Dagmar Beier1,2, Martin Proescholdt3, Christiane Reinert4, Torsten Pietsch5, David T W Jones6, Stefan M Pfister6,7, Elke Hattingen8, Clemens Seidel9, Linda Dirven10, Ralf Luerding4, Jaap Reijneveld11, Monika Warmuth-Metz12, Matteo Bonsanto13,14, Michael Bremer, Stephanie E Combs15,16, Stefan Rieken15, Ulrich Herrlinger17, Holger Kuntze18, Regine Mayer-Steinacker19, Dag Moskopp20, Thomas Schneider21, Andreas Beringer22, Uwe Schlegel23, Walter Stummer24, Helmut Welker25, Astrid Weyerbrock22, Frank Paulsen26, Stefan Rutkowski27, Michael Weller28, Wolfgang Wick29, Rolf-Dieter Kortmann9, Ulrich Bogdahn4, Peter Hau4. 1. Department of Neurology, University Hospital Odense and Clinical Institute, University of Southern Denmark, Odense, Denmark. 2. Department of Neurology, University of Regensburg, Regensburg, Germany. 3. Department of Neurosurgery, University Hospital Regensburg, Regensburg, Germany. 4. Wilhelm Sander Neuro-Oncology Unit and Department of Neurology, University of Regensburg, Regensburg, Germany. 5. Institute of Neuropathology, Brain Tumor Reference Center of the Society for Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany. 6. Division of Pediatric Neuro-oncology, German Cancer Research Center, Heidelberg, Germany. 7. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. 8. Department of Radiology, Neuroradiology, University Hospital Bonn, Bonn, Germany. 9. Department of Radiotherapy and Radio-oncology, University Hospital Leipzig, Leipzig, Germany. 10. Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands. 11. Brain Tumor Center Amsterdam and Department of Neurology, VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands. 12. Department of Neuroradiology, University Hospital Würzburg, Würzburg, Germany. 13. Department of Neurosurgery, University Hospital, Lübeck, Germany. 14. Department of Radiation Oncology, Medical School Hannover, Hannover, Germany. 15. Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany. 16. Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Munich, Germany. 17. Division of Neuro-oncology, University of Bonn Medical Center, Bonn, Germany. 18. Department of Neurology, University Hospital Mainz, Mainz, Germany. 19. Department of Medical Oncology, University Hospital Ulm, Ulm, Germany. 20. Department of Neurosurgery, Vivantes Klinikum am Friedrichshain, Berlin, Germany. 21. Department of Neurosurgery, University Hospital Magdeburg, Magdeburg, Germany. 22. Department of Neurosurgery, University Hospital Freiburg, Freiburg, Germany. 23. Department of Neurology, Knappschaftskrankenhaus, University of Bochum, Bochum, Germany. 24. Department of Neurosurgery, University Hospital Münster, Münster, Germany. 25. Department of Radiation Oncology, Klinikum Stuttgart, Stuttgart, Germany. 26. Department of Radiation Oncology, University Hospital Tübingen, Tübingen, Germany. 27. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 28. Department of Neurology, Universitätsspital Zurich, Zurich, Switzerland, and Department of Neurology, University Hospital Tübingen, Tübingen, Germany. 29. Department of Neurology, University Hospital Heidelberg, and Neuro-oncology Program at the National Center for Tumor Diseases, Heidelberg, Germany.
Abstract
Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.
Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.
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