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Background: The objectives of the current study were to determine the outcome of children who were treated with chemotherapy and radiotherapy on the Children's Cancer Group (CCG) high-grade glioma protocol (CCG-945) who were diagnosed with low-grade gliomas on post hoc central pathologic review and to identify clinical and biologic features associated with prognosis., Methods: Between 1985 and 1991, 250 children with institutionally classified high-grade gliomas were enrolled on CCG-945. Patients older than 24 months with intracranial lesions were assigned randomly to receive either lomustine, vincristine, and prednisone (control regimen) or the 8-drugs-in-1-day regimen (experimental regimen); younger patients and those with primary spinal cord tumors were assigned nonrandomly to the experimental regimen. Central independent review by 5 neuropathologists led to a reclassification of low-grade glioma in 70 patients, who were the focus of the current study., Results: The study involved 42 males and 28 females (median age, 7.7 years) with a median follow-up of 10.4 years. At 5 years, the progression-free survival (PFS) rate was 63% +/- 6%, and the overall survival (OS) rate was 79% +/- 5%, compared with a PFS rate of 19% +/- 3% (P < 0.0001) and an OS rate of 22% +/- 3% (P < 0.0001) in the remainder of the cohort. Significantly poorer 5-year PFS was seen in children younger than 24 months, those with fibrillary astrocytoma, and those with posterior fossa tumors. Patients demonstrated a modest improvement in PFS but no improvement in OS compared with children with low-grade gliomas who were treated with contemporary chemotherapy-alone approaches., Conclusions: The current report calls attention to the importance of central pathologic review in large multiinstitutional trials of children with gliomas and suggests that aggressive front-line combined chemoradiotherapy does not confer a survival advantage in this highly selected population of patients., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11637)

We investigated the variation in the uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) gene in patients receiving patient-controlled analgesia with morphine. UGT2B7 was sequenced in phenotypic extremes (n = 12) of the distribution of morphine-6-glucuronide/morphine plasma ratios. A new -161C/T promoter variant was in complete linkage disequilibrium with the 802C/T variant and was more frequent in low glucuronidators (P =.039). Both variants were genotyped in all patients (n = 86), and complete linkage disequilibrium was confirmed. Trend analysis showed reduced morphine-6-glucuronide/morphine ratios in patients with T/T, C/T, and C/C genotypes (T/T > C/T > C/C) (P =.031). Morphine levels were lower in T/T patients (median, 18 ng/mL [range, 18-1490 ng/mL]) as compared with C/T and C/C patients combined (median, 66 ng/m; range, 18-3995 ng/mL) (P =.04). Morphine-6-glucuronide and morphine-3-glucuronide concentrations were significantly lower in C/C patients (median, 18 ng/mL; range, 0-66 ng/mL; and median, 152 ng/mL; range, 30-434 ng/mL; respectively) compared with C/T and T/T patients combined (median, 43 ng/mL; range, 0-193 ng/mL; and median, 242 ng/mL; range, 33-1381 ng/mL; respectively) (P =.045 and P =.004, respectively). Interindividual differences in morphine glucuronidation may be the result of genetic variation in UGT2B7, and further studies are indicated.

Event-free survival for children with acute lymphoblastic leukemia (ALL) now exceeds 80% in the most effective trials. Failures are due to relapse, toxicity, and second cancers such as therapy-related myeloid leukemia or myelodysplasia (t-ML). Topoisomerase II inhibitors and alkylators can induce t-ML; additional risk factors for t-ML remain poorly defined. The occurrence of t-ML among children who had received granulocyte colony-stimulating factor (G-CSF) following ALL remission induction therapy prompted us to examine this and other putative risk factors for t-ML in 412 children treated on 2 consecutive ALL protocols from 1991 to 1998. All children received etoposide and anthracyclines, 99 of whom received G-CSF; 284 also received cyclophosphamide, 58 of whom also received cranial irradiation. There were 20 children who developed t-ML at a median of 2.3 years (range, 1.0-6.0 years), including 16 cases of acute myeloid leukemia, 3 myelodysplasia, and 1 chronic myeloid leukemia. Stratifying by protocol, the cumulative incidence functions differed (P =.017) according to the use of G-CSF and irradiation: 6-year cumulative incidence (standard error) of t-ML of 12.3% (5.3%) among the 44 children who received irradiation without G-CSF, 11.0% (3.5%) among the 85 children who received G-CSF but no irradiation, 7.1% (7.2%) among the 14 children who received irradiation plus G-CSF, and 2.7% (1.3%) among the 269 children who received neither irradiation nor G-CSF. Even when children receiving irradiation were excluded, the incidence was still higher in those receiving G-CSF (P =.019). In the setting of intensive antileukemic therapy, short-term use of G-CSF may increase the risk of t-ML.

Purpose: To study the effectiveness of combined chemotherapy and radiotherapy for children with high-grade astrocytomas of the posterior fossa., Patients and Methods: In the CCG-945 study, 250 patients were treated by members of the Children's Cancer Group (CCG). Sixteen children were randomly assigned to one of two chemotherapy regimens, vincristine, lomustine, and prednisone or '8-in-1', using the same involved-field irradiation in both. Six infants received 8-in-1 chemotherapy before involved-field irradiation. All pathologic specimens had central review., Results: Twenty-two patients with an institutional diagnosis high-grade posterior fossa tumors received chemotherapy and/or irradiation. Fifteen were confirmed by central review to have high-grade gliomas. Overall survival for confirmed high-grade astrocytoma of the posterior fossa was approximately 36 +/- 13% at 5 years for the children (n = 11) and 25 +/- 15% at 5 years for the infants (n = 4)., Conclusions: Involved-field irradiation with chemotherapy appeared to prevent extraneural and subarachnoid metastases. We also confirmed the rarity of the tumor (6% of patients registered). Further Phase III trials are necessary to improve survival in this aggressive tumor.

Purpose: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL)., Patients and Methods: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy., Results: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for

Purpose: This Children's Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT)., Patients and Methods: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy., Results: Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course., Conclusion: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Objective: Prognoses of pediatric high-grade gliomas are unpredictable, even when clinical and histological factors are taken into account. In preliminary studies with an institutional cohort of pediatric high-grade gliomas, we observed a strong association between outcome and proliferation index, as assessed by immunolabeling with the MIB-1 antibody. To determine whether this marker could provide prognostically useful information independent of tumor histology, we examined the prognostic usefulness of this marker in the multi-institutional cohort of Children's Cancer Group Study 945, the largest group of childhood high-grade gliomas analyzed to date., Methods: The study group consisted of tumors within this cohort that were classified as high-grade gliomas on central review according to contemporary World Health Organization guidelines and that had sufficient histopathological material to permit proliferation index assessment. Paraffin-embedded sections were cut and processed, microwave antigen enhancement was used, and MIB-1 indices were calculated by percent labeling in approximately 2000 cells (5-10 high-power fields) in the areas with greatest labeling. To ensure that the review diagnostic classification and proliferation labeling index were assigned independently for each tumor, these analyses were performed by two different neuropathologists at separate institutions, and each was blinded to the results of the other., Results: Ninety-eight tumors met eligibility criteria for this study. Among these high-grade gliomas, there was a strong association between MIB-1 labeling and patient outcome: 5-year progression-free survival was 33 +/- 7% in 43 patients whose tumors had MIB-1 indices of less than 18%, 22 +/- 8% in the 27 patients whose tumors had indices between 18 and 36%, and 11 +/- 6% in the 28 patients whose tumors had indices greater than 36% (P = 0.003). As anticipated, a strong association was also observed between histology and MIB-1 labeling index in these cases. Mean labeling indices were 19.4 +/- 2.66 for tumors classified as anaplastic astrocytoma versus 32.1 +/- 3.08 for those classified as glioblastoma multiforme (P = 0.0024). Notwithstanding this correlation, a significant association was noted between labeling index and progression-free survival, even after the analysis had been stratified by histology (P = 0.001). Although histology had an independent association with outcome, the prognostic value of MIB-1 labeling transcended histological subgrouping and was apparent both in tumors classified as anaplastic astrocytoma (P = 0.02) and in those classified as glioblastoma multiforme (P = 0.046). Multivariate regression modeling confirmed the strong independent association between MIB-1 labeling index and outcome. As a group, tumors with labeling indices higher than 36% had an almost uniformly poor outcome, regardless of histology., Conclusion: MIB-1 labeling index and histological categorization are each prognostically relevant in childhood high-grade gliomas. MIB-1 labeling index can help to refine the accuracy of histologically based prognostic assessments.

This article examines the impact of four policy changes made to a State children's health insurance program (SCHIP) as it transitioned to Title XXI on program disenrollment and re-enrollment. The changes were: (1) expanded eligibility criteria, (2) reduction in the family share of the premium, (3) expansion of the mental health benefit, and (4) implementation of a 60-day wait period to re-enrollment in the program for children who involuntarily disenrolled due in non-payment of premium. Disenrollment was reduced by 20 percent after the changes were implemented. Disenrollment and re-enrollment rates varied significantly based on the child's health and family income.