PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Arthur and Sonia Labatt Brain Tumour Research Centre Hospital for Sick Children Toronto Ontario Canada

Children's National Hospital Washington DC

Clinical Cooperation Unit Neuropathology German Cancer Research Center Heidelberg Germany

Department of Biostatistics St Jude Children's Research Hospital Memphis TN

Department of Developmental Neurobiology St Jude Children's Research Hospital Memphis TN

Department of Haematology and Oncology Royal Children's Hospital Parkville Victoria Australia

Department of Hematology and Oncology University Hospital Hamburg Eppendorf Hamburg Germany

Department of Hematology Oncology Children's Hospital of Minnesota Minneapolis MN

Department of Hematology Oncology Nemours Alfred 1 duPont Hospital for Children Wilmington DE

Department of Hematology Oncology Seattle Children's Hospital Seattle WA

Department of Neuro Oncology Russian Scientific Center of Radiology Moscow Russia

Department of Neurology Hospital de Santa Maria Lisbon Portugal

Department of Neuropathology NN Burdenko Neurosurgical Institute Moscow Russia

Department of Neuroradiology NN Burdenko Neurosurgical Institute Moscow Russia

Department of Neurosciences and Pediatrics University of California San Diego and Rady Children's Hospital San Diego CA

Department of Oncology St Jude Children's Research Hospital Memphis TN

Department of Pathology and Laboratory Medicine Division of Anatomical Pathology BC Children's Hospital Vancouver British Columbia Canada

Department of Pathology Dalhousie University Halifax Nova Scotia Canada

Department of Pathology Duke University Medical Center Durham NC

Department of Pathology St Jude Children's Research Hospital Memphis TN

Department of Pediatric Oncology Children's Hospital at Westmead Westmead New South Wales Australia

Department of Pediatric Oncology Lady Ciliento Children's Hospital South Brisbane Queensland Australia

Department of Pediatrics Division of Neurology BC Children's Hospital Vancouver British Columbia Canada

Department of Pediatrics Division of Oncology Cincinnati Children's Hospital Cincinnati OH

Department of Pediatrics Pediatric Neurology Oregon Health and Science University Portland OR

Department of Pediatrics Research Institute of the McGill University Health Center Montreal Québec Canada

Department of Pediatrics University Hospital Essen Essen Germany

Department of Radiation Oncology St Jude Children's Research Hospital Memphis TN

Department of Radiation Oncology University of Texas MD Anderson Cancer Center Houston TX

Departments of Neurology and Pediatrics Stanford University Palo Alto CA

Division of Haematology Oncology Hospital for Sick Children Toronto Ontario Canada

Division of Hematology Oncology Department of Pediatrics The Hospital for Sick Children University of Toronto Toronto Ontario Canada

Division of Neurology Centre Hospitalier Universitaire Sainte Justine Montreal Québec Canada

Division of Oncology Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia PA

Division of Pediatric Hematology and Oncology University of Texas Southwestern Medical Center Dallas TX

Division of Pediatric Hematology Oncology Children's Hospital of Los Angeles Los Angeles CA

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurosurgery Department of Surgery St Jude Children's Research Hospital Memphis TN

Graduate School of Biomedical Sciences St Jude Children's Research Hospital Memphis TN

Hopp Children's Cancer Center Heidelberg Germany

Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina Universidade de Lisboa Lisboa Portugal

Kid's Cancer Centre Sydney Children's Hospital and School of Woman's and Children's Health Sydney New South Wales Australia

Pediatric Glioma Research Group German Cancer Research Center Heidelberg Germany

Prague Brain Tumor Research Group Charles University and University Hospital Motol Prague Czech Republic

Preston Robert Tisch Brain Tumor Center Duke University Durham NC

Princess Maxima Center for Pediatric Oncology Utrecht the Netherlands

Research Center for Genetic Medicine Children's National Health System Washington DC

Texas Children's Cancer Center Baylor College of Medicine Houston TX

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Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial

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ClinicalTrials.gov
NCT00085202, NCT00602667