Emi Holmes

Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas: Evidence of Diminished Cognitive and Adaptive Functioning in National Collaborative Research Studies (CCG 9891/POG 9130)

PURPOSE Clinicians often assume that children with posterior fossa tumors are at minimal risk for cognitive or adaptive deficits if they do not undergo cranial irradiation. However, small case series have called that assumption into question, and have also suggested that nonirradiated cerebellar tumors can cause location-specific cognitive and adaptive impairment. This study (1) assessed whether resected but not irradiated pediatric cerebellar tumors are associated with cognitive and adaptive functioning deficits, and (2) examined the effect of tumor location and medical complications on cognitive and adaptive functioning. PATIENTS AND METHODS The sample was composed of 103 children aged 3 to 18 years with low-grade cerebellar astrocytomas, who underwent only surgical treatment as part of Childrens Cancer Group protocol 9891 or Pediatric Oncology Group protocol 9130. The sample was divided into three groups based on primary tumor location: vermis, left hemisphere, or right hemisphere. Data were collected prospectively on intelligence, academic achievement, adaptive skills, behavioral functioning, and pre-, peri-, and postsurgical medical complications. RESULTS The sample as a whole displayed an elevated risk for cognitive and adaptive impairment that was not associated consistently with medical complications. Within this group of children with cerebellar tumors, tumor location had little effect on cognitive, adaptive, or medical outcome. CONCLUSION We did not replicate previous findings of location-specific effects on cognitive or adaptive outcome. However, the elevated risk of deficits in this population runs contrary to clinical lore, and suggests that clinicians should attend to the functional outcomes of children who undergo only surgical treatment for cerebellar tumors.

Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961

The purpose of the trial was to determine the survival and incidence of secondary tumors in children with medulloblastoma receiving radiotherapy plus chemotherapy. Three hundred seventy-nine eligible patients with nondisseminated medulloblastoma between the ages of 3 and 21 years were treated with 2340 cGy of craniospinal and 5580 cGy of posterior fossa irradiation. Patients were randomized between postradiation cisplatin and vincristine plus either CCNU or cyclophosphamide. Survival, pattern of relapse, and occurrence of secondary tumors were assessed. Five- and 10-year event-free survivals were 81 ± 2% and 75.8 ± 2.3%; overall survivals were 87 ± 1.8% and 81.3 ± 2.1%. Event-free survival was not impacted by chemotherapeutic regimen, sex, race, age at diagnosis, or gender. Seven patients had disease relapse beyond 5 years after diagnosis; relapse was local in 4 patients, local plus supratentorial in 2, and supratentorial alone in 1. Fifteen patients experienced secondary tumors as a first event at a median time of 5.8 years after diagnosis (11 >5 y postdiagnosis). All non-CNS solid secondary tumors (4) occurred in regions that had received radiation. Of the 6 high-grade gliomas, 5 occurred >5 years postdiagnosis. The estimated cumulative 10-year incidence rate of secondary malignancies was 4.2% (1.9%-6.5%). Few patients with medulloblastoma will relapse ≥ 5 years postdiagnosis; relapse will occur predominantly at the primary tumor site. Patients are at risk for development of secondary tumors, many of which are malignant gliomas. This may become an increasing issue as more children survive.

Correlation of neurosurgical subspecialization with outcomes in children with malignant brain tumors.

OBJECTIVEThis study was performed to evaluate the association between the type of neurosurgeon (general or pediatric) and either the extent of tumor removal or the frequency of complications in children undergoing malignant brain tumor resections. METHODSData were analyzed from three recent Children’s Cancer Group studies: two on medulloblastomas/primitive neuroectodermal tumors and one on malignant gliomas. Neurosurgeons were classified as general neurosurgeons, as designated pediatric neurosurgeons in their institutions, or as members of the American Society of Pediatric Neurosurgeons (ASPN), which requires pediatric neurosurgical experience and practice standards. RESULTSData forms from 732 children were analyzed; 485 were from children with medulloblastomas/primitive neuroectodermal tumors, and 247 were from children with malignant gliomas. Operations were performed by 269 neurosurgeons, including 213 general neurosurgeons, 29 designated pediatric neurosurgeons, and 27 ASPN members. The mean number of operations per surgeon was 1.8, 4.9, and 7.6 for general neurosurgeons, designated pediatric neurosurgeons, and ASPN members, respectively. There was a significant relationship between the extent of tumor resection or the amount of residual tumor and the type of neurosurgeon. Designated pediatric neurosurgeons and ASPN members were more likely to remove more than 90% of the tumor and to leave less than 1.5 cc of residual tumor than were general neurosurgeons (P < 0.05). In these studies, the probability of extensive tumor removal correlated with the number of operations the neurosurgeon performed (P < 0.01). Neurological complications occurred in the following proportion of cases: general neurosurgeons, 23%; designated pediatric neurosurgeons, 32%; and ASPN members, 18%. CONCLUSIONPediatric neurosurgeons are more likely than general neurosurgeons to extensively remove malignant pediatric brain tumors. In these tumors, extent of removal has been demonstrated to influence survival.

Isochromosome 17q Is a Negative Prognostic Factor in Poor-Risk Childhood Medulloblastoma Patients

Background: Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome. Methods: DNA from 35 medulloblastoma patients from four Childrens Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses. Results: The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups. Conclusions: Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.

Preradiation Chemotherapy in Primary High-Risk Brainstem Tumors: Phase II Study CCG-9941 of the Children’s Cancer Group

PURPOSE This Childrens 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.

Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group.

This Phase II study was designed to determine response to chemotherapy and survival after response‐based radiation (RT) in children with CNS germ cell tumors.

A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study.

An open‐label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high‐grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG).

Cognitive and adaptive outcome in extracerebellar low-grade brain tumors in children: a report from the Children's Oncology Group.

PURPOSE To determine whether pediatric patients treated with surgery only for low-grade tumors in the cerebral hemispheres, supratentorial midline, and exophytic brainstem evidence neurocognitive, academic, adaptive, or emotional/behavioral sequelae. PATIENTS AND METHODS Ninety-three patients from a natural history study of low-grade astrocytomas were tested an average of 111 days after surgery. Rates of below average (< or = 25th percentile) scores in this sample were compared with test norms, and performances were compared across anatomic sites. Finally, the relationships of pre-, peri-, and postsurgical complications to outcome were investigated. RESULTS For the entire sample, there was a significantly elevated rate of below average scores across intelligence quotient, achievement, and adaptive behavior, but not behavioral/emotional adjustment measures. Patients with hemispheric, midline, and brainstem tumors did not differ significantly. Patients with left hemisphere tumors generally performed worse than those with right hemisphere tumors. Finally, neurobehavioral outcome was unrelated to pre-, peri-, or postsurgery complications. CONCLUSION After surgery for low-grade brain tumors, a significant number of patients was found to function below average, by as much as 55% compared with 25% in the normative population. Moreover, these results suggest greater risk for patients with lesions situated in the left cerebral hemisphere. Routine neuropsychological follow-up of children after treatment for low-grade tumors is recommended.

Phase II Study of High-Dose Chemotherapy Before Radiation in Children with Newly Diagnosed High- Grade Astrocytoma Final Analysis of Children's Cancer Group Study 9933

High‐grade astrocytomas (HGA) carry a dismal prognosis and compose nearly 20% of all childhood brain tumors. The role of high‐dose chemotherapy (HDCT) in the treatment of HGA remains unclear.

Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: A report from the Children's Oncology Group†

Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved‐field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre‐irradiation chemotherapy was investigated.