A comparative analysis of clinicopathological features and survival among early adolescents/young adults and children with low-grade glioma: a report from the Children's Oncology Group.

BACKGROUND: For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15-39 years old) versus children. This study compared clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs. METHODS: This was a secondary analysis of Children's Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0-21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0-14 years old) or early AYAs (eAYAs, 15-21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs. 19.2%; p = 0.015), without other significant differences in clinicopathological features. 5-year PFS rates for children and eAYA were 80.2% (95% confidence interval [95% CI], 76.1-83.7) and 83.0% (95% CI 68.8-91.1), respectively; 5-year OS rates were 97.3% (95% CI 95.2-98.5) and 95.4% (95% CI 82.7-98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (< 1.5 cm3, hazard ratio [HR] 5.93 [95% CI 3.45-10.18]) and (≥ 1.5 cm3, HR 8.38 [95% CI 4.75-14.79]) (p < 0.001), while midline-chiasmatic location (HR 9.69 [95% CI 3.05-30.75], p < 0.001) and non-pilocytic astrocytoma histology (HR 6.77 [95% CI 2.35-19.49], p < 0.001) were independent predictors of OS. CONCLUSION: Unlike several other cancers, LGG has similar presenting features and survival for both eAYAs and children. This support continuing a unified treatment approach and enrollment of eAYAs in pediatric clinical trials for LGGs.

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study.

BACKGROUND: p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children. METHODS: Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose. RESULTS: Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles. CONCLUSIONS: This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.

Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study.

PURPOSE: We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB. PATIENTS AND METHODS: After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m(2)/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B). RESULTS: In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m(2)/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome. CONCLUSION: The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy.

Health status in long-term survivors of pediatric craniopharyngiomas.

Craniopharyngiomas are the third most common pediatric brain tumor and most common pediatric suprasellar tumor. Contemporary treatment of craniopharyngiomas uses limited surgery and radiation in an effort to minimize morbidity, but the long-term health status of patients treated in this fashion has not been well described. The purpose of this study was to analyze the health status of long-term survivors of pediatric craniopharyngioma treated primarily with radiation and conservative surgical resection. Medical records of all long-term survivors of craniopharyngioma treated at St. Jude Children's Research Hospital and then transferred to the long-term follow-up clinic were reviewed. The initial cohort comprised 55 patients. Of these, 51 (93%) were alive at the time of this analysis. The median age at diagnosis was 7.1 years (range, 1.2-17.6 years), and 29 (57%) were male. At the time of analysis, the median survival was 7.6 years (range, 5.0-21.3 years). Diagnosis and treatment included surgical biopsy, resection (n = 50), and radiation therapy (n=48). Only 1 patient received chemotherapy. Polyendocrinopathy was the most common morbidity, with hypothyroidism (96%), adrenocorticotropic hormone deficiency (84%), and diabetes insipidus (53%) occurring most frequently. Half of the patients were hypogonadal, and 33 (65%) were overweight or obese. The most common neurologic problems included shunt dependence (37%), seizures (28%), and headaches (39%). Psychological and educational deficits were also identified in a significant number of these individuals. Despite efforts to reduce morbidity in these patients, many survivors remain burdened with significant medical complications. In a small percentage of patients, complications may result in death even during extended remission of craniopharyngioma. Because of the broad spectrum or morbidities experienced, survivors of craniopharyngioma continue to benefit from multidisciplinary care.

Continual reassessment method vs. traditional empirically based design: modifications motivated by Phase I trials in pediatric oncology by the Pediatric Brain Tumor Consortium.

In this article we provide additional support for the use of a model-based design in pediatric Phase I trials and present our modifications to the continual reassessment method (CRM), which were largely motivated by specific challenges we encountered in the context of the Pediatric Brain Tumor Consortium trials. We also summarize the results of our extensive simulations studying the operating characteristics of our modified approach and contrasting it to the empirically based traditional method (TM). Compared to the TM, our simulations indicate that the modified version of CRM is more accurate, exposes fewer patients to potentially toxic doses, and tends to require fewer patients. Further, the CRM-based MTD has a consistent definition across trials, which is important, especially in a consortium setting where multiple agents are being tested in studies that are often running simultaneously and accruing from the same patient population.

An operational perspective of challenging statistical dogma while establishing a modern, secure distributed data management and imaging transport system: the Pediatric Brain Tumor Consortium phase I experience.

The Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary central nervous system (CNS) tumors of childhood. The PBTC was created in 1999 to conduct early-phase studies in a rapid fashion in order to provide sound scientific foundation for the Children's Oncology Group to conduct definitive trials. The Operations and Biostatistics Center (OBC) of the PBTC is responsible for centrally administering study design and trial development, study conduct and monitoring, data collection and management as well as various regulatory and compliance processes. The phase I designs utilized for the consortium trials have accommodated challenges unique to pediatric trials such as body surface area (BSA)-based dosing in the absence of pediatric formulations of oral agents. Further during the past decade, the OBC has developed and implemented a state-of-the-art secure and efficient internet-based paperless distributed data management system. Additional web-based systems are also in place for tracking and distributing correlative study data as well as neuroimaging files. These systems enable effective communications among the members of the consortium and facilitate the conduct and timely reporting of multi-institutional early-phase clinical trials.

M1 Medulloblastoma: high risk at any age.

BACKGROUND: The prognosis for children with M1 medulloblastoma (positive CSF cytology) has not been well-defined. METHODS: We retrospectively reviewed the records of 285 newly diagnosed medulloblastoma patients treated between 1984 and 2006. Older children received post-operative craniospinal and tumor bed irradiation; radiotherapy for younger children depended on treatment era and physician/family preference. RESULTS: 55 patients were <3 years old and 230 patients were >or= 3 years old at diagnosis. We detected significant (P < 0.0001) associations between M1 disease and EFS for the entire cohort and for both younger and older patients. Among younger children, M1 patients had lower EFS than M0 (P = 0.0044). CONCLUSIONS: Children <3 years old with M1 medulloblastoma fared poorly in our small series. Survival for older children with M1 disease treated with higher-dose CSI was better than that of M2/M3 patients, but still less than optimal; our findings do not support reduction in therapy for either cohort.

Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium Study.

PURPOSE: A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. PATIENTS AND METHODS: Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. RESULTS: Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. CONCLUSION: Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

Seizures in children with low-grade tumors: outcome after tumor resection and risk factors for uncontrolled seizures.

OBJECT: The goals of this study were to define the incidence of seizures in children with low-grade tumors, study seizure outcome after lesionectomy in these children, and identify risk factors for poor seizure outcome. METHODS: The authors performed a retrospective chart review of children who harbored low-grade brain tumors, experienced seizures, and were treated in a single institution. Statistical analyses included step-wise as well as single-variable binary logistic regression analyses. Fifty-five children (20%) with seizures were identified in a cohort of 280 children with low-grade tumors. Of these 55 children, 35 harbored cortical cerebral tumors and 20 had noncortical lesions, including six whose tumors were in the posterior fossa. Seizures were defined as controlled if there was no seizure in the 12 months preceding the last clinic visit. All cortical tumors were treated by lesionectomy as an initial procedure. Of the 27 children with cortical tumors whose seizures began before tumor diagnosis, 23 had complete resection and 52% of these 23 experienced no further seizures after surgery. Seizures are presently controlled in 84% of the total 55 patients at a median follow-up time of 4.5 years after the first seizure (range 1-17.4 years). Only two variables, a pericavity hyperintense signal on T2-weighted magnetic resonance (MR) images and at least 10 seizures prior to therapy for seizures, were associated with uncontrolled seizures. CONCLUSIONS: Lesionectomy may be appropriate in children with low-grade brain tumors. A large number of seizures before therapy and a hyperintense area around the tumor cavity on postresection MR images are associated with uncontrolled seizures. Medical therapy and tumor resection will control seizures in the majority of children with low-grade tumors.

Seizure recurrence and risk factors after antiepilepsy drug withdrawal in children with brain tumors.

PURPOSE: To study seizure outcome after antiepilepsy drug (AED) withdrawal in brain tumor patients and to analyze risk factors for seizure recurrence. METHODS: Brain tumor patients with seizures and at least one attempt at AED discontinuation were identified from the hospital database and neurology clinic records. After defining study variables, patient charts were abstracted for clinical and demographic data. Statistical analyses used log-rank tests and multivariable Cox proportional hazards models. RESULTS: Sixty-two patients discontinued AEDs at a median time of 5.6 years from the first seizure (range, 1.2-19.6 years). Median time since AED withdrawal was 2.3 years (range, 0.4-15.1 years). Seizures recurred in 17 (27%) patients within a median time of 0.8 years (range, 0.06-7.7 years). Median seizure-free period before AED withdrawal was 1.3 years (range, 0.1-11 years). More than one tumor resection and whole-brain radiation treatment (WBRT) were associated with seizure recurrence, whereas posterior fossa tumor location was correlated with reduced seizure recurrence risk. At seizure recurrence, control was easily reestablished in 10 patients with AED reinstitution and after dose adjustment in five; two patients with poor drug compliance continue to have seizures. In 48 patients who had an EEG before AED withdrawal, spikes or slow waves did not correlate with seizure recurrence. CONCLUSIONS: AED withdrawal can be successfully achieved in majority of carefully selected patients. WBRT and multiple tumor resections seem to be associated with an increased hazard for seizure recurrence.