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

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.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

“…Therefore, MEMMAT combined metronomic chemotherapy with the repurposing of nonchemotherapeutic drugs, as was previously done in the COMBAT (combined oral metronomic biodifferentiating antiangiogenic treatment) regimen . The rationale for combining the 5 oral drugs as well as bevacizumab and intraventricular therapy in MEMMAT has previously been described in detail …”

Retrospective National “Real Life” Experience of the SFCE with the Metronomic MEMMAT and MEMMAT-like Protocol

“…This does not seem to be as good as the initial report of the MEMMAT regimen [ 26 ]. The Vienna team has also further reported that, out of 29 patients with medulloblastoma treatment with MEMMAT, 9 patients were alive, with a median of 44 months after recurrence [ 31 ]. Five out of nine surviving patients are currently in CR between 96 and 164 months after starting MEMMAT therapy.…”

“…The repartition of the molecular subtypes of brain tumors included might therefore influence the EFS in this series. Anyhow, in the series from Slavc et al [ 31 ] among the 23 patients whose tumors underwent molecular subgrouping classification using a DNA methylation array and brain classifier mnp-V12.5, group 4 medulloblastomas seem to group 4 have better outcome than group 3 medulloblastoma (median survival: 43 months (14–71) vs. not reached). As group 3 medulloblastomas are commonly accepted as displaying worse prognoses, the findings reported by Slavc et al [ 31 ] seem to further highlight the potential of MEMMAT for both relapsing Group 3 and 4 medulloblastomas, which represent medical unmet needs.…”

“…Anyhow, in the series from Slavc et al [ 31 ] among the 23 patients whose tumors underwent molecular subgrouping classification using a DNA methylation array and brain classifier mnp-V12.5, group 4 medulloblastomas seem to group 4 have better outcome than group 3 medulloblastoma (median survival: 43 months (14–71) vs. not reached). As group 3 medulloblastomas are commonly accepted as displaying worse prognoses, the findings reported by Slavc et al [ 31 ] seem to further highlight the potential of MEMMAT for both relapsing Group 3 and 4 medulloblastomas, which represent medical unmet needs. Moreover, the lack of molecular profiling for most of our patients should not diminish the interesting outcomes reported despite not furthering research in precision medicine.…”

Gastric outlet obstruction in a patient with relapsed medulloblastoma on metronomic therapy

“…Metronomic, antiangiogenic strategies, such as the MEMMAT (metronomic and targeted antiangiogenesis therapy for children with recurrent/progressive medulloblastoma) protocol (NCT01356290), have thus been evaluated to offer a balance between therapeutic effectiveness and tolerability. 2 Such regimen comprises of oral and intraventricular chemotherapy, bevacizumab, and other repurposed agents, including thalidomide, fenofibrate, and celecoxib. Interim analysis from the MEMMAT study indicated a response rate of 45% and 5-year progression-free survival (PFS) of 24.6%, confirming the activity of this treatment approach.…”