Development of Randomized Trials in Adults with Medulloblastoma—The Example of EORTC 1634-BTG/NOA-23

Author:

Hau Peter12ORCID,Frappaz Didier3,Hovey Elizabeth45ORCID,McCabe Martin G.6ORCID,Pajtler Kristian W.78,Wiestler Benedikt9ORCID,Seidel Clemens10,Combs Stephanie E.11,Dirven Linda1213,Klein Martin1415,Anazodo Antoinette51617ORCID,Hattingen Elke18ORCID,Hofer Silvia19,Pfister Stefan M.78,Zimmer Claus9,Kortmann Rolf-Dieter10,Sunyach Marie-Pierre20,Tanguy Ronan20,Effeney Rachel21,von Deimling Andreas2223,Sahm Felix2223,Rutkowski Stefan24,Berghoff Anna S.25,Franceschi Enrico26ORCID,Pineda Estela27ORCID,Beier Dagmar28ORCID,Peeters Ellen29,Gorlia Thierry29,Vanlancker Maureen29,Bromberg Jacoline E. C.30,Gautier Julien31,Ziegler David S.161732ORCID,Preusser Matthias25,Wick Wolfgang3334,Weller Michael19ORCID

Affiliation:

1. Wilhelm Sander-NeuroOncology Unit, Regensburg University Hospital, 93053 Regensburg, Germany

2. Department of Neurology, Regensburg University Hospital, 93053 Regensburg, Germany

3. Neuro-Oncology Unit, Centre Léon Bérard, 69008 Lyon, France

4. Department of Medical Oncology, Sydney 2052, Australia

5. Nelune Comprehensive Cancer Centre, Prince of Wales Cancer Centre, Sydney 2031, Australia

6. Faculty of Medicine, Biology and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M20 4GJ, UK

7. Hopp-Children’s Cancer Center Heidelberg (KiTZ), Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

8. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany

9. Department of Diagnostic and Interventional Neuroradiology, Klinikum Rechts der Isar der Technischen Universität München, TUM School of Medicine, 81675 Munich, Germany

10. Department of Radiation-Oncology, University Hospital Leipzig, 04103 Leipzig, Germany

11. Department of Radiation Oncology, Klinikum Rechts der Isar der Technischen Universität München, TUM School of Medicine, 81675 Munich, Germany

12. Department of Neurology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

13. Department of Neurology, Haaglanden Medical Center, 2501 CK The Hague, The Netherlands

14. Department of Medical Psychology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands

15. Brain Tumor Center Amsterdam at Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands

16. Kids Cancer Centre, Sydney Children’s Hospital, Sydney 2031, Australia

17. School of Women’s and Children’s Health, University of New South Wales, Sydney 2031, Australia

18. Department of Neuroradiology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt, Germany

19. Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland

20. Department of Radiation Oncology, Centre Leon Berard, 69008 Lyon, France

21. Department of Radiation Oncology, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia

22. Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany

23. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research, 69120 Heidelberg, Germany

24. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

25. Division of Oncology, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria

26. Medical Oncology Department, Azienda USL/IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy

27. Barcelona Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Department of Medical Oncology, Hospital Clinic Barcelona, 08036 Barcelona, Spain

28. Department of Neurology, Odense University Hospital, DK-5000 Odense, Denmark

29. EORTC Headquarters, 1200 Brussels, Belgium

30. Erasmus Medical Center Cancer Institute, Department of Neuro-Oncology, 3015 GD Rotterdam, The Netherlands

31. Clinical Research Department, Centre Léon Bérard, 69008 Lyon, France

32. Children’s Cancer Institute, University of New South Wales, Sydney 2031, Australia

33. Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany

34. Clinical Cooperation Unit Neuro-Oncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research, 69120 Heidelberg, Germany

Abstract

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.

Funder

Deutsche Krebshilfe

Cancer Australia

CanTeen

KWF Kankerbestrijding

Ministère des Affaires Sociales et de la Santé

Swiss Brain Tumor Foundation

EORTC Brain Tumor Group

Sun Pharmaceuticals Industries Ltd.

Publisher

MDPI AG

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