Alyssa T Reddy1, Douglas R Strother2, Alexander R Judkins3, Peter C Burger4, Ian F Pollack5, Mark D Krailo6, Allen B Buxton7, Chris Williams-Hughes7, Maryam Fouladi8, Anita Mahajan9, Thomas E Merchant10, Ben Ho11, Claire M Mazewski12, Victor A Lewis2, Amar Gajjar13, Louis-Gilbert Vezina14, Timothy N Booth15, Kerry W Parsons16, Vicky L Poss17, Tianni Zhou18, Jaclyn A Biegel3, Annie Huang19. 1. Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA. 2. Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 3. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA. 4. Department of Pathology, Johns Hopkins University, Baltimore, MD. 5. Department Neurosurgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA. 6. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA. 7. Children's Oncology Group, Monrovia, CA. 8. Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 9. Department of Radiation Oncology, Mayo Clinic, Rochester, MN. 10. Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN. 11. Department of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada. 12. Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA. 13. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN. 14. Department of Radiology, The George Washington University School Medicine and Health Sciences, Washington, DC. 15. Department of Radiology, University of Texas Southwestern, Dallas, TX. 16. AstraZeneca Pharmaceuticals, Cambridge, UK. 17. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL. 18. Department of Mathematics and Statistics, California State University at Long Beach, Long Beach, CA. 19. Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Abstract
PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
PURPOSE:Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
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