Treatment of children with medulloblastoma without metastatic involvement in the age group older than 3 years: international experience and results of intercenter trial

Background. During the past 20 years, some large international studies have been conducted that evaluated the effectiveness of treatment programs for children with medulloblastoma. At the same time, in the standard risk group, fairly high rates of 5-year overall survival (OS) and event-free survival (EFS) were achieved, which amounted to 85% and 80%, respectively. At the present time some risk-adaptive therapeutic programs are developed according to molecular-biological features of tumor cells and possibility of chemotherapy and craniospinal radiation (CSI) therapy dose reduction.

Materials and methods. From 2008 to 2018 fifty one pediatric patients with primary diagnosed medulloblastoma in the age group 3–18 years were included in trial, 38 in standard risk group, 13 in high risk group (without metastatic disease). Treatment program consisted of surgical removal of the primary tumor site with subsequent chemotherapy (with high-dose cyclophosphamide or thiophosphamide) and radiation therapy (with CSI of 23.4 Gy or 36 Gy, depending on the risk group). In order to detect morphological and molecular biological distinctive features of tumor cells, the following criteria were evaluated: histological variant, molecular subgroup, methyltransferase status by DNMT and MGMT proteins expression, presence of C-MYC/N-MYC gene amplification, Iso17q and TP53 gene mutation.

Results. As a result of this study, sufficiently high rates of overall survival and progression/relapse-free survival (PRFS) were achieved in standard and high-risk groups patients, which amounted to 76.0±8.8% and 83.3±10.8% with median follow-up 62.9±6.2 months and 52.2±7.8 months, respectively. There was revealed patients group in the age 3–7 years with 100% PRFS and median follow-up 66.9±8.9 months. At the same time, morphological and molecular biological factors of an unfavorable outcome of the disease were absent in the tumor samples (large cell – anaplastic histology, C-MYC/N-MYC gene amplification, Iso17q and TP53 gene mutation). We have also achieved 100% PRFS in patients with desmoplastic tumor histology and in patients, who were treated with thiphosphamide-based chemotherapy regimen. Molecular-biological characteristics analysis of tumor cells showed a negative effect on PRFS of DNMT-positive status (Score >4, by 3 markers) and presence of N-MYC gene amplification (SHH molecular subgroup).

Conclusion. There was identified a group of patients aged 3 to 7 years, for whom the possibility for reducing of CSR dose down to 18 Gy opens. Understanding of tumor cells methyltransferase status creates the prerequisites for using of epigenetic demethylating therapy. It is necessary more observations to assess the effect of the chemotherapy regimen with high-dose thiophosphamide on the PRFS.