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Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized
Andreas Peyrl1,2, Monika Chocholous1,2, Magnus Sabel3,4
1Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
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.
Trial Registration:
ClinicalTrials.gov Identifier: NCT01356290.
Insights
The MEMMAT trial showed a new combination therapy is feasible and well-tolerated for recurrent medulloblastoma. This antiangiogenic metronomic approach demonstrated promising activity in patients previously treated with radiation.
Area of Science:
- Pediatric Oncology
- Neuro-oncology
- Clinical Trial Research
Background:
- Medulloblastoma recurrence after irradiation has a poor prognosis with no standard salvage treatment.
- Developing effective salvage regimens for relapsed or refractory medulloblastoma is critical.
Purpose of the Study:
- To evaluate the response rate of pediatric patients with recurrent medulloblastoma using the Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial (MEMMAT) approach.
- To assess the safety and efficacy of a novel combinatorial therapy including antiangiogenic and metronomic agents.
Main Methods:
- A phase 2, multicenter, nonrandomized trial involving 40 pediatric patients with relapsed/refractory medulloblastoma.
- Treatment involved daily oral thalidomide, fenofibrate, celecoxib, metronomic etoposide/cyclophosphamide, intravenous bevacizumab, and intraventricular etoposide/cytarabine.
Main Results:
- Disease control was achieved in 57.5% of patients after 6 months; 45.0% showed a response.
- Median overall survival was 25.5 months, and median progression-free survival was 8.5 months.
- The regimen was generally well-tolerated, with manageable adverse events.
Conclusions:
- The MEMMAT combination regimen is feasible, well-tolerated, and shows promising activity in previously irradiated recurrent medulloblastoma.
- This predominantly oral, outpatient treatment warrants further investigation for this challenging patient population.
