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

J 2023

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

PEYRL, Andreas, Monika CHOCHOLOUS, Magnus SABEL, Alvaro LASSALETTA, Jaroslav ŠTĚRBA et. al.

Basic information

Original name

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

Authors

PEYRL, Andreas, Monika CHOCHOLOUS, Magnus SABEL, Alvaro LASSALETTA, Jaroslav ŠTĚRBA (203 Czech Republic, belonging to the institution), Pierre LEBLOND, Karsten NYSOM, Ingrid TORSVIK, Susan N CHI, Thomas PERWEIN, Neil JONES, Stefan HOLM, Per NYMAN, Helena MOERSE, Anders OEBERG, Liesa WEILER-WICHTL, Ulrike LEISS, Christine HABERLER, Maresa T SCHMOOK, Lisa MAYR, Karin DIECKMANN, Marcel KOOL, Johannes GOJO, Amedeo A AZIZI, Nicolas ANDRE, Mark KIERAN and Irene SLAVC

Edition

JAMA ONCOLOGY, UNITED STATES, AMER MEDICAL ASSOC, 2023, 2374-2437

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30230 Other clinical medicine subjects

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

MEMMAT

Impact factor

Impact factor: 28.400 in 2022

RIV identification code

RIV/00216224:14110/23:00133148

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1001/jamaoncol.2023.4437

UT WoS

001094011500001

Keywords (in Czech)

CENTRAL-NERVOUS-SYSTEMHIGH-DOSE CHEMOTHERAPYSTEM-CELL RESCUEQUALITY-OF-LIFEPHASE-IIPEDIATRIC MALIGNANCIESMOLECULAR SUBGROUPSTUMOR-GROWTHCHILDRENTHERAPY

Keywords in English

CENTRAL-NERVOUS-SYSTEMHIGH-DOSE CHEMOTHERAPYSTEM-CELL RESCUEQUALITY-OF-LIFEPHASE-IIPEDIATRIC MALIGNANCIESMOLECULAR SUBGROUPSTUMOR-GROWTHCHILDRENTHERAPY

Abstract

V originále

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.

Links

MUNI/A/1395/2022, interní kód MU

Name: Personalizovaná léčba v dětské onkologii: multimodální theranostický přístup a „N-of-1 clinical trials“

Investor: Masaryk University

90249, large research infrastructures

Name: CZECRIN IV

Citovat

PEYRL, Andreas, Monika CHOCHOLOUS, Magnus SABEL, Alvaro LASSALETTA, Jaroslav ŠTĚRBA, Pierre LEBLOND, Karsten NYSOM, Ingrid TORSVIK, Susan N CHI, Thomas PERWEIN, Neil JONES, Stefan HOLM, Per NYMAN, Helena MOERSE, Anders OEBERG, Liesa WEILER-WICHTL, Ulrike LEISS, Christine HABERLER, Maresa T SCHMOOK, Lisa MAYR, Karin DIECKMANN, Marcel KOOL, Johannes GOJO, Amedeo A AZIZI, Nicolas ANDRE, Mark KIERAN and Irene SLAVC. Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen A Nonrandomized Controlled Trial. JAMA ONCOLOGY. UNITED STATES: AMER MEDICAL ASSOC, 2023, vol. 9, No 12, p. 1688-1695. ISSN 2374-2437. Available from: https://dx.doi.org/10.1001/jamaoncol.2023.4437.

@article{2364606,
   author = {Peyrl, Andreas and Chocholous, Monika and Sabel, Magnus and Lassaletta, Alvaro and Štěrba, Jaroslav and Leblond, Pierre and Nysom, Karsten and Torsvik, Ingrid and Chi, Susan N and Perwein, Thomas and Jones, Neil and Holm, Stefan and Nyman, Per and Moerse, Helena and Oeberg, Anders and WeilerandWichtl, Liesa and Leiss, Ulrike and Haberler, Christine and Schmook, Maresa T and Mayr, Lisa and Dieckmann, Karin and Kool, Marcel and Gojo, Johannes and Azizi, Amedeo A and Andre, Nicolas and Kieran, Mark and Slavc, Irene},
   article_location = {UNITED STATES},
   article_number = {12},
   doi = {http://dx.doi.org/10.1001/jamaoncol.2023.4437},
   keywords = {CENTRAL-NERVOUS-SYSTEMHIGH-DOSE CHEMOTHERAPYSTEM-CELL RESCUEQUALITY-OF-LIFEPHASE-IIPEDIATRIC MALIGNANCIESMOLECULAR SUBGROUPSTUMOR-GROWTHCHILDRENTHERAPY},
   language = {eng},
   issn = {2374-2437},
   journal = {JAMA ONCOLOGY},
   title = {Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen A Nonrandomized Controlled Trial},
   url = {https://jamanetwork.com/journals/jamaoncology/fullarticle/2811045},
   volume = {9},
   year = {2023}
}

TY  - JOUR
ID  - 2364606
AU  - Peyrl, Andreas - Chocholous, Monika - Sabel, Magnus - Lassaletta, Alvaro - Štěrba, Jaroslav - Leblond, Pierre - Nysom, Karsten - Torsvik, Ingrid - Chi, Susan N - Perwein, Thomas - Jones, Neil - Holm, Stefan - Nyman, Per - Moerse, Helena - Oeberg, Anders - Weiler-Wichtl, Liesa - Leiss, Ulrike - Haberler, Christine - Schmook, Maresa T - Mayr, Lisa - Dieckmann, Karin - Kool, Marcel - Gojo, Johannes - Azizi, Amedeo A - Andre, Nicolas - Kieran, Mark - Slavc, Irene
PY  - 2023
TI  - Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen A Nonrandomized Controlled Trial
JF  - JAMA ONCOLOGY
VL  - 9
IS  - 12
SP  - 1688-1695
EP  - 1688-1695
PB  - AMER MEDICAL ASSOC
SN  - 23742437
KW  - CENTRAL-NERVOUS-SYSTEMHIGH-DOSE CHEMOTHERAPYSTEM-CELL RESCUEQUALITY-OF-LIFEPHASE-IIPEDIATRIC MALIGNANCIESMOLECULAR SUBGROUPSTUMOR-GROWTHCHILDRENTHERAPY
UR  - https://jamanetwork.com/journals/jamaoncology/fullarticle/2811045
N2  - 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.
ER  -

PEYRL, Andreas, Monika CHOCHOLOUS, Magnus SABEL, Alvaro LASSALETTA, Jaroslav ŠTĚRBA, Pierre LEBLOND, Karsten NYSOM, Ingrid TORSVIK, Susan N CHI, Thomas PERWEIN, Neil JONES, Stefan HOLM, Per NYMAN, Helena MOERSE, Anders OEBERG, Liesa WEILER-WICHTL, Ulrike LEISS, Christine HABERLER, Maresa T SCHMOOK, Lisa MAYR, Karin DIECKMANN, Marcel KOOL, Johannes GOJO, Amedeo A AZIZI, Nicolas ANDRE, Mark KIERAN and Irene SLAVC. Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen A Nonrandomized Controlled Trial. \textit{JAMA ONCOLOGY}. UNITED STATES: AMER MEDICAL ASSOC, 2023, vol.~9, No~12, p.~1688-1695. ISSN~2374-2437. Available from: https://dx.doi.org/10.1001/jamaoncol.2023.4437.

Detailed Information on Publication Record