Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial

Cefalo, Graziella; Massimino, Maura; Ruggiero, Antonio; Barone, Giuseppe; Ridola, Vita; Spreafico, Filippo; Potepan, Paolo; Abate, Massimo Eraldo; Mascarin, Maurizio; Garrè, Maria Luisa; Perilongo, Giorgio; Madon, E; Colosimo, Cesare; Riccardi, Riccardo

doi:10.1093/neuonc/not320

Cited by 49 publications

(34 citation statements)

References 33 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent decades, multiple chemotherapeutic agents have been explored in phase I and II studies, albeit few have been incorporated in a front‐line setting. One of these is the methylating agent temozolomide, which has been approved for the treatment of malignant glial tumors in adults and children and has shown moderate activity as a single agent in various relapsed or refractory pediatric tumors, including neuroblastoma and medulloblastoma . Therefore, combination strategies have been applied with the aim to increase its activity.…”

Section: Introductionmentioning

confidence: 99%

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

Teuff

Castaneda-Heredia

Dufour

et al. 2019

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Aim To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET). Procedure Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one‐stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m2/day followed by topotecan at 0.75 mg/m2/day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently. Results Thirty‐two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9‐20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7‐47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3‐44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment‐related toxicities of the combination therapy were hematologic. Conclusions Temozolomide‐topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.

show abstract

Section: Introductionmentioning

confidence: 99%

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

Teuff

Castaneda-Heredia

Dufour

et al. 2019

Pediatric Blood & Cancer

View full text Add to dashboard Cite

show abstract

“…Temozolomide prolongs patient survival and delays disease progression (5). It showed anti-medulloblastoma activity in mice (6) and in patients with recurrent medulloblastomas or primitive neuroectodermal tumors (7). Temozolomide has dose-limiting hematological toxicities, like other DNA-alkylating agents (5,8).…”

mentioning

confidence: 99%

Efficacy of Asparaginase Erwinia chrysanthemi With and Without Temozolomide Against Glioma Cells and Intracranial Mouse Medulloblastoma

Sanghez

Chen

et al. 2018

View full text Add to dashboard Cite

“…Chemotherapy may also affect the MGMT status of the tumors; thus, relapsed tumors may exhibit different methylation profiles. Temozolomide is an alkylating agent that is increasingly used for relapsed medulloblastoma (20)(21)(22). Although a significant correlation between MGMT methylation status and temozolomide sensitivity has been confirmed in glioblastoma (7,8), sensitivity to temozolomide in relapsed medulloblastoma may not be predicted from the MGMT status of primarily resected tumor samples.…”

Section: Cpg Site ---------------------------------------------------mentioning

confidence: 99%

Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

et al. 2017

View full text Add to dashboard Cite

Abstract. Medulloblastoma is a highly malignant brain tumor that predominately affects children and requires multimodal treatment, including chemotherapy with alkylating agents. O 6 -methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that plays an important role in tumor resistance to alkylating agents. Recent studies demonstrated that MGMT promoter methylation suppresses the expression of MGMT and is associated with favorable outcomes of malignant glioma patients. However, the MGMT methylation status and its prognostic impact on medulloblastoma have not been fully elucidated to date. The objective of the present study was to investigate the association between MGMT status and clinical outcomes of pediatric medulloblastoma patients. The records of 15 patients with medulloblastoma treated at our institution were reviewed, and the methylation status of 18 CpG sites in the MGMT promoter region was determined using bisulfite sequencing analysis. A larger number of methylated CpG sites was identified in 9 patients with complete remission (median, 5 sites; range, 2-9 sites) compared with that in 6 patients with relapse (median, 2 sites, range, 1-4 sites; P=0.041). These results suggest that a higher number of methylated CpG sites in the MGMT promoter region are associated with a favorable outcome of medulloblastoma.

show abstract

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial

Abstract: TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.

Cited by 49 publications

References 33 publications

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

Efficacy of Asparaginase Erwinia chrysanthemi With and Without Temozolomide Against Glioma Cells and Intracranial Mouse Medulloblastoma

Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

Contact Info

Product

Resources

About