Russell Geyer

Prognostic Factors in Children with Supratentorial (Nonpineal) Primitive Neuroectodermal Tumors

Supratentorial primitive neuroectodermal tumors (S-PNETs), which have also been called cerebral neuroblastomas, have been considered to be the hemispheric equivalent of posterior fossa medulloblastomas. Twenty-seven children with S-PNETs (excluding pineoblastomas) which were confirmed by central pathology review were treated on the CCG-921 protocol from 1986 to 1992. After operation, all patients were staged with CSF cytology and spinal myelography or magnetic resonance scans and were treated with craniospinal irradiation and chemotherapy. Data from these 27 patients have been reviewed to evaluate neurosurgical treatment, survival, and prognostic variables that correlate with survival. Overall survival at 5 years was 34% (SE 20%) and progression-free survival (PFS) was 31% (SE 18%), which is lower than the survival of patients with posterior fossa PNETs (medulloblastomas). PFS was significantly worse in children 1.5-3 years of age at diagnosis and in those with evidence of tumor dissemination at the time of diagnosis. Large preoperative tumors were more likely to be associated with greater than 1.5 cm2 residual tumor postoperatively. Neurosurgeons estimated that less than 1.5 cm2 of residual tumor was present in 52% of the cases; postoperative scans confirmed that in 58%. For children with less than 1.5 cm2 residual tumor, postoperative survival at 4.0 years was 40% (SE 22%); for those with greater than 1.5 cm2 residual tumor, survival was 13% (SE 8%). The difference did not reach statistical significance, due to small numbers in this series, though a trend did exist (p = 0.19). Large series will be required to clarify the effects of extent of resection on survival.

Growth Hormone Replacement Therapy in Children With Medulloblastoma: Use and Effect on Tumor Control

PURPOSE Progress has been made in the treatment of medulloblastoma, the most common childhood malignant brain tumor: However, many long-term survivors will have posttherapy growth hormone insufficiency with resultant linear growth retardation. Growth hormone replacement therapy (GHRT) may significantly improve growth, but there is often reluctance to initiate GHRT because of concerns of an increased likelihood of tumor relapse. PATIENTS AND METHODS This study retrospectively reviewed the use of GHRT for survivors of medulloblastoma in 11 neuro-oncology centers in North America who received initial treatment for disease between 1980 and 1993 to determine its impact on disease control. A Landmark analysis was used to evaluate the relative risk of relapse in surviving patients. RESULTS Five hundred forty-five consecutive patients less than 15 years of age at diagnosis were identified. Six-year progression-free survival (mean +/- SD) was 40% +/- 5% in children less than 3 years of age at diagnosis compared with 59% +/- 3% for older patients. Older patients with total or near-total resections (P = .003) and localized disease at diagnosis (P < .0001) had the highest likelihood of survival. One hundred seventy patients (33% +/- 3% of the cohort) received GHRT. GHRT use varied widely among institutions, ranging from 5% to 73%. GHRT was begun a mean of 3.9 years after diagnosis, later in children younger than 3 years at diagnosis (5.4 years). By Landmark analyses, for those surviving 2, 3, and 5 years after diagnosis, there was no evidence that GHRT increased the rate of disease relapse. CONCLUSION This large retrospective review demonstrates that GHRT is underutilized in survivors of medulloblastoma and is used relatively late in the course of the illness. GHRT is not associated with an increased likelihood of disease relapse.

MRI as a central component of clinical trials analysis in brainstem glioma: a report from the Pediatric Brain Tumor Consortium (PBTC).

We report MRI findings from 2 pediatric clinical trials of diffuse intrinsic brainstem glioma (BSG) incorporating concurrent radiation therapy (RT) with molecularly targeted agents (gefitinib and tipifarnib). We determined associations of MRI variables with progression-free survival and overall survival and investigated effects of treatment on these variables. MRI (including diffusion and perfusion) was done before treatment, every 8 weeks (first year), every 12 weeks (thereafter), and at the end of treatment or disease progression. Reduced tumor volume (P < .0001) and tumor diffusion values (P <.0001) were apparent on the first post-RT/drug studies. Decreases in tumor volume correlated with pre-RT volume (P < .0001) and pre-RT diffusion values (P < .0001); larger decreases were noted for tumors with higher volumes and diffusion values. Patients with larger pre-RT tumors had longer progression-free survival (P < .0001). Patients with ≥ 25% decrease in tumor volume and diffusion values after RT had longer progression-free survival (P = .028) and overall survival (P = .0009). Enhancement at baseline and over time was significantly associated with shorter survival. Tumor diffusion values with baseline enhancement were significantly lower than those without (P = .0002). RT of BSG is associated with decreased tumor volume and intralesional diffusion values; patients with ≥ 25% decrease in values post-RT had relatively longer survival intervals, apparently providing an early imaging-based surrogate for relative outcomes. Patients with larger tumors and greater decreases in tumor volume and diffusion values had longer survival intervals. Tumor enhancement was associated with shorter survival, lower tumor diffusion values (increased cellularity), and a smaller drop in diffusion values after RT (P = .006). These associations justify continued investigation in other large clinical trials of brainstem glioma patients.

Psychosocial Adjustment in Long-Term Survivors of Childhood Medulloblastoma and Ependymoma Treated with Craniospinal Irradiation

Improved prognosis for pediatric brain tumors has stimulated research into the quality of life of survivors. To assess cognitive function and psychosocial and family adjustment among this population, 18 long-term survivors of childhood medulloblastoma or posterior fossa ependymoma treated with surgical resection and craniospinal irradiation were interviewed and administered achievement tests and psychosocial questionnaires. A majority of parents reported significant difficulty caring for their child with a brain tumor, but no significant adverse effects upon the family. Academic achievement was significantly impaired in 12/18 subjects. Psychosocial adjustment was normal in 10/18 subjects. Although specific treatment variables (radiation dosage, chemotherapy, etc.) were not significantly related to these two outcome measures, impaired academic achievement was correlated with young age at diagnosis (p < 0.05) and impaired psychosocial adjustment was correlated with greater time since diagnosis (p < 0.05). Overall quality of life reported by these individuals appears to be acceptable but neuropsychological and psychosocial examination is clearly indicated as part of the follow-up program.

Induction Chemotherapy and Conformal Radiation Therapy for Very Young Children With Nonmetastatic Medulloblastoma: Children's Oncology Group Study P9934

PURPOSE P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006. PATIENTS AND METHODS After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233). RESULTS Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT. CONCLUSION The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.

DTI assessment of the brainstem white matter tracts in pediatric BSG before and after therapy A report from the pediatric brain tumor consortium

PurposeTo assess changes in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in brainstem gliomas (BSG) in children and to observe the temporal evolution of changes in the white matter tracts following therapy using diffusion tensor imaging (DTI) analysis.MethodsSerial ADC and FA measurements were obtained in three patients with newly diagnosed BSG on two approved treatment protocols. Values were compared with a set of normative ADC, FA, and eigenvalues of age-matched children of the corticospinal, transverse pontine and medial lemniscal tracts. Fiber tracking of the tracts coursing through the brainstem was performed using standard diffusion tractography analysis.ResultsWe found increased ADC values within tumor at baseline compared to age-matched controls, with subsequent drop following treatment and subsequent increase with recurrence. Correspondingly, FA values were reduced at presentation, but transiently recovered during the phase of tumor response to treatment, and finally decreased significantly during tumor progression. These changes were concordant with the tractography analysis of white matter tracts in the brainstem. Based on these results, we suggest that initial changes in ADC and FA values reflects tract infiltration by tumor, but not complete disruption, whereas tumor progression results in complete loss of anisotropy possibly due to tract disruption.ConclusionSerial changes in ADC and FA values and tractography data in pediatric BSG suggest initial tumor infiltration, with transient improvement on treatment and subsequent loss of tract anisotropy during tumor progression. This technique may have potential use in assessing response to treatment regimens for pediatric BSG.

Childhood Optic Pathway Tumors Associated with Ascites following Ventriculoperitoneal Shunt Placement

Three children with optic pathway gliomas who developed ascites following ventriculoperitoneal shunt placement are presented. In all 3 cases there was an elevated cerebrospinal fluid (CSF) protein level at the time of initial shunt placement. At the time of developing ascites following placement of the ventriculoperitoneal shunt, none of the patients had evidence of infection or tumor seeding in the peritoneal cavity. The ascites completely resolved in each instance after converting the shunt to a ventriculoatrial system. Ascites following ventriculoperitoneal shunt insertion is an uncommon complication. A review of the literature and discussion of the possible etiologic factors in the development of ascites after ventriculoperitoneal shunt placement are presented. For patients diagnosed with optic gliomas, it is suggested that because the tumor is widely exposed to the CSF space, protein exuded by the mass into the subarachnoid space will cause an elevated CSF protein concentration. The elevated CSF protein may then lead to ascites as a result of poor absorption of CSF in the peritoneal cavity after placement of a ventriculoperitoneal shunt. Although ascites following ventriculoperitoneal shunt placement is not typical in patients with optic gliomas, attention should be given to CSF protein levels documented at the time of CSF diversion for hydrocephalus, recognizing that ascites may occur as a result of poor CSF absorption in the periotoneum, subsequently requiring a ventriculoatrial shunt in patients who develop hydrocephalus.

Choroid Plexus Carcinoma of the Fourth Ventricle

An 8-month-old female infant with choroid plexus carcinoma presenting in the fourth ventricle is described. The patient was initially treated with combination chemotherapy due to her young age, but de

Incidence of Postoperative Epilepsy in Children following Subfrontal Craniotomy for Tumor

Thirty-one children who underwent 36 subfrontal craniotomies were retrospectively studied to determine the incidence of postoperative epilepsy and the effectiveness of antiepileptic drugs for seizure prophylaxis. The incidence of postoperative epilepsy following a subfrontal craniotomy did not exceed 12% when examined at various time periods during a 3-year postoperative course. Antiepileptic drugs were not warranted to reduce the incidence of postoperative seizures after the 1-month postoperative period and should not be used for long-term prophylactic therapy in children following a subfrontal craniotomy.

The effect of age on the latency of radiation myelopathy.

SummaryThe latent period to forelimb paresis following photon irradiation of the cervical spinal cord was evaluated in Sprague-Dawley rats ranging in age from 9 days to adulthood. The radiation was administered dorsally in single fractions, and in 15-day-old animals, to different lengths of the rostral cord and in doses ranging from 16 to 38 Gy. The duration of the latent period was found to be directly proportional to the age of the animal at the time of irradiation, and independent of radiation dose or the volume of the cervical cord which was irradiated. In the majority of paretic animals, the irradiated segment of the spinal cord demonstrated white matter necrosis. The results indicate that in the developing rat, the manifestations of radiation myelopathy are delayed by an interval determined in part by the age of the animal at the time of irradiation.