here, time since diagnosis was centered at 4 years because it was inside the range of data and represented a commonly reported time used in other CNS late-effect studies. A positive slope indicated that neuropsychological performance increased with time since ALL diagnosis, whereas a negative slope indicated declining performance. In these analyses, individual outcome scores were allowed to vary, but performance change was fixed as common across children, as there was no evidence of individually varying change rates (all ps >.50).
After the form of the unconditional models was determined, we examined the conditional models, including different neuropsychological performance predictors of interest. The purpose of these models was to examine how different between-subject or grouping variables, that is, treatment type, age at diagnosis, demographic characteristics, were related to patterns of individual change. These analyses were accomplished by including the variables of interest in the model as predictors of the unconditional model parameters, that is, the intercept and slope values.
Although more data points lead to more precise estimation, many
developmental functions during a specific observation period are best
characterized by linear models, and, therefore, well-spaced observations are
adequate to determine individual growth trajectories
(Francis et al., 1994).
Anchored trajectories are important (i.e., baseline and final assessments),
consistent with the measurement pattern. Power analyses revealed that the
number of subjects was sufficient to detect an effect size of.66 SD
(Hedeker, Gibbons, & Waternaux, 1999).
All analyses were conducted with age-standardized scores. The disadvantage of using age-standardized scores is that standardization constrains individual variability at each age to be constant, distorting the individual growth trajectories. We used age-standardized scores here for several reasons. First, the purpose of this article was to identify whether specific areas of neuropsychological performance were altered systematically by CNS prophylaxis relative to normative expectations, not to determine the specific manner in which cognitive skills develop. Second, because children differed in age at diagnosis, different measures of neuropsychological performance were used at different ages. In order to utilize data from the entire age span, we needed to use a metric consistent across instruments. Last, standard scores are the most commonly reported metric when examining cancer treatment-related change.
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Results |
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Growth curve analysis results are presented in Table II. In the unconditional models, rates of change in neuropsychological performance with time since diagnosis were significant for ARITH, VFLU, with a trend (p <.06) for CODING. Neuropsychological performance on all other variables did not change significantly over the observation period. The expected rate of change in ARITH performance was negative in sign (-2.38 points per year since diagnosis). Therefore, by 4 years postdiagnosis, the performance of a typical ALL survivor (independent of CNS prophylaxis type) declined an average of 9.52 points from premorbid expectations, with an expected ARITH score of 93.63. For VFLU, the rate of skill decline was -4.03 points per year post ALL diagnosis, yielding a net decline of 16.12 points from premorbid performance during the 4-year observation period. However, estimated sample mean performance at 4 years postdiagnosis was in the average range. For CODING, the average decline was -1.72 points per year, with an expected mean performance at 4 years postdiagnosis of 100.67. Correspondingly, 10 children evidenced performance declines across the observation period of more than one standard deviation (15 standard score points) on ARITH, whereas 12 children showed such declines on VFLU. In terms of clinical impairment, four children obtained an ARITH score of less than 85 on the first assessment, whereas eight children did so on the final evaluation. A similar distribution was observed for VFLU (n = 2 initial, n = 8 final).
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To assess the effect of CNS prophylaxis type on the pattern of neuropsychological performance change, we examined conditional models with treatment type entered in the model as a predictor of the individual change parameters. Because the two groups differed in age at diagnosis and overall intelligence, we controlled these variables statistically. Treatment type significantly predicted rates of decline in VMI scores (t [47] = -3.03, p <.01), and VMI score at 4 years postdiagnosis (t [47] = -2.51, p <.05). The ITO group showed a near steady pattern of performance, with a rate of change of 0.95 points per year since ALL diagnosis, with an estimated mean VMI performance of 106.42 at 4 years postdiagnosis. In contrast, IT + IV children lost an average of 3.12 points per year since ALL diagnosis, yielding a cumulative change of nearly 12 points across the entire observation period. At 4 years postdiagnosis, the estimated mean VMI score was 94.65 for IT + IV children. These findings are displayed graphically in Figure 1. Four children in the IT + IV group showed declines of more than 15 VMI points, whereas only two children in the IT group did so. Three children scored in the clinically impaired range (<85) in the IT + IV group, in contrast to no children in the ITO group.
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For VFLU, depicted in Figure 2, CNS prophylactic treatment type did not predict the level of performance or the rate of change. Both groups of children evidenced significant, but similar, rates of decline in VFLU per year since diagnosis (ITO = -4.03; IT + IV = -3.60). At four years post ALL diagnosis, children treated at both centers were performing within the average range (ITO = 90.14; IT + IV = 89.75). The number of children who lost more than 15 VFLU standard score points across the observation period was similar across treatment groups (7 IT + IV; 5 ITO), whereas the number of ALL survivors who scored in the clinically impaired range differed (6 IT + IV; 2 ITO). A similar pattern was observed for ARITH, where children evidenced significant and comparable rates of decline in arithmetic skill per year since diagnosis (ITO = -2.39; IT + IV = -2.70). At 4 years post ALL diagnosis, children treated at both centers were performing within the average range (ITO = 90.57; IT + IV = 89.50). For CODING, however, performance declines were no longer marginally significant when CNS prophylactic treatment type, controlling for age at diagnosis and overall intelligence, was included in the model. Treatment type did not predict the pattern of neuropsychological performance for any of the remaining neuropsychological variables.
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Because the risk for CNS late effects depends on nontreatment-related
variables, similar conditional analyses were conducted to examine the
influences of sex, age at diagnosis of less than 6 years, and maternal
education. Sample size precluded examination of these variables in a single
model or analyzing any potential interaction, for example, sex by age at
diagnosis (Waber et al.,
1995). Sex only predicted the rate of skill decline for SPELL.
Girls gained SPELL points across the observation period (4.27 points per
year), although at 4 years post diagnosis, boys and girls had comparable SPELL
scores. Age at diagnosis under 6 years did not predict the rate of skill
change or the level of performance on any neuropsychological task.
Interestingly, maternal education predicted ARITH performance at 4 years postdiagnosis. Each additional year of maternal education beyond high school was associated with a significant performance increase of 2.54 points at 4 years postdiagnosis (t [51] = 1.96, p =.05). Maternal education, however, was unrelated to the change rate. These findings are displayed graphically in Figure 3. ARITH scores at 4 years post ALL diagnosis of children with college-educated mothers were 10.16 points higher than children with high school-educated mothers. All children however, showed similar and significant performance declines with time since diagnosis (-2.80 points per year since diagnosis).
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Discussion |
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These results support relatively modest declines in a few specific domains of neuropsychological functioning in childhood ALL survivors, namely, academic arithmetic, verbal fluency, and visual-motor skills. There was no evidence of substantive changes in domains such as reading, spelling, language, and memory. Declines in arithmetic and visual-motor skills also have been observed by researchers at M. D. Anderson (Copeland et al., 1996
) and St. Jude's Cancer Centers
(Mulhern et al., 1991;
Ochs et al., 1991). ALL
survivors in the current study demonstrated declines in fluency skills, but
not in Copeland et al., where verbal fluency test scores were averaged with
those from other Executive/Planning tests. This procedure may have served to
obscure specific deficits in verbal fluency that were apparent in this
study. Of course, these modest cognitive differences should be considered within the context of the excellent disease survival. Although significant functional declines were noted in specific areas, mean performance at 4 years postdiagnosis continued to be in the average range. In ALL survivors, the distribution of neuropsychological performance shifted downward. The results of such a shift are an increase in the number of children who perform in the clinically impaired range in selected neuropsychological domains. These findings suggest that some ALL survivors may benefit from psycho-educational support to help remediate these deficits.
The results indicate that different factors account for particular
cognitive declines. For example, ALL survivors, regardless of CNS prophylaxis
type, showed verbal fluency declines. These declines also were independent of
other pretreatment variables, such as sex, maternal education, and age at
diagnosis of less than 6 years. Verbal fluency declines do not reflect general
language impairment, as performance on other language measures was stable. It
appears that declines are specific to fluency, which is interesting given the
observed changes in visual motor skills. It may be that CNS prophylaxis
affects motor programming, manifesting in both the verbal and visual domains.
In this study, no declines in performance on the Wisconsin Card Sorting test
(Chelune & Baer, 1986) were
noted, making a general executive function deficit less likely. Other studies
also have not found declines on other executive function measures
(Copeland et al., 1996;
Ochs et al., 1991). However,
it may be that these declines in verbal fluency represent an effect of illness
per se on cognitive functioning or are related to intermittent inattention.
This study did not include a contrast group of children with cancer who did
not receive CNS prophylaxis or specific measures of attention by which to
assess such effects.
Visual motor skills appear to be particularly vulnerable to disruption by
CNS prophylaxis. In this study, children treated with intrathecal and
intravenous methotrexate showed significant visual motor integration declines.
There also was an overall trend for declining CODING performance, suggesting
that visual-motor speed, as well as integration proficiency, was affected by
CNS treatment. However, the battery did not include specific measures of
fine-motor speed or attention, making it difficult to render firm conclusions.
Visual motor declines are much more prominent in those children treated with
cranial radiation during prophylaxis
(Stehbens et al., 1991).
Declines on both measures of visual motor skills (CODING and VMI) also were
significant if children who received cranial radiation
(Espy et al., 1999) were
included with the current sample. Taken together, these results suggest that
the effects of methotrexate on the CNS may be additive. That is, children who
received cranial irradiation show the most dramatic and consistent declines in
visual motor skill, followed by ALL survivors who receive intrathecal and
systemic methotrexate, whereas no significant changes were observed in
children who received only intrathecal methotrexate. Methotrexate administered
systemically does cross the bloodbrain barrier
(Balis & Poplack, 1989) and
may serve to potentiate the neurotoxic effects of CNS prophylaxis.
Alternatively, prophylactic treatment differences may be related to
differences in intrathecal agent administration. The effect of methotrexate on
the CNS and on neuropsychological functioning may be interactive, that is,
potentiated by concurrent intrathecal administration of hydrocortisone and/or
Ara-C. This explanation is more speculative, as little evidence of the
neurotoxicity of these agents exists to date
(Balis & Poplack,
1989).
Regardless of mechanism, these findings carry important remediation implications. ALL survivors treated with intrathecal and intravenous methotrexate may benefit from occupational therapy services. In particular, occupational therapy aimed at increasing visual motor coordination and speed may help to prevent the observed declines. Such services could be provided prophylactically by the cancer center staff for children during and after cancer treatment to reduce the likelihood or severity of such declines. Occupational therapy, however, would be unnecessary for most children treated only intrathecally during prophylaxis.
Consistent with most other studies, we observed significant declines in
academic arithmetic. These differences were not related to the CNS
prophylactic treatment approach used. Interestingly, pretreatment
characteristics, namely, maternal education, predicted a portion of the
variability in arithmetic outcome, although arithmetic performance declines
remained significant when maternal education was included in the model. These
differences may be related to missed school due to hospitalization
(Lansky, Cairns, & Lansky,
1984), as this information was not gathered as a part of this
study. School performance can be affected by many variables and likely
represents an interaction of cognitive changes, pretreatment characteristics,
and hospitalization effects (Copeland et
al., 1996). Because specific measures of attention and
concentration also were not included in the battery, the impact of attention
disturbance on arithmetic performance could not be assessed.
These findings suggest a general vulnerability of motor-related skills. The
long white matter tracts vulnerable to the effects of CNS prophylaxis may
underlie these declines. Cranial radiation is known to disrupt the myelin in
CNS cell membranes (Moore, Kramer, Wara,
Halberg, & Ablin, 1991). Brouwers, Riccardi, Poplack, and
Fedio (1984) have found that
cognitive changes were more prominent in children with documented changes on
brain imaging scans. As a part of this project, measures of cerebrospinal
fluid lipid concentrations were taken as a marker of CNS damage. Future
studies are planned to examine how such concentrations relate to cognitive
declines in ALL survivors.
Many factors affect the interpretation of these findings. This study included a relatively small sample size of children who were homogeneous with respect to disease diagnosis. Although design power was estimated as adequate to detect neuropsychological declines of.66 standard deviation, a larger sample size is necessary to detect smaller group differences. These findings, therefore, should be validated in larger samples of children across treatment centers. Although the study was carried out prospectively, comparing performance across two treatment sites is difficult and precludes random assignment. Although children largely did not differ statistically between sites, small differences in demographic characteristics may have affected the findings reported here. Furthermore, this study examined administration method of methotrexate. There were differences among treatment protocols in the administration of agents other than methotrexate, and of course, as is true most clinical studies, small individual differences in treatment regimens occurred for some patients. Nevertheless, these findings provide preliminary evidence that outcome and rates of decline, particularly visualmotor skills, vary with respect to differential routes of chemotherapy administration during CNS prophylaxis.
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Acknowledgments |
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This research was supported, in part, by a NINR grant (NR02557) to Dr. Moore. The authors thank all participating families and hospital staff and recognize posthumously the contributions of Catherine J. Locke, PhD.
Received July 9, 1999; revision received November 1, 1999; accepted December 15, 1999
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