Jeff M Michalski1, Anna J Janss2, L Gilbert Vezina3, Kyle S Smith4, Catherine A Billups5, Peter C Burger6, Leanne M Embry7, Patricia L Cullen8, Kristina K Hardy9, Scott L Pomeroy10, Johnnie K Bass11, Stephanie M Perkins1, Thomas E Merchant12, Paul D Colte13, Thomas J Fitzgerald14, Timothy N Booth15, Joel M Cherlow16, Karin M Muraszko17, Jennifer Hadley4, Rahul Kumar4, Yuanyuan Han5, Nancy J Tarbell18, Maryam Fouladi19, Ian F Pollack20, Roger J Packer21, Yimei Li5, Amar Gajjar22, Paul A Northcott4. 1. Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO. 2. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA. 3. Division of Diagnostic Imaging and Radiology, Children's National Medical Center, Washington, DC. 4. Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN. 5. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN. 6. Department of Neuropathology, Johns Hopkins University, Baltimore, MD. 7. Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX. 8. Loretto Heights School of Nursing, Regis University, Denver, CO. 9. Division of Neuropsychology, Children's National Medical Center, Washington, DC. 10. Department of Neurology, Harvard Medical School, Boston, MA. 11. Department of Rehabilitation Services, St Jude's Children's Research Hospital, Memphis, TN. 12. Department of Radiation Oncology, St Jude's Children's Research Hospital, Memphis, TN. 13. Division of Hematology/Oncology/BMT, Primary Children's Hospital, Aurora, CO. 14. Image and Radiation Oncology Core-Rhode Island, Lincoln, RI. 15. Department of Radiology, UT Southwestern/Simmons Cancer Center, Dallas, TX. 16. Department of Radiation Oncology, Miller Children's and Women's Hospital Long Beach, Long Beach, CA. 17. Department of Neurosurgery, University of Michigan, Ann Arbor, MI. 18. Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA. 19. Department of Pediatrics, University of Cincinnati, Cincinnati, OH. 20. Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA. 21. Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, DC. 22. Department of Oncology, St Jude's Children's Research Hospital, Memphis, TN.
Abstract
PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
PURPOSE: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume. METHODS: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time. RESULTS: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm (P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS (P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021). CONCLUSION: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
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