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Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4795-4803 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.128 Short-Term Efficacy of Methylphenidate: A Randomized, Double-Blind, Placebo-Controlled Trial Among Survivors of Childhood CancerFrom the Division of Behavioral Medicine, Division of Neurology, Department of Hematology/Oncology, Department of Biostatistics, Pharmaceutical Department, and Department of Radiological Sciences, St Jude Children’s Research Hospital, Memphis, TN; Department of Pediatrics, Medical University of South Carolina, Charleston, SC; and Department of Psychiatry and Behavioral Sciences, and Brain Tumor Center at Duke University Medical Center, Durham, NC. Dr Brown is currently at the College of Health Professions, Temple University, Philadelphia, PA. Address reprint requests to Raymond K. Mulhern, PhD, Division of Behavioral Medicine, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: raymond.mulhern{at}stjude.org
PURPOSE: Children surviving acute lymphoblastic leukemia (ALL) and malignant brain tumors (BTs) have a higher incidence of attention and learning problems in school than do their healthy peers. The present study tests the hypothesis that the psychostimulant methylphenidate (MPH) improves cognitive and social functioning among these patients. PATIENTS AND METHODS: We report on 83 long-term survivors of ALL and BT identified as having attentional deficits on behavioral testing and parent or teacher report, and problems with academic achievement. The 47 male and 36 female patients ranged from 0.6 to 14.3 years (median, 5.4 years) of age at diagnosis and 6.7 to 17.9 years (median, 11.9 years) of age at participation. The patients (40 ALL, 43 BT) participated in a randomized, double-blind, 3-week home cross-over trial of placebo (bid), low-dose MPH (0.3 mg/kg; maximum dose, 10 mg bid), and moderate-dose MPH (0.6 mg/kg; maximum dose, 20 mg bid). The primary end points were weekly teacher and parent reports on the Conners’ Rating Scales and Social Skills Rating System. RESULTS: Compared to placebo, significant improvement with MPH was reported by teachers and parents on the Conners’ Rating Scales and by teachers on the Social Skills Rating System. However, no consistent advantage of moderate dose over low dose was observed. Of those participating, 66 (79.5%) of the 83 patients continued on best clinical management. CONCLUSION: Treatment with MPH can at least temporarily reduce some attentional and social deficits among survivors of childhood ALL and BT. Long-term follow-up will reveal those subsets of patients who are more likely to benefit from MPH.
Children surviving treatment for the two most common forms of childhood cancer, acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT), have an increased incidence of significant neurocognitive impairments compared to their healthy peers.1-3 Historically, these impairments have been characterized by declining intelligence quotient (IQ) and academic achievement test scores. A recent focus on more basic cognitive processes has revealed that deficits in attention and/or working memory may underlie the observed declines in IQ and achievement.4-6 The relationships between these processing deficits and CNS-directed chemotherapy and radiation therapy, and risk factors such as young age at treatment, are now well recognized.7,8 In addition, quantitative magnetic resonance imaging analyses have revealed that a failure to develop normally expected volumes of cerebral white matter after treatment may account for at least some of these alterations in neurocognitive function.9-11 Despite increasing knowledge regarding the etiology and pathophysiology of neurocognitive impairments among survivors of pediatric ALL and BT, and the use of this information to develop risk-adapted antineoplastic therapies, studies of methods to remediate neurocognitive impairments have been infrequent. Among otherwise healthy children diagnosed with attention deficit hyperactivity disorder (ADHD), a large body of research over the past 50 years documents the effectiveness of stimulant medications, most often methylphenidate hydrochloride (MPH), to improve cognitive performance among these children.12 MPH is a mixed dopaminergic-noradrenergic agonist that enhances the function of the fronto-striatal (anterior) attentional network.13 The most consistent and significant benefits of MPH have been demonstrated on measures of vigilance and sustained attention, but improvements in reaction time, paired-associate learning, and perceptual efficiency are also documented. Among children with ADHD, MPH may also improve social skills with peers as judged by behavioral observation and peer ratings.12 However, the efficacy of MPH for attentional problems in children following acquired brain injury is ambiguous. Two randomized, double-blind, placebo-controlled, cross-over trials have yielded conflicting results. In one report of 10 children ranging in age from 5 to 16 years at participation, no statistically significant improvement over placebo was observed on multiple measures of neuropsychological functioning. However, exposure to MPH was brief (4 days), MPH dosing may not have been optimal, and composite scores from parent and teacher measures may have obscured some differences.14 The second study involved 14 children within a similar age range who had sustained traumatic brain injury. With consistent dosing of 0.3 mg/kg bid for 2 weeks, statistically significant improvement was revealed on several objective measures of vigilance and processing speed.15 Two preliminary investigations examined the use of MPH in children with learning problems presumably secondary to their cancer treatment. In one report, 12 children surviving malignant brain tumors or ALL were treated with MPH for 6 months to 6 years (median, 23 months) and it was noted that eight children had a "good" response, two had a "fair" response, and two had a "poor" response.16 A second study reported on six children treated with MPH who had received radiation therapy 3 to 12 years earlier for malignant brain tumors.17 With a consistent dosing of 0.3 mg/kg, findings revealed no significant immediate or delayed benefits associated with MPH. One open-label trial has been published with adults treated for malignant brain tumors that employed neurocognitive testing and objective inventories to quantify response to MPH. Significant improvements in cognitive function, including psychomotor speed, memory, and executive functions, as well as mood, and activities of daily living were found, oftentimes despite progressive disease.18 Thompson et al19 was the first to investigate MPH effects in a randomized, double-blind trial of MPH among survivors of childhood cancer. The investigators screened for a specific cognitive phenotype (ie, those with academic achievement problems and problems with attention) that was thought to be most responsive to MPH. Children who met the criteria for the medication trial were randomized (n = 32) to receive placebo or MPH (0.6 mg/kg to maximum of 20 mg) in a double-blind design. Significantly greater improvement on a computerized continuous performance test of vigilance occurred in the group receiving MPH. In the present study, we extend the investigation of Thompson et al19 by reporting on the results of a 3-week, placebo-controlled, double-blind trial of low-dose (0.3 mg/kg up to a maximum of 20 mg daily in two divided doses) and moderate dose (0.6 mg/kg up to a maximum of 40 mg daily in two divided doses) MPH. Weekly teacher and parent reports were obtained on standardized behavioral inventories of cognitive and social functioning. In addition, parental reports of the frequency of adverse side effects were obtained on an objective inventory.
Patients To be eligible for participation, patients were required to be between the ages of 6 and 18 years, enrolled in school, have been treated for ALL or a malignant BT with chemotherapy or radiation therapy to the CNS that was completed at least 12 months earlier, have English as the primary language in the home, and have given written informed consent on this institutional review board-approved protocol. Exclusionary criteria included: a diagnosis of ADHD before cancer; uncontrolled seizures; tics; glaucoma; uncorrected endocrinopathies; severe sensory loss (eg, blindness or deafness that would preclude valid psychometric testing); history of drug abuse; current use of psychotropic medications; recurrent disease; or an adverse reaction to an initial exposure to MPH (Table 1). Also, at one institution (St Jude Children’s Research Hospital, Memphis, TN), to avoid competition with another open protocol, eligible patients could not reside within a 60-mile radius of the hospital. Therefore, it was impractical for patients to return to the hospital weekly for clinical evaluation or psychometric testing. As an alternative, weekly assessments were conducted by telephone with the patient’s parent and teacher at all three participating institutions.
Procedures Initial eligibility was established by medical chart review with a follow-up telephone call or introductory letter to establish interest and schedule the clinic visit. For those who agreed and provided informed consent, a screening battery of psychological tests was administered and parent/teacher report forms were obtained to identify the particular cognitive phenotype hypothesized to be responsive to MPH (Table 1), similar to that previously reported by our group.19 These tests are described in more detail in the following paragraphs. Abbreviated Wechsler Intelligence Scale for Children (WISC-III or WAIS-III). The Wechsler scales20,21 are widely used intelligence tests with well-accepted reliability and validity (normative age-adjusted mean, 100; standard deviation [SD], 15). We estimated full-scale IQ by prorating the Information, Similarities, and Block Design subtests using a formula developed by Sattler.22 To be included in this investigation, the patient was required to have an estimated IQ of 50 or greater. Conner’s Continuous Performance Test (CPT). The CPT23 is a computer-administered test that measures selective and sustained attention, reaction time, and impulsivity. It has been standardized on typically developing children and adolescents as well as those with ADHD; age-corrected standard scores are provided on a number of indices of attentional abilities and impulsivity. In typically developing children, CPT performance and IQ testing results are not significantly correlated. The CPT takes about 15 minutes to administer and is computer scored. There are no significant practice effects from repeated administration. It is one of the most widely administered computerized measures to monitor medication effects in children with ADHD.24 To be included in this investigation, the patient was required to have Errors of Omission > 75th percentile for age and sex.
Abbreviated Wechsler Individual Achievement Test (WIAT).
The WIAT25 is an individually administered standardized test of academic achievement that has acceptable reliability and validity. The age-corrected normative mean is 100 (SD, 15). This 40-minute test results in age-corrected standard scores based on a large normative sample for Basic Reading, Reading Comprehension, Spelling, and Numerical Operations and Mathematics Reasoning achievement that was used in our quantitative analyses. The WIAT was standardized using the same sample as the WISC-III. To be included in this investigation, the patient was required to have a standard score
Conner’s Rating Scales (CRS).
The Conner’s Parent Rating Scales (CPRS) and the Conner’s Teacher Rating Scales (CTRS)26 are standardized rating scales of children’s behaviors commonly described as symptomatic of ADHD. All forms contain an ADHD Index, and scales for hyperactivity and cognitive problems/inattention. The scales are objectively scored and the results compared to age and sex peers in the general population. To be included in this investigation, the patient was required to have a score
Child Behavior Checklist (CBCL).
The CBCL27 is an inventory of behavior problems and adaptive behaviors standardized on 4- to 16-year-old children. Although several age- and sex-corrected CBCL standard scores (mean, 50; SD, 10) are available, our specific intent was to identify children with clinically significant symptoms of anxiety and/or depression, which could complicate responsiveness to MPH. A score If the patient was eligible to continue with the MPH trial based on the clinical and psychometric criteria listed above, as well as informed consent, arrangements were made for the patient to participate in the clinical trial in the outpatient clinic at the hospital on 2 consecutive days. The patient was randomly assigned to either receive MPH (0.60 mg/kg; maximum dose 20 mg) on day 1 and placebo on day 2 or the reverse in a double-blind design. The patient was observed in the clinic for 4 to 6 hours each day as a safety precaution before initiating the 3-week cross-over trial in the home environment. In the absence of an adverse reaction and with parental consent, the patient proceeded to a home cross-over trial of MPH. Each patient was randomly assigned to one of six sequences for the 3-week period known only to the pharmacist: low dose (LD), moderate dose (MD), placebo (P); LD, P, MD; MD, LD, P; MD, P, LD; P, LD, MD; P, MD, LD. MD was defined as 0.60 mg/kg (20 mg maximum) bid and LD was defined as 0.30 mg/kg (10 mg maximum) bid. MPH or placebo was dispensed in opaque capsules Monday through Friday when school was in session, using the intervening weekend as a "washout period." Each week’s supply of capsules was delivered to the child’s home by courier following assessment of the patient’s progress by telephone interviews with the parent and teacher. During these interviews, the CPRS and the CTRS were completed. In addition, the Side Effects Rating Scale (SERS) was completed by the parent and the Social Skills Rating System (SSRS) was completed by both the parent and the teacher of the patient, who was identified before the commencement of the trial. These inventories are described below.
Side Effects Rating Scales.
The SERS was developed by Barkley28 as a parent-completed inventory of 17 common adverse side effects of stimulant medication. For each of the potential adverse side effects, the parent rates the severity from 0 (absent) to 9 (severe). Scores Social Skills Rating System. The SSRS29 consists of 51 to 57 items, depending upon age, completed separately by parents (SSRS-P) and teachers (SSRS-T). The SSRS assesses social skills for children and adolescents at three developmental levels: preschool, elementary, and secondary. Scales identified for analysis included Social Competence and Problem Behaviors for the SSRS-P, and Social Competence, Problem Behaviors and Academic Competence for the SSRS-T. Reliability and validity data were published by the test developers and a large normative sample of boys and girls is available. The test-retest reliability of the SSRS-P is 0.87 and the reliability for the SSRS-T ranges from 0.75 to 0.93. This scale has been previously used to evaluate treatment effects among children with ADHD.30
Statistical Approach As the statistical model used for analysis belongs to the class of mixed effects model for which standard SAS (SAS Institute, Cary, NC) procedures are available, we applied the SAS procedure for mixed models for analysis of this cross-over model. The SAS procedure for the mixed model allows for missing and unbalanced data between randomization sequences.33,34 Within this model, it was not necessary to impute values for missing data. Effect sizes for LD and MD conditions were calculated as the mean difference between the condition and placebo divided by the square root of the mean square residual for that comparison.35 The P value for statistical significance was set at .05 (two-tailed). No corrections were made for multiple comparisons.
Between February 16, 2000 and August 18, 2003 we identified 390 patients eligible for screening. Of those, 26 patients (6.7%) refused when approached for participation. Reasons for nonparticipation in the screening included patient doing well in school, not wanting to take any tests, and not wanting to participate in any more studies. Of the remaining 364, 315 patients completed screening within the time frame of this study and 125 (39.7%) met the psychometric and clinical criteria for participation. Of the 125, 32 did not proceed further in the study: Twenty-seven refused any exposure to MPH, three developed recurrent cancer, and two sought MPH treatment from their local physician. The remaining 93 proceeded to an initial single-dose challenge of MPH. Ten patients completed the MPH challenge, but did not continue to the home cross-over: three of these patients experienced serious adverse side effects from the medication and are discussed in more detail in the Results section, three refused to continue because of other medical concerns, two chose to have their local pediatrician prescribe MPH, one experienced disease progression, and one patient’s family problems prohibited reliable participation. The remaining 83 patients (Table 2) completed 1 or more weeks of the home cross-over; 74 completed all 3 weeks and nine patients completed only the placebo and LD weeks for reasons discussed in the section on Adverse Side Efects. For this analysis, 74 of the 83 patients participated at a single site, limiting the ability to analyze for differences between sites.
Therapeutic Effects The therapeutic effects of LD and MD MPH are evaluated relative to the placebo condition in terms of parent and teacher ratings on the CRS and SSRS. As shown in Table 3, the design of the study had sufficient power to detect an effect size (ES) of at least 0.30 at P = .05 (two-tailed). ES of this magnitude is between those traditionally characterized as small (or smaller than typical) to medium (or typical) for the applied behavioral sciences.32
On the CRS, both parent and teacher ratings revealed a statistically significant benefit for LD and MD MPH for inattention and problems relating to cognition. In addition, both parent and teacher ratings revealed a statistically significant benefit for LD and MD MPH for symptoms included in the ADHD Index. Teacher, but not parent, reports also indicated improvement with LD and MD MPH for symptoms associated with hyperactivity. However, for none of these comparisons was there a statistically significant advantage of MD over LD treatment. With regard to the SSRS, teachers reported statistically significant improvement with LD and MD MPH with regard to social competence and academic competence without a clear advantage of MD over LD MPH. With MD MPH, teachers reported a statistically significant improvement in problem behaviors not seen with LD MPH. However, for social competence and behavior problems, parents reported no significant improvement with either LD or MD MPH when compared to placebo.
An inspection of the ES for those comparisons that reached statistical significance revealed that most ES reaching the threshold for typical to larger than typical beneficial effects (ie, ES > 0.50) were reported by teachers rather than parents, both on the CRS and SSRS. Of the 83 patients participating, 66 (79.5%) showed clinical benefit, as defined by
Adverse Side Effects Nine patients who completed the initial MPH challenge and who were enrolled on the 3-week cross-over trial failed to complete 1 or more weeks because of MPH sensitivity (Table 4). Two of the nine patients displayed significant sensitivity during the initial MPH challenge with a single dose of 0.60 mg/kg (maximum dose of 20 mg) and, per protocol, they participated only in the placebo and LD weeks. The remaining seven patients failed to complete their planned 3-week trial because of problems with the MD week. An inspection of the characteristics of these nine patients reveals considerable variability with regard to age at diagnosis and participation, sex, and weight. However, seven of the nine patients were treated for brain tumors compared to the 52% of patients treated for brain tumors who participated in the trial.
All 83 patients who participated in 1 or more weeks of the 3-week trial are represented in terms of adverse side effects in Table 5, with the more severe adverse side effects listed first. Overall, 5% or fewer patients exhibited any single side effect that was dose-limiting. As expected, the most common adverse side effects were those relating to insomnia and, less frequently, emotional lability with decreased appetite and withdrawn behavior. All dose-limiting symptoms were completely reversed with reduction or discontinuation of MPH. No symptoms of tic disorders or lowering of seizure threshold were noted. Of interest, some symptoms (eg, irritability, daydreaming) were common (although not severe) in the placebo week, and reinforce the importance of a placebo-controlled design.
The present study is unique because it is the first investigation to examine the effects of two standardized doses of MPH on behavior at home and in the classroom among survivors of childhood cancer. Statistically significant and clinically relevant improvements in attention and cognitive behaviors were reported by parents and teachers, with teachers also reporting improvements in social behaviors and academic competence. The trend for teachers to perceive more benefits from MPH than do parents can be explained by the pharmacokinetics of MPH. With a half-life of approximately 4 hours, the lunchtime dose would not be expected to be active during the late afternoon and evening when parents would have the greatest opportunity for observation of the patients. Transient, adverse side effects of varying degrees of severity were noted in many patients. Only three (3.5%) of 86 patients had reactions that precluded further exposure to MPH, with one patient requiring medical intervention as well. An additional nine (10.8%) of the 83 patients showed a lack of tolerance to the higher dose of MPH but tolerated the lower dose. The finding that children treated for brain tumors appear less tolerant of higher MPH doses should be kept in mind when following treatment guidelines for healthy children with attentional problems.36 These data add to the evidence from preliminary reports and acute trials that MPH may provide amelioration of cognitive symptoms for children16,19 and adults18 surviving cancer after treatment to the CNS, as well as for other groups of children experiencing acquired brain injury.15 More recently, additional evidence has emerged for the efficacy of low-dose MPH in treating attentional disorders among adults after traumatic brain injury.37 Although the data for MPH efficacy in some studies have not been compelling,14,17 it is likely that differences in dosing and outcome measures, as well as differences in experimental design and data analysis strategies, may account for these discrepancies. In addition, the therapeutic response and adverse side effects profile of MPH is highly idiosyncratic, limiting the usefulness of dosing by weight.12 For this reason, patients in our investigation that showed objective benefit from MPH in the 3-week trial were continued on an open-label trial for an additional 12 months with dosing titrated to best clinical effect. Although recent studies in otherwise healthy children with ADHD have minimized concerns regarding adverse MPH effects on growth and development,38 the long-term impact on survivors of childhood cancer is unknown. The primary limitations of the current study are that the study does not address the question of whether the benefits of MPH can be maintained over an extended time interval or whether the benefits extend beyond parent and teacher perceptions of behavioral improvement to actual improvements in neuropsychological functioning and academic achievement. The literature on the use of MPH in the ADHD population has not provided support for enhanced academic achievement with MPH treatment.12 Our future plans include 3-, 6-, and 12-month follow-up evaluations of those patients who continued to receive MPH after the 3-week trial and to correlate demographic, clinical, and psychometric data with MPH response. At the final evaluation, achievement and neuropsychological performance will be examined. Another potential limitation is that the inventories used to assess clinical benefit have not been validated for telephone administration as compared with standard administration. However, this concern is mitigated by the fact that patients served as their own controls in assessing benefit as opposed to comparisons to normative values. Also, because of our intent to avoid confounding of our results, we eliminated patients with clinically significant symptoms of anxiety and depression, which limits the generalization of our findings to childhood cancer survivors with such comorbid disorders. In addition to longer and more comprehensive follow-up assessments of patients receiving MPH, future studies will be needed to develop algorithms that accurately predict which children are most likely to benefit from MPH, to investigate other drugs that may be equally or more effective for those children and adolescents that cannot tolerate or show no response to MPH, and to identify possible mechanisms of MPH action among this population of children. One intriguing hypothesis posed by a group of ADHD investigators is that MPH treatment may result in structural changes in the brain identifiable by magnetic resonance imaging.39 Despite these unanswered questions, the present results support the conclusion that MPH may provide at least temporary improvement for some cognitive and behavioral symptoms found among children surviving cancer after CNS treatment.
This clinical trial is designed, carried out, and analyzed with a cross-over design in which three treatments (placebo [P], LD, MD) were administered, respectively, in 3 consecutive weeks to each patient.31 Patients were randomly and evenly assigned to six permutation sequences of three treatments: P, LD, MD; P, MD, LD; LD, P, MD; LD, MD, P; MD, P, LD; MD, LD, P. Each patient received three treatments in blinded order according to one of these sequences. The cross-over design is similar to the widely used design of pre-post tests in the aspect that different treatments are administered to a same subject in serial periods rather than to different subjects in one period. The efficiency of tests for comparing different treatments can be improved by cancelling the subject effects (variability of which is often large) and hence the sample size can be smaller for achieving same power of test. However, as with pre-post tests, the cross-over design can only be applied to studies in which effect of a treatment goes away quickly as the treatment stops. Compared with the pre-post test design, the cross-over design has following improvements: (1) treatments can be blinded to patients and/or investigators; (2) more than two treatments can be administered to each patient; (3) the carryover effects of treatments can be assumed non-zero, and thus can be estimated by statistical analysis, and it can be removed from the estimates of treatment effects.
For this study, the behavioral rating scores are not only affected by the treatment condition (placebo, LD, MD), but are also potentially affected by the carry-over effect from the previous period to next period. Because of this, we developed a model including these factors32: Yikm = µ + Dj(k) + Cj(k-1) + sim + For example, according to the table, for the case of i = 1 and k = 2, which indicates the second week in the sequence PLM, we have Dj(k)+Cj(k-1) = Dl+Cp because for this sequence (i = 1) the dose (treatment) is LD for current period (k = 2), and is Placebo for previous period (k-1 = 1). In this model we did not include the effects of periods (3 columns) and the randomization sequences (6 rows) as covariate variables because we assume that the effect of a period or a randomization sequence is completely specified by the combination of treatment effects and carryover effects in that period or randomization sequence, and thus inclusion of effects of periods and randomization sequences in the model would be redundent and distorting the treatment effects and carryover effects. For data analysis, as this model belongs to the class of mixed effects model for which standard SAS procedures are available, we applied SAS procedure for mixed model for analysis of this cross-over model. In data preparation, for each patient the treatment effect Dj(k) is coded as Dp, Dl, Dm, and the carry-over effect Cj(k-1) is coded as 0, or Cp, Cl, or Cm, according to the doses taken at previous and current periods. With the estimated parameters for the cross-over model, we then calculated the predicted mean scores of the jth condition by: mean score = µ + Dj, where µ is the estimate of overall mean, Dj is the estimate of effect of jth condition (j = 1, 2, 3 for placebo, LD, and MD). In the above prediction, we excluded the carry-over effects. Being similar to the simple means from raw data for easy checking, the least square mean scores of the jth drug group plus the mean of the cross-over effects were predicted by: mean score = µ + Dj + C, where C is the mean of carry-over effects (ie, the mean of 0, Cp, Cl, and Cm). The SAS procedure for the mixed model allows missing data, by which we not only did analysis for balanced and completed data (equal sample sizes for each of randomization sequences and all patients had completed all treatments; total 54 patients), but also for unbalanced and completed data (sample sizes could be different for randomization sequences, but only patients who had completed all treatments were included for analysis; total 74 patients), as well as for unbalanced and uncompleted data (the sample sizes could be different for randomization sequences and include nine patients who had not completed all treatments; total 83 patients).33,34 The estimates of parameters from the three data analysis are very similar, which indicates that the proposed model is well applicable to the data if sample sizes in combination cells of periods and randomization sequences are not seriously out of balance. The SAS procedure provides also tests comparing effects of placebo, LD, and MD within the mixed model. The comparisons of treatment effects based on the model are reported in Table 3 within the text.
The authors indicated no potential conflicts of interest.
We thank Drs Mark Sapp, Emily Baum, Paul Chapman, Melissa Jones, and Rene Rencher for their assistance in conducting the study.
Supported in part by Cancer Center Support (CORE) Grant P30 CA21765, R01 CA78957 (R.K.M.), U01 CA81445 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities. Portions of this study have been presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; 11th International Symposium on Pediatric Neuro-Oncology, Boston, MA, June 13-16, 2004; and Cancer Survivorship: Pathways to Health After Treatment, Washington, DC, June 16-18, 2004. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
90 in one or more academic areas. 
75th percentile for age and sex on one or more of the ADHD index, hyperactivity, or cognitive problems/inattention scales. 
ikm, where µ is the overall mean, Dj(k) is the effect of j(k)th (treatment) condition and takes value of Dp, Dl, Dm for taking placebo, LD, and MD at the kth period (k = 1, 2, 3); sim is a random effect (or baseline effect) of mth patient (m = 1,...,ni) in the ith permutation sequence (i = 1,...,6); Cj(k-1) is the carry-over effect of the dose in previous period (ie, (k-1)th period) and takes value of 0, Cp, Cl, Cm for taking nothing, placebo, LD, and MD at the (k-1)th period (k-1 = 0,1, 2; Cj(0) = 0); and 
