Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study

Yoshiki Shiba Departments of Neurosurgery and

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Kazuya Motomura Departments of Neurosurgery and

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Rieko Taniguchi Pediatrics, Nagoya University School of Medicine, Nagoya;

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Michihiro Kurimoto Department of Neurosurgery, Aichi Children’s Health and Medical Center, Nagoya; and

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Kosuke Mizutani Departments of Neurosurgery and

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Fumiharu Ohka Departments of Neurosurgery and

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Kosuke Aoki Departments of Neurosurgery and

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Eiji Ito Departments of Neurosurgery and

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Tomohide Nishikawa Departments of Neurosurgery and

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Junya Yamaguchi Departments of Neurosurgery and

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Yuji Kibe Departments of Neurosurgery and

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Hiroki Shimizu Departments of Neurosurgery and

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Sachi Maeda Departments of Neurosurgery and

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Takuma Nakashima Departments of Neurosurgery and
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan

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Hiromichi Suzuki Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan

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Hideki Muramatsu Pediatrics, Nagoya University School of Medicine, Nagoya;

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Yoshiyuki Takahashi Pediatrics, Nagoya University School of Medicine, Nagoya;

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Ryuta Saito Departments of Neurosurgery and

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OBJECTIVE

This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse.

METHODS

The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma.

RESULTS

The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics.

CONCLUSIONS

This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

ABBREVIATIONS

AT/RT = atypical teratoid/rhabdoid tumor; Bev = bevacizumab; CNS = central nervous system; COG = Children’s Oncology Group; CPT-11 = irinotecan; CR = complete response; CSF = cerebrospinal fluid; FFPE = formalin-fixed paraffin-embedded; GTR = gross-total resection; M = metastatic stage; OS = overall survival; PD = progression of disease; PFS = progression-free survival; PR = partial response; SD = stable disease; STR = subtotal resection; TMZ = temozolomide; UGT = uridine 5′-diphospho-glucuronosyltransferase; VEGF = vascular endothelial growth factor.
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Figure from See et al. (pp 617–623).
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