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Nonmetastatic medulloblastoma of early childhood: results from the prospective clinical trial HIT-2000 and an extended validation cohort

PURPOSEThe 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 METHODSFrom 2001-2011, 87 patie...

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Main Authors: Mynarek, Martin (Author) , Hoff, Katja von (Author) , Pietsch, Torsten (Author) , Ottensmeier, Holger (Author) , Warmuth-Metz, Monika (Author) , Bison, Brigitte (Author) , Pfister, Stefan (Author) , Korshunov, Andrey (Author) , Sharma, Tanvi (Author) , Jäger, Natalie (Author) , Ryzhova, Marina (Author) , Zheludkova, Olga (Author) , Golanov, Andrey (Author) , Rushing, Elisabeth Jane (Author) , Hasselblatt, Martin (Author) , Koch, Arend Wolfgang (Author) , Schüller, Ulrich (Author) , Deimling, Andreas von (Author) , Sahm, Felix (Author) , Sill, Martin (Author) , Riemenschneider, Markus Johannes (Author) , Dohmen, Hildegard (Author) , Monoranu, Camelia Maria (Author) , Sommer, Clemens (Author) , Staszewski, Ori (Author) , Mawrin, Christian (Author) , Schittenhelm, Jens Florian (Author) , Brück, Wolfgang (Author) , Filipski, Katharina Johanna (Author) , Hartmann, Christian (Author) , Meinhardt, Matthias (Author) , Pietschmann, Klaus (Author) , Haberler, Christine (Author) , Slavc, Irene (Author) , Gerber, Nicolas U. (Author) , Grotzer, Michael (Author) , Benesch, Martin (Author) , Schlegel, Paul-Gerhardt (Author) , Deinlein, Frank (Author) , Bueren, André von (Author) , Friedrich, Carsten (Author) , Juhnke, Björn-Ole (Author) , Obrecht, Denise (Author) , Fleischhack, Gudrun (Author) , Kwiecien, Robert (Author) , Faldum, Andreas (Author) , Kortmann, Rolf-Dieter (Author) , Kool, Marcel (Author) , Rutkowski, Stefan (Author)
Format: Article (Journal)
Language:English
Published: April 24, 2020
In: Journal of clinical oncology
Year: 2020, Volume: 38, Issue: 18, Pages: 2028-2040
ISSN:1527-7755
DOI:10.1200/JCO.19.03057
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1200/JCO.19.03057
Verlag, lizenzpflichtig, Volltext: https://ascopubs.org/doi/10.1200/JCO.19.03057
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Author Notes:Martin Mynarek, MD; Katja von Hoff, MD; Torsten Pietsch, MD; Holger Ottensmeier, PhD; Monika Warmuth-Metz, MD; Brigitte Bison, MD; Stefan Pfister, MD; Andrey Korshunov, MD, PhD; Tanvi Sharma, MSc; Natalie Jaeger, PhD;Marina Ryzhova, MD, PhD; Olga Zheludkova, PhD, MD; Andrey Golanov, PhD, MD; Elisabeth Jane Rushing, MD;Martin Hasselblatt, MD; Arend Koch, MD; Ulrich Schüller, MD; Andreas von Deimling, MD; Felix Sahm, MD; Martin Sill, PhD; Markus J. Riemenschneider, MD; Hildegard Dohmen, MD; Camelia Maria Monoranu, MD; Clemens Sommer, MD;Ori Staszewski, MD; Christian Mawrin, MD; Jens Schittenhelm, MD; Wolfgang Brück, MD; Katharina Filipski, MD;Christian Hartmann, MD; Matthias Meinhardt, MD; Klaus Pietschmann, MD; Christine Haberler, MD; Irene Slavc, MD; Nicolas U. Gerber, MD; Michael Grotzer, MD; Martin Benesch, MD; Paul Gerhardt Schlegel, MD; Frank Deinlein, MD; André O. von Bueren, MD, PhD; Carsten Friedrich, MD; Björn-Ole Juhnke, MD; Denise Obrecht, MD; Gudrun Fleischhack, MD; Robert Kwiecien, PhD; Andreas Faldum, PhD; Rolf Dieter Kortmann, MD; Marcel Kool, PhD; and Stefan Rutkowski, MD

MARC

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245 1 0 |a Nonmetastatic medulloblastoma of early childhood  |b results from the prospective clinical trial HIT-2000 and an extended validation cohort  |c Martin Mynarek, MD; Katja von Hoff, MD; Torsten Pietsch, MD; Holger Ottensmeier, PhD; Monika Warmuth-Metz, MD; Brigitte Bison, MD; Stefan Pfister, MD; Andrey Korshunov, MD, PhD; Tanvi Sharma, MSc; Natalie Jaeger, PhD;Marina Ryzhova, MD, PhD; Olga Zheludkova, PhD, MD; Andrey Golanov, PhD, MD; Elisabeth Jane Rushing, MD;Martin Hasselblatt, MD; Arend Koch, MD; Ulrich Schüller, MD; Andreas von Deimling, MD; Felix Sahm, MD; Martin Sill, PhD; Markus J. Riemenschneider, MD; Hildegard Dohmen, MD; Camelia Maria Monoranu, MD; Clemens Sommer, MD;Ori Staszewski, MD; Christian Mawrin, MD; Jens Schittenhelm, MD; Wolfgang Brück, MD; Katharina Filipski, MD;Christian Hartmann, MD; Matthias Meinhardt, MD; Klaus Pietschmann, MD; Christine Haberler, MD; Irene Slavc, MD; Nicolas U. Gerber, MD; Michael Grotzer, MD; Martin Benesch, MD; Paul Gerhardt Schlegel, MD; Frank Deinlein, MD; André O. von Bueren, MD, PhD; Carsten Friedrich, MD; Björn-Ole Juhnke, MD; Denise Obrecht, MD; Gudrun Fleischhack, MD; Robert Kwiecien, PhD; Andreas Faldum, PhD; Rolf Dieter Kortmann, MD; Marcel Kool, PhD; and Stefan Rutkowski, MD 
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520 |a PURPOSEThe 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 METHODSFrom 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.RESULTSFive 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).CONCLUSIONSystemic 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. 
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Gerber, MD; Michael Grotzer, MD; Martin Benesch, MD; Paul Gerhardt Schlegel, MD; Frank Deinlein, MD; André O. von Bueren, MD, PhD; Carsten Friedrich, MD; Björn-Ole Juhnke, MD; Denise Obrecht, MD; Gudrun Fleischhack, MD; Robert Kwiecien, PhD; Andreas Faldum, PhD; Rolf Dieter Kortmann, MD; Marcel Kool, PhD; and Stefan Rutkowski, MD"]},"id":{"eki":["1733648607"],"doi":["10.1200/JCO.19.03057"]},"physDesc":[{"extent":"13 S."}],"relHost":[{"pubHistory":["1.1983 -"],"part":{"issue":"18","extent":"13","pages":"2028-2040","year":"2020","text":"38(2020), 18, Seite 2028-2040","volume":"38"},"language":["eng"],"title":[{"subtitle":"JCO : an American Society of Clinical Oncology journal","title":"Journal of clinical oncology","title_sort":"Journal of clinical oncology"}],"note":["Fortsetzung der Druck-Ausgabe","Gesehen am 22.05.23"],"corporate":[{"display":"American Society of Clinical Oncology","role":"isb"}],"physDesc":[{"extent":"Online-Ressource"}],"disp":"Nonmetastatic medulloblastoma of early childhood results from the prospective clinical trial HIT-2000 and an extended validation cohortJournal of clinical oncology","id":{"zdb":["2005181-5"],"issn":["1527-7755"],"eki":["313116962"]},"recId":"313116962","origin":[{"publisherPlace":"Alexandria, Va. ; Baltimore, Md. 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SRT |a MYNAREKMARNONMETASTA2420 

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