Martin Mynarek1, Katja von Hoff1,2, Torsten Pietsch3, Holger Ottensmeier4, Monika Warmuth-Metz5, Brigitte Bison5, Stefan Pfister6,7,8, Andrey Korshunov9, Tanvi Sharma6,7,10, Natalie Jaeger6,7, Marina Ryzhova11, Olga Zheludkova12, Andrey Golanov13, Elisabeth Jane Rushing14, Martin Hasselblatt15, Arend Koch16, Ulrich Schüller1,17, Andreas von Deimling9, Felix Sahm6,9, Martin Sill6,7, Markus J Riemenschneider18, Hildegard Dohmen19, Camelia Maria Monoranu20, Clemens Sommer21, Ori Staszewski22, Christian Mawrin23, Jens Schittenhelm24, Wolfgang Brück25, Katharina Filipski26, Christian Hartmann27, Matthias Meinhardt28, Klaus Pietschmann29, Christine Haberler30, Irene Slavc31, Nicolas U Gerber32, Michael Grotzer32, Martin Benesch33, Paul Gerhardt Schlegel4, Frank Deinlein4, André O von Bueren34, Carsten Friedrich35, Björn-Ole Juhnke1, Denise Obrecht1, Gudrun Fleischhack36, Robert Kwiecien37, Andreas Faldum37, Rolf Dieter Kortmann38, Marcel Kool6,7, Stefan Rutkowski1. 1. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Department of Pediatric Oncology, Hematology and Stem Cell Transplantation, Charite - University Medical Center Berlin, Berlin, Germany. 3. Institute of Neuropathology, Brain Tumor Reference Center of the German Society for Neuropathology and Neuroanatomy, University of Bonn, German Center for Neurodegenerative Diseases, Bonn, Germany. 4. Department of Pediatric Hematology and Oncology, University Children's Hospital Wuerzburg, Wuerzburg, Germany. 5. Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany. 6. Hopp Children's Cancer Center at the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany. 7. Division of Pediatric Neurooncology (B062), German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany. 8. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. 9. Clinical Cooperation Unit Neuropathology, German Cancer Research Center; and Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany. 10. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 11. Department of Neuropathology, N. N. Burdenko Neurosurgical Institute, Moscow, Russia. 12. Department of Pediatric Oncology, Russian Scientific Center of Roentgenoradiology, Moscow, Russia. 13. Department of Stereotactic Radiotherapy and Radiosurgery, N. N. Burdenko National Medical Research Center of Neurosurgery, Moscow, Russia. 14. Institute of Neuropathology, University Medical Center Zurich, Zurich, Switzerland. 15. Institute of Neuropathology, University Hospital Muenster, Muenster, Germany. 16. Department of Neuropathology, Charite - University Medical Center Berlin, Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany. 17. Department of Neuropathology, University Medical Center Hamburg-Eppendorf; and Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. 18. Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany. 19. Institute for Neuropathology, University Hospital Gießen and Marburg, Gießen, Germany. 20. Institute of Pathology, Department of Neuropathology, University of Wuerzburg; and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany. 21. Institute for Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 22. Institute of Neuropathology and Berta-Ottenstein-Programme for Advanced Clinician Scientists, University of Freiburg, Freiburg, Germany. 23. Institute for Neuropathology, University of Magdeburg, Magdeburg, Germany. 24. Department of Neuropathology, Institute for Pathology and Neuropathology, University Medical Center Tuebingen, Tuebingen, Germany. 25. Institute for Neuropathology, University Medical Center Goettingen, Goettingen, Germany. 26. Institute of Neurology (Edinger Institute), University Hospital, Frankfurt Am Main; German Cancer Consortium, Partner Site Frankfurt/Mainz; and German Cancer Research Center, Heidelberg, Germany. 27. Department of Neuropathology, Institute for Pathology, Hannover Medical School, Hannover, Germany. 28. Institute for Pathology, University Medical Center Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 29. Department for Radiotherapy, Poliklinik Chemnitz, Chemnitz, Germany. 30. Institute of Neurology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 31. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 32. Department of Oncology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland. 33. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria. 34. Department of Pediatrics, Obstetrics and Gynecology, Division of Pediatric Hematology and Oncology, University Hospital of Geneva; and Department of Pediatrics, CANSEARCH Research Laboratory, University of Geneva, Geneva, Switzerland. 35. Division of Pediatric Oncology and Hematology, University Children's Hospital Rostock, Rostock, Germany. 36. Pediatric Hematology and Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany. 37. Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany. 38. Department of Radiation Oncology, University of Leipzig, Leipzig, Germany.
Abstract
PURPOSE: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.
PURPOSE: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.
Authors: David N Louis; Arie Perry; Pieter Wesseling; Daniel J Brat; Ian A Cree; Dominique Figarella-Branger; Cynthia Hawkins; H K Ng; Stefan M Pfister; Guido Reifenberger; Riccardo Soffietti; Andreas von Deimling; David W Ellison Journal: Neuro Oncol Date: 2021-08-02 Impact factor: 13.029