Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort-Reference-Cited by-同舟云学术

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort

Published:2020-06-20 Issue:18 Volume:38 Page:2028-2040
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Mynarek Martin¹,von Hoff Katja¹²,Pietsch Torsten³,Ottensmeier Holger⁴,Warmuth-Metz Monika⁵,Bison Brigitte⁵,Pfister Stefan⁶⁷⁸,Korshunov Andrey⁹,Sharma Tanvi⁶⁷¹⁰,Jaeger Natalie⁶⁷,Ryzhova Marina¹¹,Zheludkova Olga¹²,Golanov Andrey¹³,Rushing Elisabeth Jane¹⁴,Hasselblatt Martin¹⁵,Koch Arend¹⁶,Schüller Ulrich¹¹⁷,von Deimling Andreas⁹,Sahm Felix⁶⁹,Sill Martin⁶⁷,Riemenschneider Markus J.¹⁸,Dohmen Hildegard¹⁹,Monoranu Camelia Maria²⁰,Sommer Clemens²¹,Staszewski Ori²²,Mawrin Christian²³,Schittenhelm Jens²⁴,Brück Wolfgang²⁵,Filipski Katharina²⁶,Hartmann Christian²⁷,Meinhardt Matthias²⁸,Pietschmann Klaus²⁹,Haberler Christine³⁰,Slavc Irene³¹,Gerber Nicolas U.³²,Grotzer Michael³²,Benesch Martin³³,Schlegel Paul Gerhardt⁴,Deinlein Frank⁴,von Bueren André O.³⁴,Friedrich Carsten³⁵,Juhnke Björn-Ole¹,Obrecht Denise¹,Fleischhack Gudrun³⁶,Kwiecien Robert³⁷,Faldum Andreas³⁷,Kortmann Rolf Dieter³⁸,Kool Marcel⁶⁷,Rutkowski Stefan¹

Affiliation:

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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.19.03057

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