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Increased understanding of the underlying mechanisms of cognitive remediation is needed to facilitate development of intervention strategies for childhood cancer survivors experiencing cognitive late effects. Accordingly, a pilot functional magnetic resonance imaging (fMRI) study was conducted with 14 cancer survivors (12.02 ± 0.09 years old), who participated in a cognitive remediation clinical trial, and 28 healthy children (12.7 ± 0.6 years old). The ventral visual areas, cerebellum, supplementary motor area, and left inferior frontal cortex were significantly activated in the healthy participants during a continuous performance task. In survivors, brain activation in these regions was diminished at baseline, and increased upon completion of remediation and at a 6-month follow-up. The fMRI activation index for each region of interest was inversely associated with the Conners' Clinical Competence Index (p

Survivors of childhood cancer whose malignancy and/or treatment involved the central nervous system may demonstrate a consistent pattern of neurocognitive deficits. The present study evaluated a randomized clinical trial of the Cognitive Remediation Program (CRP). Participants were 6- to 17-year-old survivors of childhood cancer (N = 161; 35% female, 18% Hispanic, 10% African American, 64% Caucasian, 8% other) who were at least 1 year off treatment and who manifested an attentional deficit. They were enrolled at 7 sites nationwide. Two thirds of the participants were randomly assigned to cognitive remediation. All participants were assessed using a battery of academic achievement/neurocognitive tests and parent/teacher measures of attention. The CRP resulted in parent report of improved attention and statistically significant increases in academic achievement. Effect sizes were modest but were comparable with those for other clinical trials of brain injury rehabilitation and for psychological interventions in general. The CRP is presented as a potentially beneficial treatment for many survivors of pediatric cancer. Long-term clinical significance remains unproven. Further work is needed to improve effect sizes and treatment compliance and to address the needs of other populations with pediatric brain injury.

Objective To investigate the acute efficacy and adverse side effects of methylphenidate (MPH) among survivors of childhood cancer [acute lymphoblastic leukemia (ALL) or brain tumor (BT)] with learning impairments. Methods Participants (N ¼122) completed a two-day, in-clinic, double-blind, cross-over trial during which they received MPH (0.60mg/kg of body weight) and placebo that were randomized in administration order across participants. Performance was evaluated using measures of attention, memory, and academic achievement. Results A significant MPH versus placebo effect was revealed on a measure of attention, cognitive flexibility, and processing speed (Stroop Word-Color Association Test). Male gender, older age at treatment, and higher intelligence were predictive of better medication response. No significant differences were found for number or severity of adverse side effects as a function of active medication. Conclusions MPH shows some neurocognitive benefit and is well tolerated by the majority of children surviving ALL and BT.

Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors ( n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose–volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.

BACKGROUND The primary objective of this study was to test the hypothesis that survivors of childhood acute lymphoblastic leukemia (ALL) have deficits in neurocognitive performance, and smaller white-matter volumes are associated with these deficits. METHODS The patients studied included 112 ALL survivors (84 patients who had received chemotherapy only, 28 patients who had received chemotherapy and irradiation; 63 males, 49 females; mean age ± standard deviation, 4.1 yrs ± 2.6 yrs at diagnosis; mean ± standard deviation yrs since diagnosis, 6.0 ± 3.5 yrs), and 33 healthy siblings who participated as a control group. Neurocognitive tests of attention, intelligence, and academic achievement were performed; and magnetic resonance images were obtained and subsequently were segmented to yield tissue volume measurements. Comparisons of neurocognitive measures and tissue volumes between groups were performed, and the correlations between volumes and neurocognitive performance measures were assessed. RESULTS Most performance measures demonstrated statistically significant differences from the normative test scores, but only attention measures exceeded 1.0 standard deviation from normal. Patients who had received chemotherapy alone had significantly larger volumes of white matter than patients who had received treatment that also included cranial irradiation, but their volumes remained significantly smaller than the volumes in the control group. Smaller white-matter volumes were associated significantly with larger deficits in attention, intelligence, and academic achievement. CONCLUSIONS Survivors of childhood ALL had significant deficits in attention and smaller white-matter volumes that were associated directly with impaired neurocognitive performance. Cranial irradiation exacerbated these deficits. Cancer 2006. © 2006 American Cancer Society.

To assess the effects of radiation dose-volume distribution on the trajectory of IQ development after conformal radiation therapy (CRT) in pediatric patients with ependymoma.The study included 88 patients (median age, 2.8 years +/- 4.5 years) with localized ependymoma who received CRT (54-59.4 Gy) that used a 1-cm margin on the postoperative tumor bed. Patients were evaluated with tests that included IQ measures at baseline (before CRT) and at 6, 12, 24, 36, 48, and 60 months. Differential dose-volume histograms (DVH) were derived for total-brain, supratentorial-brain, and right and left temporal-lobe volumes. The data were partitioned into three dose intervals and integrated to create variables that represent the fractional volume that received dose over the specified intervals (e.g., V(0-20 Gy), V(20-40 Gy), V(40-65 Gy)) and modeled with clinical variables to develop a regression equation to estimate IQ after CRT.A total of 327 IQ tests were performed in 66 patients with infratentorial tumors and 20 with supratentorial tumors. The median follow-up was 29.4 months. For all patients, IQ was best estimated by age (years) at CRT; percent volume of the supratentorial brain that received doses between 0 and 20 Gy, 20 and 40 Gy, and 40 and 65 Gy; and time (months) after CRT. Age contributed significantly to the intercept (p0.0001), and the dose-volume coefficients were statistically significant (V(0-20 Gy), p = 0.01; V(20-40 Gy), p0.001; V(40-65 Gy), p = 0.04). A similar model was developed exclusively for patients with infratentorial tumors but not supratentorial tumors.Radiation dosimetry can be used to predict IQ after CRT in patients with localized ependymoma. The specificity of models may be enhanced by grouping according to tumor location.

Purpose To evaluate the impact of tumor location, clinical parameters, and therapy on neurocognitive, neuroendocrine, and functional outcomes in children ≤ 3 years old with intracranial CNS malignancies who survived at least 2 years after diagnosis. Patients and Methods Records were retrospectively reviewed for 194 children diagnosed from 1985 to 1999 at St Jude Children's Research Hospital (Memphis, TN). Results The median age at diagnosis was 1.8 years (range, 0.1 to 3.5 years). Median follow-up was 7.64 years (2.0 to 19.4 years). Tumors were infratentorial (102), diencephalic (53), and hemispheric (39); 47% required ventriculoperitoneal shunts, 36% developed seizure disorders, and 20% developed severe ototoxicity. Therapy included no radiation therapy (RT) in 57 (30%), local RT in 87 (45%), and craniospinal irradiation (CSI) in 49 (25%). Overall survival at 10 years was 78 ± 4%. In a longitudinal analysis of 126 patients with at least one neurocognitive evaluation (NE), the mean rate of intelligence quotient (IQ) change for patients who received CSI (−1.34 points per year) and local RT (−0.51 points per year) was significantly different from the no RT group (0.91 points per year; P = .005 and P = .036, respectively). Patients with hemispheric tumors had a significantly greater IQ decline (−1.52 points per year) than those with midline tumors (0.59 points per year; P = .038). Among those with NE ≥ 5 years after diagnosis, 71.4% of CSI recipients compared with 23% of local RT recipients had IQ less than 70 (P = .021). Patients undergoing CSI were more likely to develop endocrinopathies (P < .0001) and to require special education (P = .0007). Conclusion In young children with CNS tumors, CSI and hemispheric location are associated with significant declines in IQ scores.

Purpose This prospective, longitudinal study examined the effects of risk-adapted craniospinal irradiation (CSI) dose and the interactions of dose with age and time from diagnosis on intelligence quotient (IQ) and academic achievement (reading, spelling, and math) among patients treated for medulloblastoma (MB). Patients and Methods Patients received serial neurocognitive testing spanning from 0 to 6.03 years after diagnosis (median, 3.14 years). The multi-institutional study included 111 patients, who were 3 to 20 years of age at diagnosis (median age, 7.4 years), treated for MB with risk-adapted CSI followed by four cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, and vincristine) with stem-cell support. High-risk patients (HR; n = 37) received CSI to 36 to 39.6 Gy and conformal boost treatment of the primary site to 55.8 to 59.4 Gy. Average-risk patients (AR; n = 74) received CSI to 23.4 Gy and conformal boost treatment of the posterior fossa to 36.0 Gy and primary site to 55.8 Gy. Results Multivariate modeling revealed statistically significant declines in mean IQ (−1.59 points/yr; P = .006), reading (−2.95 points/yr; P < .0001), spelling (−2.94 points/yr; P < .0001), and math (−1.87 points/yr; P = .003) scores for the entire group. The effects of risk-adapted radiation therapy on IQ, reading, and spelling were moderated by age, with the greatest rates of decline observed for the HR patients who were younger (< 7 years old) at diagnosis. Conclusion Young age at diagnosis was the most prominent risk factor for neurocognitive deficits among survivors of MB despite reductions in CSI dosing and efforts to limit the boost volume. Younger patients exhibited substantial problems with the development of reading skills.

Children surviving certain cancers have a high incidence of cognitive deficits caused by central nervous system (CNS) disease or treatments directed at the CNS. To establish the feasibility of using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study cognitive deficits in survivors of childhood cancer, we tested the hypothesis that this population has the same BOLD response to visual stimulation as healthy subjects. We used BOLD fMRI to measure spatial and temporal patterns of brain activity after brief visual stimulation in 16 survivors of childhood cancer, 11 age-similar healthy siblings of survivors, and 16 healthy adults. Functional data for the survivors were analyzed with two general linear models, one used a canonical hemodynamic response function (HRF) and the other used a Fourier set as basis functions. The measured BOLD signal and brain activation patterns were similar in the survivors with both models. The BOLD signal for survivors was qualitatively similar in timing and shape, but there were significant quantitative differences as compared with healthy subjects. The activation was normally located in the primary visual cortex in 13 survivors, but the activation volume was significantly smaller in brain tumor survivors than in other groups. These findings demonstrate the feasibility of using BOLD fMRI to investigate brain function in survivors of childhood cancer. However, fMRI studies in this population must take into account effects of quantitative differences in their BOLD responses as compared to healthy subjects.

Brain tumors constitute approximately 20% of pediatric malignancies. Because of the inherent risk of these tumors, patients receive aggressive CNS therapy that often comprises maximal surgical resection, local and craniospinal irradiation (CSI), and adjuvant chemotherapy. Consequently, long-term survivors are at risk of cognitive delays or deficits that impair their academic performance, employment opportunities, and quality of life (Dennis et al., 1996; Mulhern et al., 1998; Ris et al., 2001). In survivors of childhood medulloblastoma (MB), deficits in IQ and academic achievement appear to reflect a diminished ability to acquire new information (Palmer et al., 2001). One or more cognitive processing mechanisms, including attention, short-term memory, speed of processing, visual-motor coordination, and sequencing ability, may be impaired (Schatz et al., 2000). These processes depend on the integrity of widely distributed neural networks supported by interhemispheric and intrahemispheric white matter tracts. Recent findings have shown that in pediatric patients treated for brain tumors, a reduced volume of normal-appearing white matter (NAWM)3 is associated with reduced attentional ability and a decline in IQ and academic achievement (Reddick et al., 2003). The proportion of intracranial volume that is NAWM is normally expected to increase into early adulthood. This increase is usually modeled as a quadratic function in which growth is most rapid in the first five years, continues to rise at a moderate rate over the next 10 years, and then slows to asymptotically approach the adult volume (Giedd et al., 1999; Sowell et al., 2002). Previous studies of the association between NAWM and cognitive function have yielded mixed results (Andreasen et al., 1993; Reiss et al., 1996). NAWM volume is not strongly related to IQ in healthy children but is significantly associated in other populations with pathological conditions such as attention deficit-hyperactivity disorder (Castellanos et al., 2002). At least one author has suggested a threshold effect in which cognitive impairment becomes apparent only below a certain volume of NAWM (Inzitari, 2000). Studies that have quantified toxic effects on white matter and investigated the association between neurotoxicity and cognitive deficits in children have focused primarily on survivors of MB of the posterior fossa (approximately 20% of pediatric brain tumors). One such study compared patients treated for MB with age-similar controls who had received surgery alone for low-grade tumors of the posterior fossa; the survivors of MB had a significantly smaller volume of NAWM, a substantially greater volume of cerebrospinal fluid (CSF), and an equal volume of gray matter (Reddick et al., 1998). This study also demonstrated that chemotherapy did not have a significant detectable impact on tissue volumes. The MB patients also had significantly lower IQs (Mulhern et al., 1999). However, because of their cross-sectional design, these studies could not discern whether the smaller NAWM volume reflected loss of tissue, decreased myelination, or both. A subsequent longitudinal study revealed a significant loss of NAWM volume in patients undergoing treatment for MB; this loss was more rapid among patients who received a CSI dose of 36 Gy versus CSI of 23.4 Gy (Reddick et al., 2000). However, this study was limited by a relatively short median follow-up period of one year. NAWM volume can explain approximately 70% of the association between IQ impairment and age at the time of irradiation (Mulhern et al., 2001). In a recent cross-sectional study, patients treated for MB showed significantly impaired performance on all neurocognitive measures of intellect, attention, memory, and academic achievement (Reddick et al., 2003). The study produced a developmental model in which academic achievement was predicted by NAWM volume, attentional ability, and IQ; these factors explained approximately 60% of the variance observed in reading and spelling and almost 80% of the variance observed in mathematics. The primary consequence of reduced NAWM volume was decreased attentional ability, which reduced patients’ IQ and academic achievement (Reddick et al., 2003). We designed a retrospective longitudinal study to compare brain volume development of patients treated for MB with that of healthy, age-similar peers. To control for the effect of irradiation dose, we included only patients who received a CSI dose of 35 to 40 Gy (once used to treat all cases of MB and now used for patients at high risk). This retrospective design has three limitations that could conceivably cause results to differ from more comprehensive prospective trials: (1) Imaging was limited to a single representative section, (2) diffusion tensor imaging was not acquired as a routine part of clinical imaging during this period, and (3) extent and incidence of regions of T2 hyperintensity in other locations could not be assessed by the single index section. However, this retrospective study was designed to comprise as homogeneous a group of subjects as possible: Patients received similar doses of CSI to treat the same type of tumor, which arose in the same location. This study builds on previous work by including serial magnetic resonance (MR) studies to determine the effect of age at irradiation, time since irradiation, gender, use of chemotherapy, and use of ventricular shunt on the development of brain parenchyma (Reddick et al., 1998).

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.

(2004). ReviewNeurocognitive sequelae of childhood cancers and their treatment. Pediatric Rehabilitation: Vol. 7, No. 1, pp. 1-14.

As survival rates for the most prevalent types of childhood cancer have dramatically improved over the past three decades, the concept of “cure” has evolved to include optimizing the quality of life among survivors. Although significant progress has been made in addressing some adverse late effects of treatment that limit quality of life, such as endocrinopathies, other late effects remain problematic. This paper will review neurocognitive late effects as defined by problems with thinking, learning, and remembering among survivors of childhood cancer. After defining the neurocognitive phenotype that characterizes many such children, we will review the etiology and risk factors for damage to the central nervous system associated with childhood cancer and its treatment. We will then discuss methods of pharmacological, behavioral, and ecological intervention that may be helpful in reducing learning problems among surviving children. Finally, we will identify areas of future research that will be critical to the elimination of neurocognitive late effects in childhood cancer survivors and the resources needed to implement such research.

Atonic seizures are part of some childhood epilepsy syndromes and can also result from acquired central nervous system insult. Of 93 survivors of childhood cancer with uncontrolled seizures, 10 (11%) with atonic seizures form the basis for this report. Seven survived acute leukemia, and three survived brain tumors. The median age at cancer diagnosis was 9 months (range 2—52). Nine received systemic and six intrathecal chemotherapy; cranial irradiation was given to seven. All have learning difficulties, abnormal brain magnetic resonance images, and an abnormal electroencephalogram; six are developmentally delayed. All have difficult-to-control seizures, but six improved on myoclonus-specific drugs with accelerated development in two younger patients. Atonic seizures in cancer survivors are associated with difficult-to-control seizures and pervasive cognitive impairments. Young age at cancer diagnosis and cranial irradiation may predispose the patient to development of this syndrome. Recognition and appropriate treatment of atonic seizures in cancer survivors could improve seizure control, neurologic development, and quality of life. ( J Child Neurol 2003;18:397—400).

Fifty children diagnosed with medulloblastoma completed 188 psychological evaluations using the Wechsler Intelligence Scales for Children (D. Wechsler, 1974, 1991) over a 7-year study period following 35-40 Gy postoperative craniospinal irradiation. Random coefficient models were used to predict the trend in the children's intellectual performance as a function of time since diagnosis, with both patient and treatment variables as parameters of this function. A quadratic model demonstrated a delay prior to decline in performance for older patients, whereas the younger patients showed an immediate loss of performance with a plateau at approximately 6 years postdiagnosis. A steeper decline was found for those with higher baseline performance. Clinicians may use the proposed predictive model to identify those patients who are at risk of significant intellectual decline.

To review our institution's experience in the treatment of craniopharyngioma and assess the merits of initial therapy with limited surgery and irradiation.The data of 30 patients (median age 8.6 years) with a diagnosis of craniopharyngioma between April 1984 and September 1997 were reviewed. Their course of treatment, neurologic, endocrine, and cognitive function, and quality of life at last follow-up were compared.Fifteen patients were initially treated with surgery (8 required irradiation after relapse) and 15 with limited surgery and irradiation (2 required additional treatment for tumor progression). Only 1 patient died of tumor progression. The surgery group lost a mean of 9.8 points in full-scale IQ, and the combined-modality group lost only 1.25 points (p0.063). Patients in the surgery group who had relapses (n = 9) lost a mean of 13.1 points (p0.067). A loss of 10 points was considered clinically significant. The surgery group also had more frequent neurologic, ophthalmic, and endocrine complications. The mean Health Utility Index (a functional quality-of-life index) was higher for the combined-modality group (0.85) than for the surgery group (0.71; p0.063, one-sided t test).The acute neurologic, cognitive, and endocrine effects of surgery often affect long-term function and quality of life. Our experience suggests that limited surgery and radiotherapy cause lesser or comparable sequelae. Diabetes insipidus was the only endocrine deficiency that differed substantially in frequency between the two groups. Newer radiation planning and delivery techniques may make a combined-modality approach a good initial option for most patients.

Mothers of children with serious illnesses have lower levels of well-being than mothers in the general population. Problem-solving therapy (PST), a cognitive-behavioral intervention, has been shown to be effective in treating negative affectivity (depression, anxiety) and other manifestations of reduced well-being. This report describes a problem-solving skills training (PSST) intervention, based on problem-solving therapy, for mothers of newly diagnosed pediatric cancer patients. Ninety-two mothers were randomly assigned to receive PSST or to receive standard psychosocial care (Control Group). After the 8-week intervention, mothers in the PSST Group had significantly enhanced problem-solving skills and significantly decreased negative affectivity compared with controls. Analysis revealed that changes in self-reports of problem-solving behaviors accounted for 40% of the difference in mood scores between the two groups. Interestingly, PSST had the greatest impact on improving constructive problem solving, whereas improvement in mood was most influenced by decreases in dysfunctional problem solving. The implications of these findings for refinement of the PSST intervention and for extension to other groups of children with serious illnesses are discussed.

Purpose: To provide evidence that radiation therapy alone in the form of craniospinal irradiation (CSI) and a boost to the primary site of disease provides effective disease control and limited additional morbidity for patients with CNS germinoma. Methods and Materials: Twelve patients with a median age of 12 years (range 9–16 years) with CNS germinoma were treated with CSI (median 25.6 Gy, range 23.4–32 Gy) and a boost to the primary site of disease (50.4 Gy, range 45–54 Gy) between January 1987 and June 1998. All patients were biopsied prior to radiation therapy and none received chemotherapy. No patients were lost to follow-up and the majority had long-term (> 45 month) pre- and postirradiation endocrine and psychology assessment. Results: All 12 patients are alive and no failures have occurred with a median follow-up of 69 months (range 14–143 months). Preirradiation endocrine deficiencies were present in 6 of 6 suprasellar tumors and 1 of 6 pineal tumors; with follow-up there was no substantial difference between age and gender adjusted pre- and postirradiation stature and weight. With long-term follow-up, there were no significant differences between pre- and postirradiation full-scale, verbal, and performance IQ scores. Conclusions: This study confirms the ability of radiation therapy alone to achieve disease control with a high rate of success in pediatric patients and demonstrates that the treatment toxicity faced by these patients may be less than anticipated. Because these patients present with substantial preexisting morbidity at diagnosis and may be of an age where the potential for radiation-related side effects is relatively small, the superiority of treatment alternatives may be difficult to prove.

Although previous studies have documented a significant risk of intellectual loss after treatment for childhood medulloblastoma (MED), the pathophysiology underlying this process is poorly understood. The purpose of this study was to test the hypotheses that (1) patients treated for MED in childhood have reduced volumes of normal white matter (NWM) related to their treatment with craniospinal irradiation with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their intellectual performance. Eighteen pediatric patients previously treated for MED were matched on the basis of age at the time of evaluation to 18 patients previously treated for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7 months). Evaluations were conducted with age-appropriate neurocognitive testing and quantitative magnetic resonance imaging by using a novel automated segmentation and classification algorithm constructed from a hybrid neural network. Patients treated for MED had significantly less NWM (p < 0.01) and significantly lower Full-Scale IQ values than those treated for low-grade tumors (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically significant association with Full-Scale IQ among the patients treated for MED. We conclude that irradiation- or chemotherapy-induced destruction of NWM can at least partially explain intellectual and academic achievement deficits among MED survivors.

PURPOSE: Young children treated for medulloblastoma are at especially high risk for morbidity and mortality from their disease and therapy. This study sought to assess the relationship, if any, between patient outcome and M stage. Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS: Twenty-nine consecutively diagnosed infants and young children were treated for medulloblastoma at St Jude Children's Research Hospital between November 1984 and December 1995. All patients were treated with the intent of using postoperative chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis was 2.6 years. Six patients completed planned chemotherapy without progressive disease and underwent irradiation at completion of chemotherapy. Twenty-three children experienced disease progression during chemotherapy and underwent irradiation at the time of progression. The 5-year overall survival rate for the entire cohort was 51% ± 10%. The 5-year progression-free survival rate was 21% ± 8%. M stage did not impact survival. All patients lost cognitive function during and after therapy at a rate of −3.9 intelligence quotient points per year (P = .0028). Sensory functions declined significantly after therapy (P = .007). All long-term survivors required hormone replacement therapy and had growth abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma experienced disease progression during initial chemotherapy. However, more than half of these patients can be cured with salvage radiation therapy, regardless of M stage. The presence of metastatic disease did not increase the risk of dying from medulloblastoma. All patients treated in this fashion have significant neuropsychologic deficits. Our experience demonstrates that medulloblastoma in infancy is a curable disease, albeit at a significant cost.

Summary This article describes a cognitive-behavioral therapy intervention for teaching mothers of newly diagnosed patients with pediatric cancer to solve their problems, problems related to their child's illness, and the family's emotional reactions to the illness. The authors discuss the challenges and effects of maternal adjustment throughout the various stages of the child's illness, review the characteristics of adult learners, describe a maternal problem-solving therapy program, and provide an overview of the structured educational process, followed by a detailed discussion of a six-step maternal problem-solving therapy intervention. Finally, they describe an inventory that measures the effects of the intervention, which is being tested in a randomized controlled trial.

Our objective was to test a hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients who are clinically free of stroke. We prospectively compared 50 patients with 52 healthy age-similar controls, using quantitative magnetic resonance imaging. A previously validated precise and accurate inversion-recovery method was used to measure T1 in a slice at the basal ganglia. We also used the Wechsler test to measure intelligence quotient (IQ) in a randomly selected subset of 27 patients. Brain T1 was significantly lower in patients in every gray matter structure evaluated but in none of the white matter structures. Regression suggests that T1 in caudate, nucleus pulvinares, and cerebral cortex was abnormal by age 4 years. Psychometric testing showed that 33% of patients were functioning in the range of mild mental deficiency (IQ, 50-70), compared with a published prevalence of 1.45% in inner-city black children. Thus, in our patients, SCD was associated with a 23-fold increase in the risk of mild mental deficiency. Full-scale IQ of SCD patients was a function of hematocrit (Hct), and when Hct was used to stratify patients, those with an Hct of less than 27% had significantly lower psychometric test scores, and significantly lower gray matter T1, than those with an Hct of 27 or more. Both cognitive deficits and subtle T1 abnormalities were associated with a low Hct, and both could be present when conventional magnetic resonance imaging findings were normal. Our findings suggest that chronic hypoxia of brain tissue can occur in SCD patients free of clinical stroke.

We have examined the influence of selected factors (gender, marital status, socio-economic status, co-morbid conditions, access to medical care, age at diagnosis, intensity of therapy and time since diagnosis) on subsequent health status and health-related quality of life (HRQL) of long-term survivors of pediatric solid tumors. Two hundred and twenty individuals who had survived a pediatric solid tumor 15 years or longer completed telephone and written assessments of their current status. Health status was assessed using the Late Effects of Normal Tissues toxicity scale. HRQL was investigated using the Ferrans and Powers Quality of Life Index–Cancer (QLIC) and the EORTC Quality of Life Questionnaire C30 (QLQ-C30). Results indicated that health status and HRQL were better in survivors treated with low-intensity therapy. One hundred and thirty respondents (59.1%) reported at least 1 serious toxicity. Dyspnea and fatigue were commonly reported in survivors of Hodgkin's disease. Correlational analyses showed that predictors of health status included socio-economic status, marital status and the presence of co-morbid factors. Mean HRQL scores for the 4 domains of the Ferrans and Powers QLIC and the functional scales of the EORTC QLQ-C30 indicated that most of the survivors were experiencing moderately good to excellent HRQL. One-third of survivors reported that their history of cancer had an adverse impact on their current financial status. Prediction models constructed for 3 of the domains from the 2 HRQL instruments are presented (health and functioning, global HRQL and financial impact). Within these 3 models, consistent predictors of HRQL outcomes included health status, presence of dyspnea or pain, marital status and socio-economic status. Int. J. Cancer Suppl. 12:25–31, 1999. ©1999 Wiley-Liss, Inc.

Children surviving medulloblastoma have a high risk for chronic, treatment-related neurocognitive deficits. Neuropsychological testing provides important data regarding the comparative toxicities of various therapeutic approaches. However, such testing can be expensive and logistically difficult, especially if a consulting psychologist is not readily available at the treating institution. Our purpose was to investigate the usefulness of a health-related quality of life inventory that does not require a psychologist for completion. We assessed the concurrent validity of traditional intelligence (IQ) testing and levels on the Cognition attribute of the multi-attribute Health Utilities Index Mark 2 (HUI 2) in estimating academic achievement scores of 22 patients treated for medulloblastoma with craniospinal irradiation following surgical resection. The results demonstrated that the Cognition utility scores were significantly lower than scores from the other components of the HUI 2 (Sensation, Mobility, Emotion, Self-Care, Pain). Cognition scores were also significantly positively correlated with IQ and achievement scores. Furthermore, Cognition scores were significantly lower among children who had received special educational services when compared with those who had not received such services. Our results provide preliminary evidence of the potential usefulness of the HUI 2 Cognition attribute in estimating IQ, achievement and the likelihood of the need for special educational services among children treated for medulloblastoma.

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.

Objective To assess the psychological functioning of adolescent and young adult survivors of pediatric malignancy, and identify risk factors for maladjustment. Design Patients age ≥ 14.5 years (N = 161) receiving surveillance follow-up at a major pediatric cancer center completed the SCL-90-R, a self-report measure of psychological symptomatology. Comparisons were made with the normative standardization sample, and the relationship of selected demographic and medical variables with psychological distress was explored using logistic regression analyses. Results Survivors mean scores on all SCL-90-R subscales were lower than those of the standardization sample, and the distribution of scores on the Anxiety, Psychoticism, Global severity Index, and Positive Symptom Total scales were significantly below normative values. No SCL-90-R subscale displayed an excessive frequency of clinically elevated scores. For patients who displayed clinical elevations on the SCL-90-R, three factors were identified which were associated with increased risk of maladjustment; older patient age at follow-up, more frequent disease relapse, and more severe functional impairment. Conclusions This cohort of childhood cancer survivors is characterized by very low levels of psychological distress and significantly better psychological health than would be expected according to normative data. These findings contrast with those of another study from the same institution in which a fourfold increase in social and behavioral problems was found amongst younger survivors, in the age range 7–15. The use of self-report vs. parent-report, and the potential influence of repressive adaptation on the self-reports of pediatric cancer survivors, are raised as possible explanations for these findings. Med. Pediatr. Oncol. 29:582–588, 1997. © 1997 Wiley-Liss, Inc.

We evaluated efficacy of a cognitive-behavioral therapy (CBT) intervention compared to a standard care condition (SCC) in 55 pediatric patients with central nervous system cancer, aged 6 to 18 years, undergoing magnetic resonance imaging (MRI). There were no significant differences between the CBT and the SCC groups on child, parent, or staff ratings of MRI distress, child self-reports of expected MRI distress, or observed behavioral distress. The CBT intervention was effective, however, in reducing distress during intravenous line (IV) insertion preceding the index MRI on the basis of staff but not child or parent ratings of distress. No significant differences in need for sedation were present between the CBT and the SCC groups. Positive changes in staff-patient interactions and improved patient education regarding the MRI were apparent. Discussion focuses on recommendations for future studies examining cognitive-behavioral interventions in pediatric patients.

Cross-cultural aspects of siblings' adaptation to childhood cancer were examined in two studies as part of a cooperative multi-institutional investigation in Israel and the United States. Study 1 compared the behavioral adaptation of Israeli siblings of patients with childhood cancer with matched clinically referred and normal Israeli children. Study 2 compared the behavioral adaptation of case-matched samples of Israeli and American siblings and assessed the contribution of family relations and parental coping to the siblings' behavioral adjustment. Israeli patients' siblings and normal samples scored significantly lower on the Child Behavior Checklist (CBCL) than the clinically referred sample did, indicating fewer behavior problems, with no differences between the sibling and normal samples. The CBCL scores of the Israeli and American samples did not differ significantly on the Externalizing and Internalizing subscales and the Total Behavior Problem score. Significant correlations were found in both the Israeli and American samples between the parental coping and family relations variables and the CBCL scores, indicating that greater internal family support and emotional expressiveness and lower conflict were associated with less behavior disturbance in the sibling. The authors consider cross-cultural and methodologic issues when interpreting similarities and differences among Israeli and American siblings of pediatric cancer patients.

Investigated the prevalence of anticipatory nausea and vomiting (ANV) among 59 pediatric cancer patients who had routinely received ondansetron (Zofran) antiemetic therapy and determined patient- and treatment-related factors associated with ANV. Of the sample, 59% indicated at least mild ANV symptoms, suggesting that a significant number of patients report ANV and are bothered by it, despite the use of Zofran. These children were compared to those reporting no ANV symptoms. Most ANV symptomatology was consistent with a traditional classical conditioning model although cognitive processes may also play a role. Children with greater expectations of severe postchemotherapy vomiting and those who were more distressed by nausea and vomiting were more likely to experience ANV symptoms. Implications for psychological and pharmacological treatments of ANV are discussed.

Objective This seven-site study examined the overall health status, healthcare utilization, somatization, and health-risk behaviors of siblings of children with cancer compared to these factors in matched controls or normative data. The study also examined whether informants (i.e., siblings, parents, physicians) differed in their assessments of the above health domains. Design Subjects were 254 siblings of children with cancer from seven different pediatric oncology treatment centers that participated in the Sibling Adaptation to Childhood Cancer Collaborative study group. Predictors of the siblings' health status, healthcare utilization, somatization, and health-risk behaviors were identified, and the relationship between these health domains and the siblings' resiliency vs. dysfunctionality were explored via interviews. Results Overall, siblings were found to be moderately healthy, although siblings report significant problems with sleeping and eating. Healthcare utilization appears to be reduced for siblings. Most importantly, the parents of these siblings are less likely to seek medical help for a variety of conditions for which parents of control children would bring their children to a doctor. A pattern emerged of parental underreporting of sibling health variables when compared to what the siblings themselves reported. When the relationship between health outcomes and the siblings' adaptation to their sick sibling's illness was examined, the resilient and dysfunctional groups significantly differed from each other. It appears that health outcomes are related to sibling adaptation to the changes brought about by their sick sibling's cancer diagnosis and treatment. Conclusions The focus of care for families of children with cancer is often limited to the child with cancer. As indicated in this study, the “healthy” siblings may be overlooked in the process. While parents appear to recognize that their “healthy” children are complaining more about aches and pains, they may have little energy or time to attend to the needs of these other family members. It is the intent of this study to document what clinicians may expect and to highlight the need for evaluation of this otherwise neglected group. © 1996 Wiley-Liss, Inc.

Purpose: To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from

Nutritional problems often result from malignancies and aggressive multimodal treatment. Early identification of reliable risk factors associated with malnutrition and need for nutritional support is necessary for development of preventative approaches. Nutritional and treatment-related characteristics were examined for 173 pediatric oncology patients referred for nutritional support and a comparison sample of 43 patients matched on treatment protocol and/or diagnosis who had never been referred for nutritional support. Abnormally low serum albumin levels, poor oral intake, mucositis, prior radiation therapy, and increased gastrointestinal toxicity were significantly more frequent among referred than non-referred patients. A discriminant function analysis indicated that poor oral intake was the single best predictor of need for nutritional support. Patients with solid tumors were more nutritionally depleted at the time of referral; all bone marrow transplant patients received nutritional support. Patients with central nervous system (CNS) tumors required nutritional support for longer time periods. We conclude that routine documentation of poor oral intake (i.e., observation of change in a child's eating patterns) is the most reliable indicator of children who eventually require nutritional support and who may benefit from interventions that could delay or prevent nutritional problems. Prophylactic interventions should be tailored to meet the specific needs of individual diagnostic groups.

The health-related beliefs and behaviors of long-term survivors of childhood cancer are important because of vulnerability to adverse late effects from their primary malignancy and its therapy. A health behavior survey was completed by 110 parents of long-term survivors ranging in age from 11-17 years, and by 40 adult long-term survivors of childhood cancer ranging in age from 18-29 years. The survey included questions on the former patient's frequency of alcohol and tobacco use, as well as diet, exercise, sleep, dental, and seatbelt habits. The reported prevalence of tobacco and alcohol use was less than 10% among those less than 18 years old. Among the adults, tobacco (17.5%) and alcohol (72.5%) use was greater, but problem drinking was infrequently reported. In order to assess their perceived vulnerability, we asked the parents and the young adult patients to rate the strength of their belief that it is more important for the patient to keep healthy compared to most other children or young adults. Contrary to our expectation, demographic factors such as the patient's gender, socioeconomic level, or time elapsed since completion of therapy exerted minimal influence on their responses. Over 80% of parents and 60% of young adult survivors believed that it was more important for the former patient to remain healthy compared to most other people. However, this shared belief in increased vulnerability was inconsistently expressed in the patient's health behaviors. These results suggest that specific changes are needed in the health assessment and education of long-term survivors of childhood cancer.

Purpose: A prospective assessment of neurocognitive performance was conducted in children with acute lymphoblastic leukemia (ALL) following isolated central nervous system (CNS) relapse to evaluate the impact of additional systemic/intrathecal (IT) chemotherapy and craniospinal irradiation (CSI) upon longterm intellectual function. Methods and Materials: Twenty-one children with ALL manifesting an isolated CNS relapse between 1984 through 1989 underwent serial evaluations of intellectual function. Neurocognitive function was measured by the full-scale intelligence quotient (FSIQ) as determined by the age-appropriate Wechsler Intelligence Scale and by achievement in reading, math, and spelling as assessed by the Wide Range Achievement Test (WRAT). Intelligence testing was initiated following isolated CNS relapse after clearance of cerebrospinal fluid (CSF) cytology but prior to CSI and continued at annual intervals for a minimum of 4 years postmeningeal failure. Protocol treatment for isolated CNS relapse consisted of reinduction and maintenance systemic therapy, intrathecal (IT) triple-agent chemotherapy, and early CSI (cranium to 24 Gy and spine to 15 Gy at 1.5 Gy/fraction) as outlined on the institutional «Total XI» trial. Results: All 21 children attained secondary CNS remission and underwent the planned additional systemic/IT chemotherapy and CSI. Fourteen of the 21 children remain in secondary continuous remission, while the remaining 7 experienced a second relapse and were removed from further neurocognitive assessment. For the eight female and six male long-term survivors, mean ages at original diagnosis and at CSI were 5.7 years (range=0.6-16.2) and 7.0 years (range=1.8-17.0), respectively. At a median follow-up interval of 4.6 years (ranges 1.7-6.8) post-CNS relapse, comparison of group mean initial to final FSIQs revealed no statistically significant difference between the two measures (94.5 vs. 95.9, respectively, n=11, p=0.52). None of the children are functioning in the mentally retarded range. Final FSIQ outcome directly correlated with initial FSIQ (p=0.00005, p=11), age at diagnosis (p=0.009, n=14), and age at CSI (p=0.011, n=14). In addition, change between initial and final FSIQ scores inversely correlated with age at diagnosis (p=0.009) and age at CSI (p=0.018) but not with baseline IQ score (p=0.41). Initial FSIQ scores were not influenced by either age at diagnosis (p=0.12) or age at CSI (p=0.14). Final group mean (range) WRAT scores in reading, math, and spelling were measured to be 94.7 (68-132), 95.6 (69-126), and 93.7 (77-122), respectively (n=13). Final reading and math scores directly correlated with both age at diagnosis (p=0.01) and age at CSI (p=0.009). Spelling outcome did not correlate with either age at diagnosis (p=0.25) or age at CSI (p=0.24). Nine children are placed in regular classrooms, while the remaining five require a mixed classroom environment. Conclusion: In our study, children with ALL experiencing an isolated CNS relapse tolerated additional systemic/IT chemotherapy and CSI without apparent deterioration of group serial intellectual scores. However, longitudinal analyses of group intellectual measures obscured the independent impact of initial FSIQ, age at original diagnosis, and age at CSI upon individual neurocognitive outcome. Early and more intensive psychoeducational stimulation may be needed in very young children presenting with low initial FSIQ scores who are treated with CSI and additional chemotherapy following isolated CNS relapse in ALL

Investigated responses of siblings (N = 254) of children with cancer to structured interviews designed to elicit thoughts and feelings about effects of cancer on self and family. Siblings indicated distress about family separations and disruptions, lack of attention, focus of family on the ill child, negative feelings in themselves and family members, cancer treatments and their effects, and fear of death. Siblings also reported becoming more compassionate, families becoming closer, and having experiences they otherwise would not have had. Age and gender differences in responses indicated distinctive perceptions of and vulnerability to the cancer experience. Older siblings were far more likely to report positive effects than younger siblings suggesting that level of maturity can moderate the stress of an ill child within the family.

Eight infants with choroid plexus carcinomas were treated with surgery, prolonged postoperative chemotherapy and delayed radiation. The results suggest that some infants with choroid plexus carcinomas can be successfully treated with multimodality therapy, even allowing children with less than a gross total resection to have prolonged disease-free intervals.

Malignant pediatric tumors of the central nervous system (CNS) have a poor prognosis, with local failure rates as high as 50%. In an attempt to improve local tumor control, we used stereotactic interstitial therapy with 125I implants in patients with recurrent/secondary or newly diagnosed CNS malignancies. Catheters were placed using computed tomography (CT) guidance; computerized dosimetry was completed with the aid of orthogonal films. Implants delivered 1,000 cGy/day to the tumor periphery (0.5 cm beyond the boundary of enhancement on CT scans), to a total dose of 60 Gy. Hyperfractionated external beam irradiation (HEBI), started 2-4 weeks after removal of implants, delivered total doses of 66-70.4 Gy in 110-cGy fractions twice daily to a 3-cm margin around the implant volume. Eight of the 11 patients with newly diagnosed tumors also received 48.4 Gy HEBI to the craniospinal axis. Tumor regression was noted at 2 months after implantation in the 4 patients treated for recurrent/secondary tumors; local progression was subsequently documented in 2 cases at 6 and 20 months after implantation, while a third patient died 6 months after implantation with no evidence of local recurrence. The remaining recurrent/secondary tumor patient has no evidence of active recurrence 15 months after implantation. Local control was maintained in 9 of the 11 patients treated for primary tumors for a median of 27 months (range 15 to 48+ months). The two local failures occurred at 5 and 7 months after implantation. Six patients are alive without evidence of progressive disease (median = 23 months after implantation). There were no severe acute toxicities, but 7 patients later developed histologically confirmed tumor necrosis. Quality of life assessment (QLA) following initial primary therapy with implantation was evaluated utilizing an established criteria and found to be excellent with only one child showing marked QLA score decrease which was related to neurosurgical intervention for radiation-induced necrosis and dysfunctional family social situation. This small series suggests that stereotactic 125I implantation followed by HEBI merits further evaluation in selected children with supratentorial malignant lesions.

We investigated the epidemiology of pediatric anxiety and distress associated with magnetic resonance imaging procedures (MRIPs). Scores on the State-Trait Anxiety Inventory (Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983) and the State-Trait Anxiety Inventory for Children (Spielberger, Edwards, Lushene, Montuori, & Platzek, 1973), and subjective ratings of distress associated with MRIP were obtained from 55 pediatric oncology patients and their parents. Approximately 30% of children and their parents reported that MRIP produced significant distress. However, parents' ratings of their child's distress were significantly higher than children's self-ratings, and agreement between child and parent pairs was poor. Insertion of an intravenous line was identified as the most aversive component of MRIP by both parents (55%) and children (38%). The selective application of cognitive-behavioral interventions for noninvasive diagnostic procedures is suggested.

To establish the relationship between physical distress and depression, we assessed the severity of physical symptoms as well as depressive symptoms on the Children's Depression Inventory (CDI; Kovacs, 1983), a modified version of the CDI excluding physical symptoms (CDI-23), maternal reports on the Depression scale of the Child Behavior Checklist (Achenbach & Edelbrock, 1983), and maternal ratings twice within a 6-week interval among 92 children with cancer. Fewer than 10% of children ever exhibited symptomatology at or above threshold for diagnosis of mild depression. Approximately 40% of children displayed changes in severity of their depressive symptoms in the same direction as changes in severity of their physical symptoms. Children who were more vulnerable to continuing symptoms of depression following improvement in physical condition were correctly classified on the basis of their initial symptoms with 66% to 73% accuracy. These results can assist in discriminating children who may benefit from ps...

Summary Childhood ALL has provided the model for basic therapeutic principles in the past and now provides the model for late effects studies. Common threads which run throughout the literature in this area of clinical research are the importance of young age with increased vulnerability to long-term treatment induced sequelae and the relatively large contribution of radiation as compared with chemotherapy in the pathogenesis of adverse sequelae. Previous retrospective studies of long-term childhood ALL survivors focused on neuropsychologic changes and anatomic changes in the CNS after cranial irradiation. More recent retrospective studies have made the following new observations: (i) the high frequency of significant short adult stature in those less than 6 years of age at diagnosis who received 24 Gy cranial irradiation; (ii) actuarial risk of 2.5% of developing a second malignancy with approximately one-half of secondary malignancies occurring in the CNS in children 5 years of age or less who received cranial irradiation; (iii) the association of secondary ANLL with epipodophyllotoxin use, and (iv) delayed cardiac toxicity despite anthracycline dosage reduction. Current therapy regimens, especially in high-risk patients, are both more successful and more intensive than those used in the past. While it will be another decade before many of the long-term sequelae begin to emerge, one can anticipate, based on current experience, some of the problems that will occur.

PURPOSE To evaluate survival and neurodevelopmental outcomes following radiation therapy in infants and young children with residual or progressive medulloblastoma after primary chemotherapy. PATIENTS AND METHODS Thirteen young patients (< or = 36 months old) with medulloblastoma were treated with preirradiation multiagent chemotherapy and maximal surgical resection. Patients were scheduled to receive radiation therapy at the time of documented disease progression or upon completion of chemotherapy with residual disease. All patients underwent neurodevelopmental evaluation at the time of diagnosis, before receiving radiation therapy, and at yearly intervals posttreatment. RESULTS Two patients completed the scheduled chemotherapy with residual disease and received delayed radiation therapy. The remaining 11 patients had either local or leptomeningeal progression during chemotherapy (median time to progression, 5 months). Six patients had a complete response (CR) to radiation therapy, and three of these children are alive 48 to 104 months postdiagnosis. Of the five patients who had progressive disease (PD) during radiation therapy or residual imaging abnormalities after treatment, only one is alive (with stable enhancing leptomeningeal abnormalities) 48 months postirradiation. Two additional survivors were rendered disease-free by surgical resection before radiation therapy and are without evidence of disease at 91 and 107 months after diagnosis. Thus, six of 13 patients are alive at 48 to 107 months postdiagnosis. Neurodevelopmental scores tended to be below age norms at diagnosis; scores improved during chemotherapy, but then decreased during posttreatment follow-up evaluation. CONCLUSION Radiation therapy appears to produce long-term disease-free survival in a proportion of very young patients who have progressive or residual medulloblastoma during or after primary chemotherapy. However, neurodevelopmental deficits are frequent among long-term survivors.

In order to describe the status of long-term survivors of brain stem glioma, neuropsychological and behavioral measures were obtained a median of 2.5 (range 1.5-5.6) years after diagnosis from 16 survivors of 51 consecutively diagnosed children with brain stem glioma between 1983 and 1991. Among 11 children with dorsally exophytic tumors, 7 were treated with surgery alone (SRG) and 4 received conventionally fractionated local cranial radiation therapy (CFRT; 54-56 Gy) to the brain stem following surgery, 3 of these because of recurrent disease. Five others with diffusely infiltrative brain stem tumors received hyperfractionated radiation therapy (HFRT; 70.2 Gy) to the brain stem; 4 following biopsy or limited resection and 1 without prior surgery. IQs of children in the CFRT (mean 89, SD 24.4) and HFRT (mean 85, SD 12.7) groups were not significantly different. Children in the SRG group had significantly higher IQs (mean 100, SD 11.0) and fewer neurologic deficits than those who had received CFRT or HFRT. However, after statistically controlling for severity of neurologic deficits, treatment had no effect on IQ. The severity of residual neurologic deficits accounted for 42% of the variance in IQ scores; children with fewer neurologic problems scored higher. Additional studies are required to evaluate the potential neuropsychological benefits of equivalent total doses of HFRT compared to CFRT.

We prospectively studied the efficacy and adverse effects of chlorpromazine (30 mg/m2 given intravenously) plus lorazepam (0.04 mg/kg given intravenously) versus chlorpromazine alone in a controlled, double-blind, randomized, parallel-design investigation in 25 children (1.5 to 17.3 years of age) with acute lymphoblastic leukemia. Response to other antiemetics in eight children refusing random assignment to treatment was also evaluated. All children were receiving intravenous infusions of teniposide plus cytarabine, the pharmacokinetics of which were characterized for each of the one to four courses. There were no differences between the 11 patients randomly assigned to receive chlorpromazine alone and the 14 randomly assigned to receive lorazepam plus chlorpromazine in the number of emesis episodes (6.0 vs 5.9; p = 0.53), frequency of dystonic reactions (3% vs 5%), or akathisia (13 vs 10%). The only serious adverse event, symptomatic hypotension, occurred in a boy receiving chlorpromazine plus lorazepam. An exploratory pharmacodynamic analysis revealed that the only variable that correlated with vomiting was cytarabine 1 1/2-hour plasma concentration (p = 0.007). Children who received either chlorpromazine plus lorazepam or chlorpromazine alone had fewer episodes of vomiting than those who received "conventional" antiemetic therapy (6.0 vs 8.6; p = 0.01). We conclude that the severity of emesis is related to the plasma concentration of cytarabine; that intravenously administered chlorpromazine is as effective as chlorpromazine plus lorazepam in preventing chemotherapy-induced vomiting; and that the potential for adverse effects with the addition of lorazepam may be a disadvantage.