Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a "MEMMAT-like" Metronomic Antiangiogenic Approach

Irene Slavc, Lisa Mayr, Natalia Stepien, Johannes Gojo, Maria Aliotti Lippolis, Amedeo A Azizi, Monika Chocholous, Alicia Baumgartner, Cora S Hedrich, Stefan Holm, Astrid Sehested, Pierre Leblond, Karin Dieckmann, Christine Haberler, Thomas Czech, Marcel Kool, Andreas Peyrl, Irene Slavc, Lisa Mayr, Natalia Stepien, Johannes Gojo, Maria Aliotti Lippolis, Amedeo A Azizi, Monika Chocholous, Alicia Baumgartner, Cora S Hedrich, Stefan Holm, Astrid Sehested, Pierre Leblond, Karin Dieckmann, Christine Haberler, Thomas Czech, Marcel Kool, Andreas Peyrl

Abstract

Medulloblastoma (MB) recurrence is usually incurable despite intensive therapy including high-dose chemotherapy. An evolving alternative approach to conventional chemotherapy aims at interfering with tumor angiogenesis at different levels. We report on a novel combinatorial metronomic antiangiogenic approach. The study is a retrospective observational study of 29 consecutive patients with first or multiple recurrences prospectively treated according to the MEMMAT strategy ("MEMMAT-like") before the formal protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) started. The study period was 11/2006 to 06/2016. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by IV bevacizumab and intraventricular therapy consisting of alternating etoposide and liposomal cytarabine. Median overall survival (OS) after recurrence for the whole group was 29.5 months, OS was 48.3 ± 9.3% at three years and 34.5 ± 8.8% at five years, and progression-free survival was 42.0 ± 9.5% at three years and 29.4 ± 9% at five years. As of 07/2022, 9/29 patients are alive 86 to 164 months after the recurrence that prompted the "MEMMAT-like" therapy. Treatment was primarily out-patient and generally well-tolerated. Toxicities did occur but were manageable. In conclusion, antiangiogenic therapy according to the MEMMAT strategy increased median OS of patients with recurrent MB and may lead to long-term survival. Adherence to the protocol, including intraventricular therapy, appears important.

Keywords: MEMMAT; antiangiogenic therapy; bevacizumab; intraventricular therapy; low-dose oral therapy; medulloblastoma recurrence; metronomic therapy.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Drugs, dosing, and schedule of MEMMAT-based therapy.
Figure 2
Figure 2
Overall survival (OS) for all 29 patients from time of diagnosis of recurrence that prompted MEMMAT-like therapy. Median OS was 29.5 months (KI 2-57).
Figure 3
Figure 3
Progression-free survival (PFS) for all 29 patients from time of diagnosis of recurrence that prompted MEMMAT-like therapy. Median PFS was 22.1 months (KI 6-39).
Figure 4
Figure 4
Event-free survival (EFS) for all 29 patients from time of diagnosis of recurrence that prompted MEMMAT-like therapy. Median EFS was 21.0 months (KI 7-35).
Figure 5
Figure 5
Overall survival (OS) of MB_G3 versus MB_G4 of 21 patients with recurrent non-WNT/non-SHH medulloblastoma for which molecular group was known.
Figure 6
Figure 6
Event-free survival (EFS) of MB_G3 versus MB_G4 of 21 patients with recurrent non-WNT/ non-SHH medulloblastoma for which molecular group was known.

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Source: PubMed

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