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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.

SUBMITTER: Slavc I

PROVIDER: S-EPMC9601092 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Slavc Irene I Mayr Lisa L Stepien Natalia N Gojo Johannes J Aliotti Lippolis Maria M Azizi Amedeo A AA Chocholous Monika M Baumgartner Alicia A Hedrich Cora S CS Holm Stefan S Sehested Astrid A Leblond Pierre P Dieckmann Karin K Haberler Christine C Czech Thomas T Kool Marcel M Peyrl Andreas A

Cancers 20221019 20

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 ...[more]

PMID: 36291912

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Project description:Abstract BACKGROUND: Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. We report on 28 patients with recurrent medulloblastoma and ATRT treated with an alternative approach to conventional chemotherapy that targets neovascularisation by interfering with tumor angiogenesis at various levels. Patients and METHODS: From 11/2006 to 06/2016, 28 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (13 first, 7 multiple recurrences) and eight with recurrent ATRT (5 first, 3 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 1.5 (1–13) years for ATRT. Results: As of 11/2016, 12/20 patients with medulloblastoma are alive at a median of 25 (12–97) months after their last recurrence. 8/12 surviving patients are currently in CR for 97, 94, 93, 29, 27, 23, 19 and 18 months, five off therapy for 79, 62, 60, 22 and 18 months, three are in PR 23, 12 and 2 months after their last recurrence and one patient has stable disease 12 months after her last recurrence. 5-year-OS is 57.6 ± 13.2%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy and one patient with a very good PR died of a septicemia seven months after his last recurrence. Two patients had prior been treated with the same antiangiogenic approach and had recurred 67 and 40 months after their last recurrence while off therapy for 36 and 21 months and both patients are in remission again, one off therapy for 18 months. 3/8 patients with ATRT are alive. Follow-up since last recurrence is 72, 27 and 24 months and all patients are off therapy for 52, 14 and 13 months. One patient died of another cause without evidence of tumor at autopsy 54 months after recurrence and while off therapy for 46 months. One surviving patient with a germ line mutation and a fourth recurrence was prior treated with the same approach albeit without intrathecal therapy. He recurred 78 months after his last recurrence while off therapy for 36 months. He is again in CR and off therapy for 13 months. Therapy is primarily outpatient, was generally well tolerated, and toxicities were manageable. CONCLUSION: The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

Project description:ImportanceMedulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.ObjectiveTo 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 participantsThis 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.InterventionsTreatment 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 measuresThe 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.ResultsOf 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 relevanceThis 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 registrationClinicalTrials.gov Identifier: NCT01356290.

Project description:Abstract BACKGROUND Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 32 patients with recurrent medulloblastoma and ATRT treated with an antiangiogenic combination therapy. PATIENTS AND METHODS From 11/2006 to 02/2018, 32 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (14 first, 6 multiple recurrences) and 12 with recurrent ATRT (6 first, 6 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and aqueous or liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 3 (1–12) years for ATRT. RESULTS As of 05/2018, 10/20 patients with medulloblastoma are alive, eight in CR, six off therapy for 96, 79, 77, 34, 12, and 4 months. 5-year-OS is 54.5 ± 11.2% and 5-year-EFS is 25.0 ± 9.7%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy. 6/12 patients with ATRT are alive and in CR for 123, 90, 45, 9, 6 and 3 months after start of antiangiogenic therapy, the first three off therapy. OS for the whole cohort was 47.7 ± 16.6% at 3 years and 31.8 ± 17.1% at 5-years with a median OS of 22.8 months (KI 0.0–66.8). Therapy was generally well tolerated and toxicities were manageable. CONCLUSION The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

Project description:Abstract Introduction: Patients with recurrent medulloblastoma have a poor prognosis with approximately 8% surviving more than 5 years irrespective of salvage therapy used. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 18 patients treated with an antiangiogenic combination therapy at the Medical University of Vienna Patients and Methods: From 11/2006 to 10/2015, 18 patients were diagnosed with a recurrent medulloblastoma (12 first, 6 multiple recurrences). Subgroup of medulloblastoma was group 3 or 4 in 13 patients, WNT in one patient, SHH infant in one, and not known in three. Median age at primary diagnosis was 7 years (range 0.5–12) and at start of antiangiogenic therapy 10 years (range 1–24). Treatment of their current relapse consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine). Results: As of 03/2016, 11/18 patients are alive at a median of 20 (4 to 89) months after their last recurrence. 7/11 surviving patients are currently in CR 89, 86, 85, 59, 20, 18, 15, 15, 10, 11, and 4 months after their last relapse, six of them off therapy for 69, 52, 50, 27, 6, and 5 months. Three are in partial remission after 4 to 10 months and one has progressive disease 15 months after his last recurrence. Six patients died of tumor progression 63, 27, 10, 6, 4, and 3 months after their last recurrence. One patient died of an accident without signs of tumor progression on MRI 23 months after initiation of antiangiogenic therapy. OS was 76 ± 11% after 1 and 2 years,and 63 ± 15% at 5 years. Conclusion: Our results suggest that an antiangiogenic metronomic strategy is superior to conventional and high-dose chemotherapy for recurrent medulloblastoma. An international formal phase II study is currently recruiting patients (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290).

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

Publications

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

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