Pediatr Blood Cancer 2013;60:1022–1026 REVIEW Children’s Oncology Group’s 2013 Blueprint for Research: Central Nervous System Tumors Amar Gajjar, MD, 1 * Roger J. Packer, MD, 2y N.K. Foreman, MD, Ch.B, 3 Kenneth Cohen, MD, MBA, 4z Daphne Haas-Kogan, MD, 5§ and Thomas E. Merchant, DO, PhD 6k on behalf of the COG Brain Tumor Committee INTRODUCTION The landscape for pediatric brain tumor biology and treatment is undergoing a rapid transition as data from several studies are dis- covering key pathways and genetic changes that are critical for tumor initiation and maintenance. The key challenge for clinical investigators engaged in neuro-oncology research is to harness this information and design clinical protocols with novel agents that will seek to cure patients with CNS malignancies in childhood. STATE OF THE DISEASE—CLINICAL Medulloblastoma Overview and incidence. Medulloblastoma is the most com- mon malignant brain tumor in childhood [1]. Medulloblastoma can arise from infancy through adulthood, with a peak incidence occurring around 6 years of age. Approximately 400–450 new pediatric patients (infants to 21 years of age) with medulloblasto- ma are diagnosed annually in North America. Medulloblastoma is the most widely studied pediatric brain tumor, and clinical proto- cols from the European Union and North America have contrib- uted to major advances in the standard of care for patients with this disease. Staging/stratification. Current medulloblastoma protocols use a clinical-staging system that essentially separates children with standard-risk disease from those with high-risk disease based on whether metastatic (M 1–3 ) disease or residual tumor (1.5 cm 2 ) is present [2]. Tumor histology was recently introduced into the staging system, when patients with large cell/anaplastic histology were recognized as being at greater risk of disease relapse. Hence, medulloblastoma with large cell/anaplastic histology is now clas- sified as high-risk disease [3]. A growing body of literature indicates that medulloblastoma consists of at least four distinct molecular disease entities: WNT, Hedgehog (HH), Group 3, and Group 4 [4–7]. These molecular diseases have distinct clinical and molecular features and different cure rates. Patients with WNT tumors have the most favorable outcomes, even when they present with metastatic disease. Those with Group 3 tumors with large cell/anaplastic histology and MYCC/MYCN amplification have a dismal prognosis with current therapy. Children with HH or Group 4 tumors have an intermedi- ate prognosis [8]. Current outcome. Current therapy for medulloblastoma includes maximal safe surgical resection of the tumor, craniospi- nal irradiation (CSI) irradiation boost to the primary tumor bed for patients older than 3 years, and adjuvant chemotherapy. This approach cures more than 80% of patients with standard-risk disease. For standard-risk medulloblastoma, a systematic reduc- tion of CSI from 36 to 23.4 Gy and weekly vincristine treatments is also an effective approach that results in less impairment of long-term neuro-cognitive functioning in children younger than 8 years [9]. Adjuvant chemotherapy regimens consisting of either cisplatin/vincristine/CCNU or cisplatin/vincristine/cyclophospha- mide have resulted in excellent overall survival (OS) [10]. For patients with high-risk disease, data suggest that the addition of chemotherapy to higher-dose radiation (craniospinal dose of 36 Gy) and adjuvant chemotherapy may cure approximately 65% of patients [11]. In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to <10%. For children with medulloblastoma, the most common malignant brain tumor, 5-year survival ranges from >80% (standard-risk) to 60% (high-risk). For those with high-grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5-year survival remains <10%. Sixty-five percent patients with ependymoma are cured after surgery and radiation therapy depending on the degree of resection and histopathology of the tumor. Phase II trials for brain tumors will investigate agents that act on cMET, PDGFRA, or EZH2 in HGG, DIPG, or medulloblastoma, respectively. Phase III trials will explore risk-based therapy stratification guided by molecular and clinical traits of children with medulloblastoma or ependymoma. Pediatr Blood Cancer 2013;60:1022–1026. ß 2012 Wiley Periodicals, Inc. Key words: ependymoma; high-grade glioma and diffuse intrinsic pontine glioma; medulloblastoma 1 Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee; 2 Brain Tumor Institute, Children’s National, Washington, District of Columbia; 3 Department of Pediatrics, Univer- sity of Colorado, Denver; 4 Oncology and Pediatrics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; 5 Department of Radiation Oncology, Helen Diller Com- prehensive Cancer Center, San Francisco, California; 6 Department of Radiological Sciences, St. Jude Children’s Research Hospital, Mem- phis, Tennessee y Senior Vice-President, Neuroscience and Behavioral Medicine; Director. z Director, Pediatric Neuro-Oncology, Associate Professor, Oncology and Pediatrics. § Professor of Radiation Oncology and Neurological Surgery; Program Director and Vice Chair. k Division Chief, Radiation Oncology. *Correspondence to: Amar Gajjar, MD, Co-Chair and Member, De- partment of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105. E-mail: amar.gajjar@stjude.org Received 15 October 2012; Accepted 9 November 2012 ß 2012 Wiley Periodicals, Inc. DOI 10.1002/pbc.24427 Published online 19 December 2012 in Wiley Online Library (wileyonlinelibrary.com).