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Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen A Nonrandomized Controlled Trial

We are very excited to share the final results of the MEMMAT trial for the medullobastoma cohort- a gamme changer ! The results have been published by the JAMA Oncology journal. The article is entitled : Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen A Nonrandomized Controlled Trial MGHI is very proud to be part of this work.

Andreas Peyrl; Monika Chocholous ; Magnus Sabel ; Alvaro Lassaletta ; Jaroslav Sterba; Pierre Leblond; Karsten Nysom; Ingrid Torsvik ; Susan N. Chi; Thomas Perwein; Neil Jones; Stefan Holm; Per Nyman; Helena Mörse; Anders Öberg; Liesa Weiler-Wichtl; Ulrike Leiss; Christine Haberler; Maresa T. Schmook; Lisa Mayr; Karin Dieckmann; Marcel Kool; Johannes Gojo; Amedeo A. Azizi; Nicolas André; Mark Kieran; Irene Slavc

from the : 1Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria 2Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria 3Childhood Cancer Centre, Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden 4Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 5Department of Pediatric Neuro-Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain 6Pediatric Oncology Department, University Hospital Brno, Brno, Czech Republic 7Pediatric Oncology Unit, Oscar Lambret Comprehensive Cancer Center, Lille, France 8Centre Léon Bérard, Institut d’Hématologie et d’Oncologie Pediatrique, Lyon, France 9Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark 10Department of Paediatric and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway 11Department of Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 12Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria 13Kinderonkologie, Salzburger Universitätsklinikum, Salzburg, Austria 14Department of Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden 15Department of Paediatrics, Linköping University Hospital, Linköping, Sweden 16Pediatric Cancer Center, Skane University Hospital, Lund, Sweden 17Department of Pediatrics, Uppsala University, Uppsala, Sweden 18Department of Neurology, Medical University of Vienna, Vienna, Austria 19Department of Biomedical Imaging and Image-Guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria 20Department of Radio-Oncology, Medical University of Vienna, Vienna, Austria 21Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany 22Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany 23Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands 24Départment of Pediatric Oncology, Assistance Publique-Hopitaux de Marseille, Marseille, France 25Aix Marseille University, Cancer Research Center of Marseille, Marseille, France


Importance Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.

Objective: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).

Design, Setting, and Participants: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021.

Interventions: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine.

Main Outcomes and Measures: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety.

Results: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia.

Conclusions and Relevance: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation.

the full text of the article is freely available here.